Abstract
Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered ‘junk’ molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA–lncRNA interactions that affect cell death regulation.
Similar content being viewed by others
Facts
-
ncRNAs comprise a major part of poly-A tailed mature RNAs and are no longer considered ‘transcriptional noise’ as they have key functions that do not involve translation.
-
Both miRNA and lncRNA, either alone or in interaction with each other, extensively modulate the inter-related steps and mediators of programmed cell death.
-
Current cell death networks are charted mostly on protein regulators, whereas ncRNAs constitute the ‘invisible’ but intertwined part of these networks.
-
ncRNA binding is mostly sequence/structure dependent, which makes some of their unexplored death-regulating activities, for example, the regulation of necroptosis by lncRNA, partially predictable by in silico bioinformatics.
Open questions
-
In other evolving forms of programmed cell death such as ferroptosis, pyroptosis and autophagy, what is the role of ncRNA and how does it interact with established protein networks.
-
Does a newly proposed sequence-dependent competition model between mRNAs and lncRNAs with miRNAs apply to cell death regulation?
-
Can necroptosis-related lncRNAs predicted in silico be validated in experimental models and applied to therapeutics for inflammation?
Study of the human genome, which contains over 3 billion base pairs, has revealed that relatively few transcripts lead to productive protein translation. Specifically, primary transcripts for as much as 93% of genomic sequences1 were identified in the cytoplasm by the Encyclopedia of DNA Elements (ENCODE) Project, highlighting that a mere 1% undergo protein encoding (Figure 1a). Poly-adenylated (poly-A) tails are a hallmark of mature RNAs, which function to stabilize the RNA and facilitate its export from the nucleus. However, poly-A tails are present in not only mature mRNAs, but also many non-coding RNAs (ncRNA) of either intermediary2, 3 or mature forms.4 The cytosolic poly-A RNAs represent about 5–10% of the genome sequence,5 which still dwarfs the small 1% that account for protein encoding. Therefore, the vast majority of poly-A RNAs are indeed ncRNAs (Figure 1b).
Traditionally, ncRNAs have been arbitrarily categorized into long non-coding RNAs (lncRNAs), which are longer than 200nt, and small ncRNAs (sncRNAs), which are shorter than 200nt. The latter can be further subdivided into various categories, including micro RNAs (miRNAs), piwiRNAs (piRNAs) and small nuclear RNAs (snoRNAs).6 Although these may collectively or individually alter cell death, this review will focus on the two most important ncRNAs currently identified in cell death regulation: miRNA and lncRNA.
miRNA and programmed cell death
Mechanisms of miRNA-mediated gene expression regulation
The miRBase (version 21.0) confirms that 28 645 miRNA transcripts from 206 species, including 2661 human miRNA transcripts,7 regulate over 60% of human genes8 (Figure 1c). miRNAs typically bind to the 3'-untranslated region (UTR)9 of protein-coding mRNA by imperfect sequence-specific recognition9, 10 to either degrade it11, 12, 13 or repress its translation.13 As such, mechanisms such as the alternative cleavage and polyadenylation that generates different 3'-UTR isoforms affect the miRNA targeting efficiency,14 whereas the translation suppression is dependent on the miRNA-induced silencing complex (miRISC) and the CCR4-NOT complex, which recruits and locks the eIF4A2 on the mRNA region between the pre-initiation complex and the start codon. The eIF4A2 then serves as a roadblock that prevents the former from scanning along the mRNA strand and reaching the latter.15, 16, 17 CCR4-NOT also uses its subunit CNOT1 to recruit DDX6 as a downstream factor, therefore disrupting CNOT1–DDX6 interaction abrogates miRNA repression.18 Those mRNAs with regulatory AU-rich elements (AREs) in their 3'-UTR can be bound by HuR, which dissociates miRISC and therefore relieves miRNA repression.19 In addition, competing endogenous RNAs (ceRNAs), such as lncRNA (will be discussed later) and cirRNA,20, 21 sequester miRNAs and therefore prevent them from binding and repressing target mRNAs. Some miRNAs, like miR-Let-7 and miR369-3, which normally suppress translation, can activate translation under certain situations such as cell cycle arrest, or in cooperation with some transcription factors.22 miRNAs can bind to mRNA 5'-UTR as well,23 which mostly activates transcription, although suppression has also been reported.24, 25
miRNA and intrinsic apoptosis
Mediators of intrinsic apoptosis
Although the term ‘intrinsic apoptosis’ typically refers to mitochondrial-centered apoptosis pathways, other organelles, like ER,26, 27, 28, 29 lysosomes30, 31, 32, 33, 34 and Golgi apparatus,35, 36 also participate in apoptosis. The term ‘intrinsic apoptosis’ used in this review, unless otherwise specified, denotes mitochondrial-related apoptosis. Initiation of intrinsic apoptosis essentially relies on three categories of B-cell lymphoma 2 (BCL2) family members, namely the pro-apoptotic members: Bcl-2-associated X protein (BAX) and Bcl-2 homologous antagonist/killer (BAK), the anti-apoptotic members: BCL2, MCL1, BCL-XL, etc., and the BCL2 homology domain 3 (BH3)-only proteins: Bim, Bid, Puma, Bad, etc. Perturbation of the dynamic balance between counter-acting members leads to oligomerization of BAX and BAK on the outer membrane of mitochondria and the mitochondria outer membrane permeabilization (MOMP), thus initiating cytochrome-c release into cytosol. Cytosolic cytochrome-c binds Apaf-1 (ref. 37) to facilitate the formation of the multi-protein complex known as the apoptosome.38, 39 This process is negatively regulated by heat shock protein 70 (HSP70), which is typically seen during cellular stress.40 The apoptosome activates caspase-9 and the downstream caspase cascade.41 Caspase-3, which is located at the convergence of intrinsic and extrinsic apoptosis that initiates the ultimate apoptotic executioner mechanisms, is sequentially activated by caspase-9. Caspase-9 can also be cleaved and activated by caspase-3 as a positive feedback control.
miRNAs work on BCL2 to regulate intrinsic apoptosis
miRNAs are profoundly involved in cell death regulation, as the deletion of the miRNA-processing RNase III enzyme Dicer42, 43 in neural stem cells44 and neural crest derivative cells45 leads to pervasive cell death. Other miRNA processors, such as Drosha, DGCR8 and XPO5, also profoundly affect cell death.46, 47 Specifically, numerous miRNAs regulate BCL2, a key mediator of the intrinsic apoptosis pathway (Figure 2 and Table 1) that is overexpressed in certain pathological situations. In B-cell malignancies such as chronic lymphocytic leukemia (CLL), the overexpression of BCL2 is concomitant with the marked downregulation of two miRNAs: miR-15 and miR-16, both induce apoptosis by suppressing BCL2 when ectopically expressed.48 The typical binding sites of numerous BCL2-inhbiting mRNAs, such as miR-195 miR-24 and miR-365-2, are within the 3'-UTR. Overexpression of these miRNAs facilitate apoptosis in otherwise apoptosis-resistant breast cancer MCF7 cells.49 Especially, miR-195 triggers apoptosis through free fatty acids and thus may have therapeutic potential in lipotoxic cardiomyopathy.50
As the overexpression of BCL2 is one of the major contributing factors to the development of multidrug resistance (MDR, a mechanism by which cancer cells resist structurally and mechanistically unrelated chemotherapeutic drugs), BCL2-specific miRNAs can also be used to treat MDR. For example, miR-181b that reduces BCL2 expression overcomes MDR by facilitating apoptosis in several MDR cancer cell lines.51 miR-181d also targets BCL2 to induce apoptosis and cell cycle arrest.52 Refractive B-cell MDR malignancy can be treated by inducing miR-125b and miR-155-mediated BCL2 suppression.53 BCL2-specific miRNAs also induce apoptosis in other cancer cells, whether MDR or not, for example, miR-125b in hepatocellular carcinoma (HCC) cells,54 miR-7 in the non-small cell lung cancer cell line A549 cells55 and miR-497 in gastric and lung cancer cell lines.56
Physiological or pathological perturbations both inside and outside cells often influence the expression of miRNAs, which could in turn precipitate intrinsic apoptosis. For instance, in heart ischemia–reperfusion injury (IRI), fluctuations of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a and miR-320 levels change the expression of many miRNA-regulated genes, including phosphoinositide 3-kinase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, HSP60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Sirt-1, etc., which can individually or collectively trigger intrinsic apoptosis and thus affect the severity and manifest of injury.57
miRNAs directly or indirectly affect BAX to modulate intrinsic apoptosis
miRNAs also work on BAX. This pro-apoptotic BCL2 family protein is mainly found in the cytosol and undergoes conformational changes upon apoptosis induction58 by associating with the mitochondrial membrane59 to mediate the formation of MOMP.58, 60 Ischemic preconditioning, a strategy that increases heart tissue resistance to subsequent IRI, leads to downregulation of BAX, and upregulation of miR-1 and miR-21, indicating both may target BAX to inhibit apoptosis and confer resistance to further cardiac IRI.61 Viral vectors can be used to deliver miRNA against BAX. For example, the adenovirus-mediated miR-22 overexpression indirectly inhibits BAX by working on CREB-binding protein.62 miRNAs can inhibit BAX not only at the expression level, as miR-24 has been shown to suppress the translocation of BAX from the cytosol to the mitochondrial membrane, thus inhibiting cytochrome-c release and execution of apoptosis.63 Similar protective effects of miRNAs were also observed in the central nervous system. miR-23a and miR-27a were rapidly downregulated in the first hour following traumatic brain injury, and their ‘mimetics’ effectively inhibited neuronal cell apoptosis to limit the cortical lesion volume.64
miRNAs modulate intrinsic apoptosis by affecting Bim or Bim-related mechanisms
Other than being directly regulated by miRNAs, as a typical BH3-only member, Bim contains a BH3 (ref. 65) with which it interacts with other members of the BCL2 family such as BCL2,65 BCL2-XL65, 66 and MCL1,67, 68 and integrates miRNAs regulation exerted on them. miR-20, miR-92 and miR-302 target and regulate Bim to maintain the low-apoptotic threshold for survival of mammalian primed pluripotent stem cells.69 MiR-24, as mentioned previously, also directly binds to the 3'-UTR of Bim to suppress it. After mouse acute myocardial infarction, miR-24 is downregulated in the left ventricular ischemic border zone. Using lipofectamine-mediated transfection for in vivo local delivery to mouse hearts, ‘miR-24 mimics’ inhibited apoptosis and reduced infarct size as well as cardiac dysfunction by specifically suppressing Bim.70 Interestingly, BAX translocation inhibition by miR-24 can be overcompensated for by Bim deletion. Upon Bim deletion, BAX translocation following miR-24 treatment is reduced below basal levels, indicating miR-24 indirectly inhibits BAX translocation – most likely by targeting Bim. Moreover, this overcompensation hints that Bim may exploit another apoptosis-regulating mechanism that is independent of miR-24.63 Bim-regulating miRNAs can also be involved in the apoptosis-regulating effects of some clinical reagents. For example, the miR-17-92a cluster binds Bim on 3'-UTR and suppresses it. Depletion of this cluster augmented dexamethasone-triggered apoptosis, whereas its overexpression facilitated the anti-apoptotic effects of estrogen on osteoblasts.71
miRNAs regulate downstream mechanisms of intrinsic apoptosis
MOMP and release of cytochrome-c, by causing mitochondria swelling and rupture, are traditionally believed to irreversibly commit the cell to death. Owing to the loss of oxidative phosphorylation, cell death is inevitable at this point and cannot be salvaged even by caspase inhibitors.72 However, some have suggested that the irreversible death commitment point cannot only be extended beyond cytochrome-c release,73 but also that the structural and functional integrity of the mitochondria can be restored after cytochrome-c release.74 Indeed several mechanisms downstream of cytochrome-c release are also reported to be available for anti-apoptotic intervention. As a pivotal component of the apoptosome and an essential intrinsic apoptosis mediator downstream of cytochrome-c release, apaf-1 is modulated by four miRNAs (miR-23a/b and miR-27a/b) that form two clusters, miR-23a-27a-24 and miR-23b-27b-24. As such, mouse neuronal-specific transgenic overexpression of miR-23b and miR-27b attenuated hypoxia-induced apoptosis.75 Furthermore, caspase-9 contains a miR-133-binding site in its 3'-UTR, and upregulation of miR-133 by ischemic post-conditioning protects rat hearts against ischemia–reperfusion-induced apoptosis.76 Caspase-3 is targeted by miR-378, as confirmed by luciferase reporter assay, and ‘miR-378 mimic’ transfection and overexpression substantially suppressed apoptosis and enhanced cell viability in mouse myocardial ischemia. Conversely, miR-378 inhibitor aggravated hypoxia-induced apoptosis.77
Besides direct regulations, miRNAs also target caspase modulators for indirect regulation. X-linked inhibitor of apoptosis protein (XIAP),78 for example, binds and inhibits caspase-9 and caspase-3, and sequesters activated caspase-3 within the apoptosome complex to inhibit its function.79 Several miRNAs, namely miR-23a,80 miR-24,81 miR-130 (ref. 82) and miR-200bc-429 (ref. 83) cluster, target the XIAP 3'-UTR and therefore enhance apoptosis in various cell types.
miRNA and extrinsic apoptosis
Extrinsic apoptosis is initiated by the coupling of membrane-bound death receptors (DRs) to cognate ligands. There are six known DRs of which TNF receptor (TNFR) and Fas have been most well characterized. The intracellular domains of activated death ligands recruit a number of adaptor proteins that relay the extrinsic signal into the caspase cascade, which starts with caspase-8 activation. The death ligands can be targeted by miRNAs. For example, the anti-apoptotic effect of miR-21 by targeting Fas ligand (FasL) was reported in hypoxic cardiomyocytes,84 neurons85 and hepatocytes.86 Interestingly, miR-21 is subject to positive regulation by Akt, which makes miR-21 a mediator of Akt-FasL regulation.84 Adaptor proteins immediately downstream of DRs are also targeted. For example, Fas-associated protein with death domain (FADD) is targeted by miR-27a on its 3'-UTR. Similarly, the miRNA cluster miR-23a-27a-24 could independently induce apoptosis, or enhance TNFα-induced apoptosis, by reducing FADD expression.87
miRNAs work further downstream the pathway as well. miR-375 enhances TNFα-induced apoptosis, the underlying mechanisms of which remains largely elusive, although reductions in both cIAP and cFLIP-L by miR-375 have been observed.88
miRNA and programmed necrosis
Necrosis was traditionally considered as the consequence of severe, accidental, non-physiological stress, which results in un-regulated cell ‘explosion’, and the release of pro-inflammatory cytoplasmic/nuclear contents. With the discovery of several modalities of regulated necrosis (RN), such as necroptosis, it has now been accepted that necrosis can also be triggered by programmed and often counter-balanced intracellular pathways. Necroptosis, for example, can be initiated by ligation of TNF-α to TNFR) when caspase-8 is inhibited.89, 90 It is mediated by the kinases RIPK1, RIPK3 (refs 89, 90) and the pseudo-kinase MLKL.91 MiR-155 targets RIPK1 and has been shown to be markedly upregulated following hydrogen-peroxide treatment in cardiomyocyte progenitor cells (CMPCs). Overexpression of miR-155 attenuates CMPC necrosis to a level similar to that achieved with the RIPK1 inhibitor necrostatin-1.92 miR-874, on the other hand, enhances necroptosis by targeting caspase-8 and abolishing its inhibition on RIPK1/RIPK3.93, 94 In addition, Foxo3a can repress miR-874 to reduce necroptosis.95 These findings indicate that miRNA may be important potential regulators of programmed necrosis with inhibitory effects that may be comparable to pharmacological intervention. This may be of considerable therapeutic significance with the current paucity of small molecules that can block specific pathways or RN.
LncRNA and programmed cell death
LncRNA classification
As lncRNAs are transcribed by RNA polymerase II before getting capped and poly-A, they can be categorized based on their relative positions to known neighboring ‘protein-encoding’ exons. Those transcribed from between protein-encoding genes are known as long intergenic lncRNAs, which comprise the largest portion of lncRNAs, whereas those from intronic regions are called intronic lncRNAs.96 Antisense lncRNAs are transcribed from the opposite DNA strand as the protein transcript template and often overlap parts of mRNAs.97, 98 In all, 70% of mouse genes may have overlapping antisense lncRNA transcripts99 (Figure 1d). A mutated gene that has lost its protein production capability can also produce an lncRNA pseudogene.100, 101 All of the above mentioned lncRNAs epigenetically resemble protein-coding genes, in that they feature similar high histone 3 lysine 4 tri-methylation (H3K4me3) marks. In contrast, enhancer lncRNAs (eRNAs), which are transcribed from the intergenic enhancer regions, distinguish themselves by expressing histone 3 lysine 4 mono-methylation (H3K4me1) marks instead.102, 103, 104, 105
LncRNAs were once considered transcription ‘noise’ partly because they lack enough sequence conservation, a hallmark of protein-coding genes. However, Johnsson et al.106 revealed that their secondary, rather than primary, structure could be evolutionarily conservative, and thus could serve as the main functional unit. In addition, tissue specificities of lncRNAs are also better preserved than primary sequences,107 hinting at the importance of conservative secondary structure.
Mechanisms of lncRNA-mediated gene expression regulation
LncRNAs could potentially affect the expression of a vast majority of genes, as in the mouse genome, 70% of protein-coding genes have at least one homologous antisense lncRNA,99 which is not even the major subtype of lncRNA (Figure 1d). LncRNAs can regulate gene expression via several different mechanisms. First, they can directly act on the genomic DNA to regulate expression. Recent studies have established that some lncRNAs are either retained to their transcription sites (cis) or translocated to remote sites (trans)108, 109, 110 to recruit chromatin modifying complexes that dictate the formation of heterochromatin that represses transcription. Other lncRNAs activate transcription by either inducing 3-dimensional chromatin conformation changes111, 112 or triggering enhancer regions.113 Second, lncRNAs can interact with proteins, namely transcription factors and some RNA-binding proteins, to indirectly regulate transcription. In this manner, LncRNA acts as a decoy and sequesters transcription factors from binding to their DNA targets.114, 115, 116 LncRNA has also been reported to allosterically modify RNA-binding proteins that regulate transcription.117 In particular, the steroid receptor activator (SRA) lncRNA acts as a component of the steroid coactivator complex,118, 119 wherein it relies on its secondary structure120 to co-activate other transcription factors,121 which again underlines the importance of secondary structure in lncRNA function. As an lncRNA, SRA lncRNA is somewhat eccentric in that it actually encodes several short peptides by utilizing different promoters and splicing patterns. These peptides in turn bind to SRA lncRNA and inhibit it from co-activating other transcription factors, forming a negative feedback loop.122, 123, 124 Third, lncRNAs can indirectly alter gene expression by competing with miRNA as ceRNAs,125 an important regulatory RNA category comprises various ncRNAs and even some mRNAs with profound effects beyond cell death.126 More about the miRNA-centered ceRNA crosstalk is discussed in section LncRNAs interact with miRNA in regulating cell death – 'lncRNA–miRNA interaction'.
LncRNAs regulate apoptosis on various levels
Numerous reports indicate that lncRNAs may modulate apoptosis on various levels and in different patterns (Figure 3 and Table 1). Many of these studies were conducted in cancer cell lines that augment their lncRNAs expression to evade apoptosis. The urothelial cancer-associated 1 (UCA1) lncRNA, which is highly expressed in human bladder cancer cells, upregulates wingless-type MMTV integration site family member 6 (Wnt6), therefore enhancing the inhibition of BAX by Akt, and conferring resistance to cisplatin-induced apoptosis.127, 128 In addition, T-ALL-R-LncR1, an lncRNA that is associated with T-cell acute lymphoblastic leukemia (T-ALL) and is abnormally expressed in some tumor tissues, suppresses caspase-3, inhibits Par-4 (which inhibits BCL-2 and NF-κB)129 induces apoptosis, and augments pro-apoptotic Smac protein expression.130 URHC (upregulated in HCC) lncRNA is highly expressed in HCC and inhibits the apoptosis-inducing sterile alpha motif and leucine zipper containing kinase AZK (ZAK) gene.131 Other apoptosis-suppressing lncRNAs expressed by cancer cell lines include: HOXA-AS2, which suppresses TRAIL expression and the cleavage of caspase-8, -9 and -3 in the promyelocytic leukemia cell line NB4;132 SPRY4-IT1, which is an inhibitor of MAPK pathway (MAPK pathway leads to p38α activation, upregulates BAX Bim Noxa Fas-FasL) in the melanoma cell line WM1552C;133 PlncRNA-1 in the prostate cancer cell line LNCaP,134 and AFAP1-AS1, which inhibits caspase-3 cleavage, in the esophageal adenocarcinoma cell line OE-33 (ref. 135) and the esophageal squamous cell carcinoma.136
In contrast, several lncRNAs have been shown to promote apoptosis and therefore mediate pathological injury or damage. AK139328, an lncRNA that is highly expressed in normal mouse liver, mediates apoptosis in liver IRI. Knockdown of AK139328 reduces caspase-3 activation and ameliorates injury.137 In vascular smooth muscle cells, the lncRNA HIF 1 alpha-antisense RNA 1, which is under positive regulation of Brahma-related gene 1, activates caspase-3 and promotes apoptosis and contributes to pathogenesis of thoracic aortic aneurysms.138 Aside from aberrant expression of anti-apoptotic lncRNAs, cancer cells could also downregulate pro-apoptotic lncRNAs to evade apoptosis. Growth arrest-specific 5 (GAS5) lncRNA, which effectively promotes apoptosis, is significantly downregulated in prostate cancer cells as they acquire resistance to apoptosis.139 Apoptosis induced by GAS5 is dependent on caspase-8 but not caspase-9,140 and may involve the upregulation of p53.141 In human HCC cells, the apoptosis-promoting uc002mbe.2 lncRNA is significantly lower compared with normal cells, but can be induced to be expressed 300-fold higher following treatment of Trichostatin A (TSA), a histone deacetylase inhibitor, and thus has a pivotal role in TSA’s antitumor effect.142, 143
The regulation of p53 by lncRNAs
p53 provides crucial upstream apoptosis control of both intrinsic and extrinsic pathways by directly regulating several key mediators such as BAX,144 NOXA,145 PUMA146 and Bid147 (which bridges the intrinsic and extrinsic pathway), all of which contain p53-responsive elements in their promoters.148 Besides its direct regulation of BAX, p53 also indirectly promotes mitochondrial translocation and polymerization of BAX by effectively regulating PUMA149 because of its significantly higher affinity to the PUMA promoter than to the BAX promoter.150 p53 also triggers the extrinsic apoptosis pathway as it induces cell surface DRs including Fas, TRAIL-R2 (DR5) and PERP, by promoting either mRNA expression (Fas, DR5, PERP),151, 152, 153, 154 or protein translocation from Golgi apparatus to cell surface (Fas),155 all of which lead to caspase-8 activation.
p53 may itself be subject to sophisticated regulation in transcription, mRNA stability, translation and post-translation levels.156, 157, 158 However, reports of the regulation of p53 by lncRNA currently are limited to post-transcriptional levels.159 Modulation of p53 by lncRNAs could be amplified by the aforementioned regulation networks, with profound effects in downstream apoptotic pathways. Wrap53α lncRNA is an endogenous antisense transcript of p53, which shares a 227bp overlap with p53 exon1 and stabilizes the p53 transcript through RNA–RNA interaction. Knockdown of Wrap53α abrogates p53-induced apoptosis, whereas overexpressing Wrap53α potentiates it.160 The maternally expressed gene 3 (MEG3) lncRNA utilizes its secondary motif M2 and M3 to activate p53,161 and selectively facilitates the activation of downstream p53-dependent apoptotic genes.161, 162, 163 The expression level of lncRNA MALAT1 is inversely correlated with that of p53, but without any proven structural evidence the correlation seems likely to be indirect.164 A particularly special p53-regulating lncRNA is ROR, which strongly suppresses p53 through formation of a complex with heterogeneous nuclear ribonucleoprotein I (hnRNP I). The expression of ROR itself is induced by p53, thus forming a negative feedback loop in control of p53 expression,165, 166 illustrating the complex nature of lncRNA–p53 interactions.
Intrinsic apoptosis mediators regulated by lncRNA
INXS is an lncRNA transcribed from the opposite genomic strand of BCL-X, which shifts alternative splicing of BCL-X from the anti-apoptotic BCL-XL to the pro-apoptotic BCL-XS. Overexpression of INXS leads to accumulation of BCL-XS, activation of caspase-9 and -3, and subsequent apoptosis.167 PTEN, an indispensable mediator of STS-induced caspase-3 activation and cytochrome-c release,168 is subject to positive regulation by lncRNA PTEN pseudogene1 (PTENpg1), whereas PTENpg1 itself is regulated by two antisense transcript lncRNAs: PTENpg1 asRNAα and β. Specifically, the α isoform binds the PTEN promoter and inhibits transcription, whereas the β isoform stabilizes PTENpg1 and subsequently strengthens the upregulation of the PTEN gene.169 In addition, the aforementioned lncRNA MEG3 reduces BAX protein expression and caspase-3 activity, suppressing intrinsic apoptosis.170 Cancer cells could also deviate expression of intrinsic apoptosis-related lncRNAs to evade death. lncRNA-LET, for example, is downregulated by hypoxia in gallbladder cancer cells conferring apoptotic resistance, whereas ectopic expression of lncRNA-LET leads to an increased BAX/BCL-2 ratio, caspase-3 activation, and apoptosis.171 The crucial role of lncRNA in cancer is also highlighted by their relationships to some key oncogenes. Although tumorigenesis is typically attributed to multiple genetic abnormalities, it is shown to be dependent on one or a few key oncogenes, such as Myc, the deletion of which achieves a wide spectrum of anticancer effects, a phenomenon termed as ‘oncogene addiction’.172, 173 The lncRNAs that are regulated by Myc174, 175 may facilitate it in sustaining cancer cells, which makes them potential therapeutic targets, given the recent progress in nanoparticle-mediated miRNA delivery,176 corresponding therapeutic strategies may emerge in the foreseeable future.
Extrinsic apoptosis mediators regulated by lncRNA
Mediators of the extrinsic apoptotic pathway, such as death-signal ligands, receptors and caspases, can be regulated directly or indirectly by lncRNAs. Soluble Fas (sFas), which sequesters FasL, is generated by RBM5-mediated alternative splicing of Fas mRNA that skips exon 6. The Fas antisense transcript lncRNA FAS-AS1 binds and inhibits RBM5 to inhibit sFas expression and strengthen Fas-FasL ligation.177 lncRNAs also target caspase-8, which is downstream of DR ligation, for example, lncRNA MALAT1 inhibits caspase-8 expression, which contributes to its anti-apoptotic function.178
LncRNA and RN including necroptosis
The potential relationship of lncRNA to the regulation of necroptosis and other forms of RN is largely undefined at this time. Many lncRNAs have been predicted by computational scoring as necroptotic pathway regulators, and there is a commercially available microarray that integrates hundreds of these predicted lncRNAs. However, as of this writing, little experimental evidence has been published supporting such predictions.
LncRNAs interact with miRNA in regulating cell death
Theoretically, lncRNA and miRNA could interact with each other, adding an extra layer of complexity to the regulation of cell death by this class of RNA. In a transcriptome-wide bioinformatics analysis with several available databases, Jalali et al.179 recognized extensive interactions between numerous lncRNA–miRNA pairs. Specifically, many lncRNAs feature miRNA recognition elements preferentially clustered in their mid-to-3’ region, which makes them potential targets of cognate miRNAs. On the other hand, some lncRNAs harbor miRNA regulatory elements with which they may target miRNAs. This study provided structural evidence for miRNA–lncRNA interactions, and highlighted the potential of bioinformatics in regulatory RNA studies. Indeed several miRNAs have consistently been reported to regulate lncRNA. For example, miR-125b, which binds and degrades p53 mRNA, has been found to target lncRNA 7sl as well (Figure 4a). This may also contribute to its anti-apoptotic function.179 Conversely, some lncRNAs have been shown to modulate miRNA function or expression, in at least two patterns. First, lncRNAs may sponge up and sequester miRNAs, in which case they work as a ceRNA to prevent the miRNA–mRNA contact,125, 180 for example, lncRNA FER1L4 and LncRNA RB1 are a pair of ceRNAs that both bind and sequester miR-106a-5p from targeting PTEN181 (Figure 4b). It is noteworthy, however, that a mere increase in miRNA target abundancy does not affect miRNA function,182 which means despite its name, ceRNA (including lncRNA) work by not only simply competing for miRNA binding, but may rely on spatial occlusion to block miRNAs from reaching their targets in the first place. Second, lncRNAs may suppress miRNA expression, as can be demonstrated by the example of lnc HULC, which suppresses the expression of the CREB-targeting miR-372 in HCC, and therefore affects CREB-mediated epigenetic modifications that govern the expression of a series of cell death/survival related genes.183 The regulatory relationship between a given pair of lncRNA–miRNA may be not only unidirectional but also bidirectional, which further interweaves the regulatory network among lncRNA, miRNA and cell death. For example, anti-apoptotic lncRNA PCGEM1 and pro-apoptotic miRNA miR-145 not only antagonize each other in regulating apoptosis but also suppress each other’s expression, thus forming a regulation loop that regulates seemingly opposite effects on apoptosis184 (Figure 4c).
LncRNA–miRNA interactions are often dictated by protein factors and thus is integrated as a foundational element within an extensive cell death regulation network. As an upstream cell death modulator, p53’s extensive effects on cell death is at least partially exerted through such lncRNA–miRNA interactions. Specifically, p53 targets a p53-response element within the upstream region of a pro-apoptotic lncRNA, loc285194, and induces its expression. A reciprocal repression has been shown to exist between loc285194 and the anti-apoptotic miRNA miR-211. Hence, the two regulatory ncRNAs and their intertwined effects on cell death are incorporated into an even more complicated p53 signaling network by the p53–lncRNA connection185 (Figure 4d). Even some of the protein-encoding mRNAs may exert an additional non-coding regulatory effect by competing with other mRNAs or lncRNAs for miRNA binding, and therefore also act as ceRNAs.186 This potential mechanism remains to be confirmed for death-related mRNAs.
In summary, ncRNAs are currently somewhat analogous to invisible dark matter in the universe. Just as dark matter accounts for >80% of universal mass and fundamentally affects the visible universe, the regulatory ncRNAs, despite being ‘invisible’ in terms of encoded protein, comprise over 80% of total mature RNA and have many crucial but as yet, undefined roles in regulating programmed cell death. The two major subtypes of regulatory ncRNAs, miRNA and lncRNA interact with not only each other but also various intracellular components to extensively modulate the inter-related steps and mediators of regulated forms of cell death including apoptosis and necrosis. Thus, they may be in a pivotal position to regulate cell death. Although the interactions of the various components of regulatory ncRNA are incredibly complex and interactions will require considerable work to unravel, death-regulating ncRNAs may represent hugely important but as yet underutilized therapeutic targets in the manipulation of cell death and organ injury in diverse inflammatory clinical conditions.
Abbreviations
- ncRNA:
-
non-coding RNA
- miRNA:
-
micro RNA
- LncRNA:
-
long non-coding RNA
- UTR:
-
untranslated region
- MOMP:
-
mitochondria outer membrane permeabilization
- BCL2:
-
B-cell lymphoma 2
- BAX:
-
Bcl-2-associated X protein
- BAK:
-
Bcl-2 homologous antagonist/killer
- FasL:
-
Fas ligand
References
Consortium EP Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.
Saini HK, Griffiths-Jones S, Enright AJ . Genomic analysis of human microRNA transcripts. Proc Natl Acad Sci USA 2007; 104: 17719–17724.
Yoshikawa M, Peragine A, Park MY, Poethig RS . A pathway for the biogenesis of trans-acting siRNAs in Arabidopsis. Genes Dev 2005; 19: 2164–2175.
Amaral PP, Mattick JS, Noncoding RNA . in development. Mamm Genome 2008; 19: 454–492.
Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S et al. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science 2005; 308: 1149–1154.
Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS . Non-coding RNAs: regulators of disease. J Pathol 2010; 220: 126–139.
Kozomara A, Griffiths-Jones S . miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 2014; 42: D68–D73.
Friedman RC, Farh KK, Burge CB, Bartel DP . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19: 92–105.
Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 2005; 122: 553–563.
Pasquinelli AE . MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 2012; 13: 271–282.
Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E . mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 2006; 20: 1885–1898.
Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K et al. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 2006; 312: 75–79.
Wu L, Fan J, Belasco JG . MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci USA 2006; 103: 4034–4039.
Nam JW, Rissland OS, Koppstein D, Abreu-Goodger C, Jan CH, Agarwal V et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 2014; 53: 1031–1043.
Lu WT, Wilczynska A, Smith E, Bushell M . The diverse roles of the eIF4A family: you are the company you keep. Biochem Soc Trans 2014; 42: 166–172.
Meijer HA, Kong YW, Lu WT, Wilczynska A, Spriggs RV, Robinson SW et al. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 2013; 340: 82–85.
Izaurralde E . A role for eIF4AII in microRNA-mediated mRNA silencing. Nat Struct Mol Biol 2013; 20: 543–545.
Rouya C, Siddiqui N, Morita M, Duchaine TF, Fabian MR, Sonenberg N . Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. RNA 2014; 20: 1398–1409.
Kundu P, Fabian MR, Sonenberg N, Bhattacharyya SN, Filipowicz W . HuR protein attenuates miRNA-mediated repression by promoting miRISC dissociation from the target RNA. Nucleic Acids Res 2012; 40: 5088–5100.
Taulli R, Loretelli C, Pandolfi PP . From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nat Struct Mol Biol 2013; 20: 541–543.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013; 495: 333–338.
Vasudevan S, Tong Y, Steitz JA . Switching from repression to activation: microRNAs can up-regulate translation. Science 2007; 318: 1931–1934.
Lytle JR, Yario TA, Steitz JA . Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5' UTR as in the 3' UTR. Proc Natl Acad Sci USA 2007; 104: 9667–9672.
Da Sacco L, Masotti A . Recent insights and novel bioinformatics tools to understand the role of microRNAs binding to 5' untranslated region. Int J Mol Sci 2012; 14: 480–495.
Vasudevan S . Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA 2012; 3: 311–330.
Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC . Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003; 22: 8608–8618.
Morishima N, Nakanishi K, Tsuchiya K, Shibata T, Seiwa E . Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. J Biol Chem 2004; 279: 50375–50381.
Szegezdi E, Logue SE, Gorman AM, Samali A . Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 2006; 7: 880–885.
Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 2001; 276: 13935–13940.
Hishita T, Tada-Oikawa S, Tohyama K, Miura Y, Nishihara T, Tohyama Y et al. Caspase-3 activation by lysosomal enzymes in cytochrome c-independent apoptosis in myelodysplastic syndrome-derived cell line P39. Cancer Res 2001; 61: 2878–2884.
Ivanova S, Repnik U, Bojic L, Petelin A, Turk V, Turk B . Lysosomes in apoptosis. Methods Enzymol 2008; 442: 183–199.
Kagedal K, Zhao M, Svensson I, Brunk UT . Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem J 2001; 359 (Pt 2): 335–343.
Ogata M, Inanami O, Nakajima M, Nakajima T, Hiraoka W, Kuwabara M . Ca(2+)-dependent and caspase-3-independent apoptosis caused by damage in Golgi apparatus due to 2,4,5,7-tetrabromorhodamine 123 bromide-induced photodynamic effects. Photochem Photobiol 2003; 78: 241–247.
Walls KC, Ghosh AP, Franklin AV, Klocke BJ, Ballestas M, Shacka JJ et al. Lysosome dysfunction triggers Atg7-dependent neural apoptosis. J Biol Chem 2010; 285: 10497–10507.
Chiu R, Novikov L, Mukherjee S, Shields D . A caspase cleavage fragment of p115 induces fragmentation of the Golgi apparatus and apoptosis. J Cell Biol 2002; 159: 637–648.
How PC, Shields D . Tethering function of the caspase cleavage fragment of Golgi protein p115 promotes apoptosis via a p53-dependent pathway. J Biol Chem 2011; 286: 8565–8576.
Purring-Koch C, McLendon G . Cytochrome c binding to Apaf-1: the effects of dATP and ionic strength. Proc Natl Acad Sci USA 2000; 97: 11928–11931.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–489.
Kim HE, Du F, Fang M, Wang X . Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci USA 2005; 102: 17545–17550.
Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES . Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2: 476–483.
Jiang X, Wang X . Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 2000; 275: 31199–31203.
Tsutsumi A, Kawamata T, Izumi N, Seitz H, Tomari Y . Recognition of the pre-miRNA structure by Drosophila Dicer-1. Nat Struct Mol Biol 2011; 18: 1153–1158.
Lee YS, Nakahara K, Pham JW, Kim K, He Z, Sontheimer EJ et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 2004; 117: 69–81.
Kawase-Koga Y, Low R, Otaegi G, Pollock A, Deng H, Eisenhaber F et al. RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells. J Cell Sci 2010; 123 (Pt 4): 586–594.
Zehir A, Hua LL, Maska EL, Morikawa Y, Cserjesi P . Dicer is required for survival of differentiating neural crest cells. Dev Biol 2010; 340: 459–467.
Wegert J, Ishaque N, Vardapour R, Georg C, Gu Z, Bieg M et al. Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer Cell 2015; 27: 298–311.
Walz AL, Ooms A, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM et al. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell 2015; 27: 286–297.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005; 102: 13944–13949.
Singh R, Saini N . Downregulation of BCL2 by miRNAs augments drug-induced apoptosis—a combined computational and experimental approach. J Cell Sci 2012; 125 (Pt 6): 1568–1578.
Zhu H, Yang Y, Wang Y, Li J, Schiller PW, Peng T . MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1. Cardiovasc Res 2011; 92: 75–84.
Zhu W, Shan X, Wang T, Shu Y, Liu P . miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. Int J Cancer 2010; 127: 2520–2529.
Wang XF, Shi ZM, Wang XR, Cao L, Wang YY, Zhang JX et al. MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. J Cancer Res Clin Oncol 2012; 138: 573–584.
Willimott S, Wagner SD . miR-125b and miR-155 contribute to BCL2 repression and proliferation in response to CD40 ligand (CD154) in human leukemic B-cells. J Biol Chem 2012; 287: 2608–2617.
Zhao A, Zeng Q, Xie X, Zhou J, Yue W, Li Y et al. MicroRNA-125b induces cancer cell apoptosis through suppression of Bcl-2 expression. J Genet Genomics 2012; 39: 29–35.
Xiong S, Zheng Y, Jiang P, Liu R, Liu X, Chu Y . MicroRNA-7 inhibits the growth of human non-small cell lung cancer A549 cells through targeting BCL-2. Int J Biol Sci 2011; 7: 805–814.
Zhu W, Zhu D, Lu S, Wang T, Wang J, Jiang B et al. miR-497 modulates multidrug resistance of human cancer cell lines by targeting BCL2. Med Oncol 2012; 29: 384–391.
Ye Y, Perez-Polo JR, Qian J, Birnbaum Y . The role of microRNA in modulating myocardial ischemia-reperfusion injury. Physiol Genomics 2011; 43: 534–542.
Nechushtan A, Smith CL, Hsu YT, Youle RJ . Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 1999; 18: 2330–2341.
Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ . Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 1997; 139: 1281–1292.
Gross A, Jockel J, Wei MC, Korsmeyer SJ . Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 1998; 17: 3878–3885.
Duan X, Ji B, Wang X, Liu J, Zheng Z, Long C et al. Expression of microRNA-1 and microRNA-21 in different protocols of ischemic conditioning in an isolated rat heart model. Cardiology 2012; 122: 36–43.
Yang J, Chen L, Yang J, Ding J, Li S, Wu H et al. MicroRNA-22 targeting CBP protects against myocardial ischemia-reperfusion injury through anti-apoptosis in rats. Mol Biol Rep 2014; 41: 555–561.
Wang L, Qian L . miR-24 regulates intrinsic apoptosis pathway in mouse cardiomyocytes. PloS One 2014; 9: e85389.
Sabirzhanov B, Zhao Z, Stoica BA, Loane DJ, Wu J, Borroto C et al. Downregulation of miR-23a and miR-27a following experimental traumatic brain injury induces neuronal cell death through activation of proapoptotic Bcl-2 proteins. J Neurosci 2014; 34: 10055–10071.
Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ . BID: a novel BH3 domain-only death agonist. Genes Dev 1996; 10: 2859–2869.
O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998; 17: 384–395.
Bae J, Leo CP, Hsu SY, Hsueh AJ . MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 2000; 275: 25255–25261.
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17: 393–403.
Pernaute B, Spruce T, Smith KM, Sanchez-Nieto JM, Manzanares M, Cobb B et al. MicroRNAs control the apoptotic threshold in primed pluripotent stem cells through regulation of BIM. Genes Dev 2014; 28: 1873–1878.
Qian L, Van Laake LW, Huang Y, Liu S, Wendland MF, Srivastava D . miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes. J Exp Med 2011; 208: 549–560.
Guo L, Xu J, Qi J, Zhang L, Wang J, Liang J et al. MicroRNA-17-92a upregulation by estrogen leads to Bim targeting and inhibition of osteoblast apoptosis. J Cell Sci 2013; 126 (Pt 4): 978–988.
Green D, Kroemer G . The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol 1998; 8: 267–271.
Deshmukh M, Kuida K, Johnson EM Jr . Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J Cell Biol 2000; 150: 131–143.
Martinou I, Desagher S, Eskes R, Antonsson B, Andre E, Fakan S et al. The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol 1999; 144: 883–889.
Chen Q, Xu J, Li L, Li H, Mao S, Zhang F et al. MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis. Cell Death Dis 2014; 5: e1132.
He B, Xiao J, Ren AJ, Zhang YF, Zhang H, Chen M et al. Role of miR-1 and miR-133a in myocardial ischemic postconditioning. J Biomed Sci 2011; 18: 22.
Fang J, Song XW, Tian J, Chen HY, Li DF, Wang JF et al. Overexpression of microRNA-378 attenuates ischemia-induced apoptosis by inhibiting caspase-3 expression in cardiac myocytes. Apoptosis 2012; 17: 410–423.
Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW et al. Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP. J Biol Chem 2003; 278: 8091–8098.
Bratton SB, Walker G, Srinivasula SM, Sun XM, Butterworth M, Alnemri ES et al. Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes. EMBO J 2001; 20: 998–1009.
Siegel C, Li J, Liu F, Benashski SE, McCullough LD . miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci USA 2011; 108: 11662–11667.
Xie Y, Tobin LA, Camps J, Wangsa D, Yang J, Rao M et al. MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells. Oncogene 2013; 32: 2442–2451.
Zhang X, Huang L, Zhao Y, Tan W . Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly. Acta Biochim Biophys Sin (Shanghai) 2013; 45: 995–1001.
Zhu W, Xu H, Zhu D, Zhi H, Wang T, Wang J et al. miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP. Cancer Chemother Pharmacol 2012; 69: 723–731.
Sayed D, He M, Hong C, Gao S, Rane S, Yang Z et al. MicroRNA-21 is a downstream effector of AKT that mediates its antiapoptotic effects via suppression of Fas ligand. J Biol Chem 2010; 285: 20281–20290.
Zhang L, Dong LY, Li YJ, Hong Z, Wei WS . miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia. Glia 2012; 60: 1888–1895.
Francis H, McDaniel K, Han Y, Liu X, Kennedy L, Yang F et al. Regulation of the extrinsic apoptotic pathway by microRNA-21 in alcoholic liver injury. J Biol Chem 2014; 289: 27526–27539.
Chhabra R, Adlakha YK, Hariharan M, Scaria V, Saini N . Upregulation of miR-23a-27a-24-2 cluster induces caspase-dependent and -independent apoptosis in human embryonic kidney cells. PloS One 2009; 4: e5848.
Wang J, Huang H, Wang C, Liu X, Hu F, Liu M . MicroRNA-375 sensitizes tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis in head and neck squamous cell carcinoma in vitro. Int J Oral Maxillofac Surg 2013; 42: 949–955.
Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325: 332–336.
He S, Wang L, Miao L, Wang T, Du F, Zhao L et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137: 1100–1111.
Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 2013; 39: 443–453.
Liu J, van Mil A, Vrijsen K, Zhao J, Gao L, Metz CH et al. MicroRNA-155 prevents necrotic cell death in human cardiomyocyte progenitor cells via targeting RIP1. J Cell Mol Med 2011; 15: 1474–1482.
Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 2011; 471: 368–372.
Biton S, Ashkenazi A . NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell 2011; 145: 92–103.
Wang K, Liu F, Zhou LY, Ding SL, Long B, Liu CY et al. miR-874 regulates myocardial necrosis by targeting caspase-8. Cell Death Dis 2013; 4: e709.
Rearick D, Prakash A, McSweeny A, Shepard SS, Fedorova L, Fedorov A . Critical association of ncRNA with introns. Nucleic Acids Res 2011; 39: 2357–2366.
Wight M, Werner A . The functions of natural antisense transcripts. Essays Biochem 2013; 54: 91–101.
Ma L, Bajic VB, Zhang Z . On the classification of long non-coding RNAs. RNA Biol 2013; 10: 925–933.
Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M et al. Antisense transcription in the mammalian transcriptome. Science 2005; 309: 1564–1566.
Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 2009; 458: 223–227.
Mighell AJ, Smith NR, Robinson PA, Markham AF . Vertebrate pseudogenes. FEBS Lett 2000; 468: 109–114.
Mousavi K, Zare H, Dell'orso S, Grontved L, Gutierrez-Cruz G, Derfoul A et al. eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci. Mol Cell 2013; 51: 606–617.
Orom UA, Shiekhattar R . Noncoding RNAs and enhancers: complications of a long-distance relationship. Trends Genet 2011; 27: 433–439.
De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK et al. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 2010; 8: e1000384.
Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007; 39: 311–318.
Johnsson P, Lipovich L, Grander D, Morris KV . Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta 2014; 1840: 1063–1071.
Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 2014; 505: 635–640.
Batista PJ, Chang HY . Long noncoding RNAs: cellular address codes in development and disease. Cell 2013; 152: 1298–1307.
Guttman M, Rinn JL . Modular regulatory principles of large non-coding RNAs. Nature 2012; 482: 339–346.
Fatica A, Bozzoni I . Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet 2014; 15: 7–21.
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 2011; 472: 120–124.
Bertani S, Sauer S, Bolotin E, Sauer F . The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol Cell 2011; 43: 1040–1046.
Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 2010; 143: 46–58.
Sun S, Del Rosario BC, Szanto A, Ogawa Y, Jeon Y, Lee JT . Jpx RNA activates Xist by evicting CTCF. Cell 2013; 153: 1537–1551.
Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 2011; 43: 621–629.
Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP . Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 2010; 3: ra8.
Wang X, Arai S, Song X, Reichart D, Du K, Pascual G et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 2008; 454: 126–130.
Beato M, Klug J . Steroid hormone receptors: an update. Hum Reprod Update 2000; 6: 225–236.
Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY et al. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 1999; 97: 17–27.
Lanz RB, Razani B, Goldberg AD, O'Malley BW . Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA). Proc Natl Acad Sci USA 2002; 99: 16081–16086.
Leygue E . Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer. Nucl Recept Signal 2007; 5: e006.
Hube F, Velasco G, Rollin J, Furling D, Francastel C . Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation. Nucleic Acids Res 2011; 39: 513–525.
Hube F, Guo J, Chooniedass-Kothari S, Cooper C, Hamedani MK, Dibrov AA et al. Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines. DNA Cell Biol 2006; 25: 418–428.
Chooniedass-Kothari S, Emberley E, Hamedani MK, Troup S, Wang X, Czosnek A et al. The steroid receptor RNA activator is the first functional RNA encoding a protein. FEBS Lett 2004; 566: 43–47.
Bak RO, Mikkelsen JG . miRNA sponges: soaking up miRNAs for regulation of gene expression. Wiley interdiscip Rev RNA 2014; 5: 317–333.
Tay Y, Rinn J, Pandolfi PP . The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344–352.
Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F et al. Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J 2014; 281: 1750–1758.
Wu W, Zhang S, Li X, Xue M, Cao S, Chen W . Ets-2 regulates cell apoptosis via the Akt pathway, through the regulation of urothelial cancer associated 1, a long non-coding RNA, in bladder cancer cells. PloS One 2013; 8: e73920.
El-Guendy N, Zhao Y, Gurumurthy S, Burikhanov R, Rangnekar VM . Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells. Mol Cell Biol 2003; 23: 5516–5525.
Zhang L, Xu HG, Lu C . A novel long non-coding RNA T-ALL-R-LncR1 knockdown and Par-4 cooperate to induce cellular apoptosis in T-cell acute lymphoblastic leukemia cells. Leuk Lymphoma 2014; 55: 1373–1382.
Xu WH, Zhang JB, Dang Z, Li X, Zhou T, Liu J et al. Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma. Int J Biol Sci 2014; 10: 664–676.
Zhao H, Zhang X, Frazao JB, Condino-Neto A, Newburger PE . HOX antisense lincRNA HOXA-AS2 is an apoptosis repressor in all trans retinoic acid treated NB4 promyelocytic leukemia cells. J Cell Biochem 2013; 114: 2375–2383.
Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS et al. The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res 2011; 71: 3852–3862.
Cui Z, Ren S, Lu J, Wang F, Xu W, Sun Y et al. The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor. Urol Oncol 2013; 31: 1117–1123.
Wu W, Bhagat TD, Yang X, Song JH, Cheng Y, Agarwal R et al. Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 2013; 144 5: e954.
Wang CM, Wu QQ, Li SQ, Chen FJ, Tuo L, Xie HW et al. Upregulation of the long non-coding RNA PlncRNA-1 promotes esophageal squamous carcinoma cell proliferation and correlates with advanced clinical stage. Dig Dis Sci 2014; 59: 591–597.
Chen Z, Jia S, Li D, Cai J, Tu J, Geng B et al. Silencing of long noncoding RNA AK139328 attenuates ischemia/reperfusion injury in mouse livers. PloS one 2013; 8: e80817.
Wang S, Zhang X, Yuan Y, Tan M, Zhang L, Xue X et al. BRG1 expression is increased in thoracic aortic aneurysms and regulates proliferation and apoptosis of vascular smooth muscle cells through the long non-coding RNA HIF1A-AS1 in vitro. Eur J Cardiothorac Surg 2014; 47: 439–446.
Pickard MR, Mourtada-Maarabouni M, Williams GT . Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta 2013; 1832: 1613–1623.
Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT . GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 2009; 28: 195–208.
Shi X, Sun M, Liu H, Yao Y, Kong R, Chen F et al. A critical role for the long non-coding RNA GAS5 in proliferation and apoptosis in non-small-cell lung cancer. Mol Carcinog 2013; 54: E1–E12.
Yang H, Zhong Y, Xie H, Lai X, Xu M, Nie Y et al. Induction of the liver cancer-down-regulated long noncoding RNA uc002mbe.2 mediates trichostatin-induced apoptosis of liver cancer cells. Biochem Pharmacol 2013; 85: 1761–1769.
Rossi MN, Antonangeli F . LncRNAs: new players in apoptosis control. Int J Cell Biol 2014; 2014: 473857.
Thornborrow EC, Patel S, Mastropietro AE, Schwartzfarb EM, Manfredi JJ . A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 2002; 21: 990–999.
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053–1058.
Nakano K, Vousden KH . PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7: 683–694.
Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS . BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 2002; 4: 842–849.
Haupt S, Berger M, Goldberg Z, Haupt Y . Apoptosis - the p53 network. J Cell Sci 2003; 116 (Pt 20): 4077–4085.
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B . PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001; 7: 673–682.
Kaeser MD, Iggo RD . Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc Natl Acad Sci USA 2002; 99: 95–100.
Bouvard V, Zaitchouk T, Vacher M, Duthu A, Canivet M, Choisy-Rossi C et al. Tissue and cell-specific expression of the p53-target genes: bax, fas, mdm2 and waf1/p21, before and following ionising irradiation in mice. Oncogene 2000; 19: 649–660.
Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW et al. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev 2000; 14: 704–718.
Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 1998; 188: 2033–2045.
Wu GS, Burns TF, McDonald ER 3rd, Jiang W, Meng R, Krantz ID et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997; 17: 141–143.
Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P . Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 1998; 282: 290–293.
Kruse JP, Gu W . Modes of p53 regulation. Cell 2009; 137: 609–622.
Halaby MJ, Yang DQ . p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene 2007; 395: 1–7.
Reisman D, Loging WT . Transcriptional regulation of the p53 tumor suppressor gene. Semin Cancer Biol 1998; 8: 317–324.
Zhang A, Xu M, Mo YY . Role of the lncRNA-p53 regulatory network in cancer. J Mol Cell Biol 2014; 6: 181–191.
Mahmoudi S, Henriksson S, Corcoran M, Mendez-Vidal C, Wiman KG, Farnebo M . Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol Cell 2009; 33: 462–471.
Zhang X, Rice K, Wang Y, Chen W, Zhong Y, Nakayama Y et al. Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 2010; 151: 939–947.
Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y et al. Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res 2010; 70: 2350–2358.
Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R et al. Activation of p53 by MEG3 non-coding RNA. J Biol Chem 2007; 282: 24731–24742.
Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet 2013; 9: e1003368.
Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D et al. The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Res 2013; 23: 340–350.
Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 2010; 42: 1113–1117.
DeOcesano-Pereira C, Amaral MS, Parreira KS, Ayupe AC, Jacysyn JF, Amarante-Mendes GP et al. Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis. Nucleic Acids Res 2014; 42: 8343–8355.
Zhu Y, Hoell P, Ahlemeyer B, Krieglstein J . PTEN: a crucial mediator of mitochondria-dependent apoptosis. Apoptosis 2006; 11: 197–207.
Johnsson P, Ackley A, Vidarsdottir L, Lui WO, Corcoran M, Grander D et al. A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 2013; 20: 440–446.
Zhang Y, Zou Y, Wang W, Zuo Q, Jiang Z, Sun M et al. Down-regulated long non-coding RNA MEG3 and its effect on promoting apoptosis and suppressing migration of trophoblast cells. J Cell Biochem 2014; 116: 542–550.
Ma MZ, Kong X, Weng MZ, Zhang MD, Qin YY, Gong W et al. Long non-coding RNA-LET is a positive prognostic factor and exhibits tumor-suppressive activity in gallbladder cancer. Mol Carcinog 2014; 54: 1397–1406.
Felsher DW . MYC inactivation elicits oncogene addiction through both tumor cell-intrinsic and host-dependent mechanisms. Genes Cancer 2010; 1: 597–604.
Weinstein IB, Joe AK . Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006; 3: 448–457.
Doose G, Haake A, Bernhart SH, Lopez C, Duggimpudi S, Wojciech F et al. MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells. Proc Natl Acad Sci USA 2015; 112: E5261–E5270.
Deng K, Guo X, Wang H, Xia J . The lncRNA-MYC regulatory network in cancer. Tumour Biol 2014; 35: 9497–9503.
Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A et al. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci USA 2014; 111: E3553–E3561.
Sehgal L, Mathur R, Braun FK, Wise JF, Berkova Z, Neelapu S et al. FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma. Leukemia 2014; 28: 2376–2387.
Guo F, Li Y, Liu Y, Wang J, Li Y, Li G . Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai) 2010; 42: 224–229.
Jalali S, Bhartiya D, Lalwani MK, Sivasubbu S, Scaria V . Systematic transcriptome wide analysis of lncRNA-miRNA interactions. PloS One 2013; 8: e53823.
Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q . lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res 2014; 13: 330–338.
Xia T, Liao Q, Jiang X, Shao Y, Xiao B, Xi Y et al. Long noncoding RNA associated-competing endogenous RNAs in gastric cancer. Sci Rep 2014; 4: 6088.
Denzler R, Agarwal V, Stefano J, Bartel DP, Stoffel M . Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol Cell 2014; 54: 766–776.
Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 2010; 38: 5366–5383.
He JH, Zhang JZ, Han ZP, Wang L, Lv Y, Li YG . Reciprocal regulation of PCGEM1 and miR-145 promote proliferation of LNCaP prostate cancer cells. J Exp Clin Cancer Res 2014; 33: 72.
Liu Q, Huang J, Zhou N, Zhang Z, Zhang A, Lu Z et al. LncRNA loc285194 is a p53-regulated tumor suppressor. Nucleic Acids Res 2013; 41: 4976–4987.
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP . A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 2011; 146: 353–358.
Acknowledgements
The work was supported by the Canadian Institutes of Health Research (CIHR) (AMJ, MOP-115048, MOP-111180). AMJ is a member of the Canadian National Transplant Research Program.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by G Raschella'
Rights and permissions
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
About this article
Cite this article
Su, Y., Wu, H., Pavlosky, A. et al. Regulatory non-coding RNA: new instruments in the orchestration of cell death. Cell Death Dis 7, e2333 (2016). https://doi.org/10.1038/cddis.2016.210
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cddis.2016.210
This article is cited by
-
Cell-type specific and differential expression of LINC-RSAS long noncoding RNA declines in the testes during ageing of the rat
Biogerontology (2024)
-
The rs3931283/PVT1 and rs7158663/MEG3 polymorphisms are associated with diabetic kidney disease and markers of renal function in patients with type 2 diabetes mellitus
Molecular Biology Reports (2023)
-
An Overview of Mesenchymal Stem Cell-based Therapy Mediated by Noncoding RNAs in the Treatment of Neurodegenerative Diseases
Stem Cell Reviews and Reports (2022)
-
Long Non-coding RNAs (lncRNAs), A New Target in Stroke
Cellular and Molecular Neurobiology (2022)
-
Long non-coding RNAs: a valuable biomarker for metabolic syndrome
Molecular Genetics and Genomics (2022)