Abstract
Apoptosis is a coordinated cellular process that occurs in several physiological situations. Dysregulation of apoptosis has been documented in numerous pathological situations, particularly cancer. Non-coding RNAs regulate apoptosis via different mechanisms. Lung cancer is among neoplastic conditions in which the role of non-coding RNAs in the regulation of apoptosis has been investigated. Non-coding RNAs that regulate apoptosis in lung cancer have functional interactions with PI3K/Akt, PTEN, GSK-3β, NF-κB, Bcl-2, Bax, p53, mTOR and other important cancer-related pathways. Globally, over-expression of apoptosis-blocking non-coding RNAs has been associated with poor prognosis of patients, while apoptosis-promoting ones have the opposite effect. In the current paper, we describe the impact of lncRNAs and miRNAs on cell apoptosis in lung cancer.
Introduction
Apoptosis is a well-organized and coordinated cellular process that happens in several physiological situations. Aberrant regulation of apoptosis has also been documented in numerous pathological situations, particularly cancer. In fact, cancer is one of the circumstances where this process is reduced, leading to evolution of malignant cells that will not perish. Apoptosis is regulated by a complex mechanism involving numerous pathways. Deficiencies in apoptotic pathways lead to malignant transformation of cells, enhancement of metastasis and induction of resistance to chemotherapy/radiotherapy. Meanwhile, apoptosis has been considered as a target of several anticancer modalities (1). Both intracellular and extracellular stimuli can regulate apoptosis. This process is described by morphological alterations in the cells including fragmentation and condensation of the nuclear compartment, permeabilization of the outer membrane of mitochondria, membrane blebbing, cell shrinkage and finally formation of apoptotic bodies (2). Two extrinsic and intrinsic pathways are involved in the induction of cell apoptosis. While the extrinsic pathway is stimulated by death receptors, namely Fas, TNF receptors and TRAILs, the intrinsic pathway is initiated by DNA damage, energy starvation and hypoxia, which can dephosphorylate and cleave pro-apoptotic proteins, resulting in their recruitment in the mitochondria (3). Both pro-apoptotic and anti-apoptotic members of the Bcl-2 family proteins regulate intrinsic apoptotic pathway (4).
Recent studies have shown that non-coding RNAs (ncRNAs) have an important regulatory role on induction of apoptosis. In fact, regulation of cell apoptosis is the main route of function of many of these transcripts in the carcinogenic events (5). This group of transcripts has several types, two of them i.e. long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have attained more attention in cancer biology. LncRNAs have typically sizes more than 200 nucleotides and are transcribed by RNA polymerase II, except for few cases do not harbor open reading frame and translation-termination region, yet, lncRNAs can be spliced, 5’-capped and get polyadenylated tails. Their specific three-dimensional conformation permits them to interact with several classes of biomolecules including proteins, DNA or RNA. These interactions are framed through base pairing or construction of network (6). LncRNAs partake in regulation of gene expression, differentiation of cells and alteration of chromatin structure (6).
miRNAs have been shown to regulate expression of a high proportion of human genes. They mainly target 3’ UTR of genes to suppress their expression or degrade the corresponding RNAs. Several aspects of cell functioning including apoptosis is regulated by miRNAs (7). Figure 1 illustrates that aberrant expression of various ncRNAs could contribute in modulation of the mitochondrial pathway of apoptosis in the context of lung cancer.
Figure 1
In the current paper, we describe the impact of lncRNAs and miRNAs on cell apoptosis in lung cancer.
miRNAs and Apoptosis in Lung Cancer
Suppression of PI3K/AKT pathway in EGFR mutant lung cancer cells has led to dysregulation of 17 miRNAs among them have been members of the miR-17~ 92 cluster. These miRNAs function in a coordinated manner to increase the activity of the EGFR cascade. Suppression of miR-19b expression in EGFR mutant lung cancer cells has led to re phosphorylation of ERK, AKT and STAT and effector proteins. Consistently, it has resulted in enhancement of apoptosis, while reduction of cell cycle progression, colony formation and migration. Administration of gefitinib along with miR-19b antagonism has decreased migration and colony formation in a synergistic manner implying the cooperation between EGFR and miR-19b in the regulation of oncogenesis. PPP2R5E and BCL2L11 have been recognized as main targets of miR-19b, through their inhibition, miR-19b regulates cell proliferation and resistance to apoptosis, respectively (10). miR-21 is another miRNA that regulates apoptosis of lung cancer cells via influencing the PI3K/Akt/NF-κB signaling pathway. Inhibition of miR-21 has enhanced apoptosis via this route. ASPP2 has been recognized as the target of miR-21 in NSCLC cells. miR-21 silencing has also inhibited migration, invasion, and epithelial-mesenchymal transition (EMT). Besides, miR-21 inhibition has stimulated cell apoptosis through caspase dependent route. Taken together, miR-21 silencing can induce cell apoptosis via reducing activity of the PI3K/Akt/NF-κB signaling (11). miR-24 is another oncogenic miRNA which is up-regulated in lung cancer tissues, particularly in high grade and large-sized tumors. Consistently, higher expression of miR-21 predicts lower overall survival (OS) of patients. Functionally, miR-24 enhances the viability, proliferation and cell cycle transition, while inhibiting cell apoptosis through binding with MAPK7 (12). miR-26 is a down-regulated miRNA in lung cancer cells. Forded over-expression of miR-26 induces cell apoptosis and enhances activity of caspase-3 and caspase-9. On the other hand, miR-26 silencing has increased levels of LC3 protein and the autophagy-associated genes in lung cancer cells. Besides, miR-26 has been shown to influence apoptosis and autophagy through suppressing expression of TGF-β in a JNK dependent route. Besides, miR-26 has been reported to affect the endoplasmic reticulum stress (ERS) signaling pathway (13). Figure 2 represents the role of several ncRNAs in regulating autophagy cascade in human lung cancer.
Figure 2
Table 1 shows the list of miRNAs that regulate apoptosis in lung cancer.
Table 1
| miR | Sample | Cell line | Target/pathway | Function | Ref |
|---|---|---|---|---|---|
| miR-19b | – | PC9, PC9ER, HCC827 | Akt, ERK1/2, PTEN, GSK-3β, STAT3, PPP2R5E, BCL2L11 | miR-19b via targeting PP2A and BIM through the EGFR signaling pathway could enhance apoptosis in NSCLC. | (10) |
| miR-21 | Mice | HBE, A549 | PI3K/Akt, NF-κB, Bcl-2, Bax, P65, Ikkβ, ASPP2, E-cadherin, N-cadherin, Vimentin | miR-21 via inhibiting the PI3K/Akt/NF-κB pathway could induce apoptosis in NSCLC. | (11) |
| miR-24 | Human | BEAS-2B, A549, H292, H1703 | MAPK7 | miR-24 by targeting MAPK7 could promote apoptosis in LC. | (12) |
| miR-26 | Human | A549, H1703, 801D | TGF-β1/JNK, Bcl-2, Bax, LC3 | miR-26 via suppressing the TGF-β1/JNK pathway could induce apoptosis in NSCLC. | (13) |
| miR-29c | Human | A549, NCI-H1299, H1650 | VEGFA, PI3K, Akt | miR-29c via targeting VEGFA could promote apoptosis in NSCLC. | (16) |
| miR-30a | Human | A549 | MEF2D, Caspase-3 | Knockdown of miR-30a via targeting MEF2D could promote apoptosis in LC. | (17) |
| miR‐30a‐5p | Human | A549, H1299, H460 | SOX4, p53 | miR‐30a‐5p by targeting SOX4 could mediate apoptosis in NSCLC. | (18) |
| miR-34b | Human | A549 | YAF2, p-Jak2, STAT3, MMP2, Caspase-3 | miR-34b via targeting YAF2 could promote apoptosis in NSCLC. | (19) |
| miR‐34b‐3p | Human | BEAS‐2B, A549, H1299 | CDK4 | miR‐34b‐3p via targeting CDK4 could repress apoptosis in NSCLC. | (20) |
| miR-106b-5p | Human | 16HBE, H1299, SKMES1, A549, H358, SPCA1 | BTG3 | miR-106b-5p via regulating BTG3 could inhibit apoptosis in NSCLC. | (21) |
| miR-124 | Human | BEAS-2B, A549, H1299, H1650 | STAT3 | miR-124 via inhibiting STAT3 could enhance radiation-induced apoptosis in NSCLC. | (22) |
| miR-125a-5p | Human | A549, H1299 | NEDD9 | miR-125a-5p via targeting NEDD9 could induce apoptosis in LUAD. | (23) |
| miR-125b | Human | A549 | PI3K/Akt, GSK3β, Bax, Wnt, β-catenin | miR-125b through the PI3K/Akt/GSK3β pathway could regulate apoptosis in NSCLC. | (24) |
| miR-129-5p | – | A549, H1299 | YWHAB | miR-129-5p via reducing YWHAB could induce apoptosis in LC. | (25) |
| miR-135a | Human | HBE, A549, H460, H1299 | PI3K, Akt, GF-1, CD34, MVD | miR-135a via the IGF-1/PI3K/Akt pathway could promote apoptosis in NSCLC. | (26) |
| miR-139-5p | Human | A549 | Hox-B2, P13k, Akt, Caspase-3 | miR-139-5p by targeting Homeobox protein (Hox-B2) could promote apoptosis in NSCLC. | (27) |
| miR-140-5p | Human | A549 | YES1, Bcl-2, Bax, Caspase-3 | miR-140-5p via targeting YES1 could induce apoptosis in NSCLC. | (28) |
| miR-142 | Human | BEAS-2B, A549, H1650 | XIAP | miR-142 via targeting XIAP could promote apoptosis in LC. | (29) |
| miR-145 | Human | A549 | EGFR/PI3K/AKT, Bax | miR-145 by regulating the EGFR/PI3K/AKT pathway could induce apoptosis in NSCLC. | (30) |
| miR-145 | Human | BEAS-2B, H1650, H1975, A549, H292 | mTOR | miR-145 via negatively regulating the mTOR signaling pathway could influence apoptosis in NSCLC. | (31) |
| miR-146a-5p | GEO and TCGA databases | A549 | TCSF | miR-146a-5p by targeting TCSF could influence apoptosis in NSCLC. | (32) |
| miR-155 | – | A549, A549/R | Bax, Bcl-2, Cyto-Nrf2, Nucl-Nrf2, NQO1 | miR-155 via activating Nrf2 could suppress apoptosis in LC. | (33) |
| miR-195-5p | Human | BEAS-2B, H1299, A549 | CEP55, Bax, Bcl-2 | miR-195-5p via targeting CEP55 could induce apoptosis in NSCLC. | (34) |
| miR-198 | Human | A549, Calu-3 | SHMT1, CDK1, Cyclin-D1/B1 | miR-198 by targeting SHMT1 could enhance apoptosis in LUAD. | (35) |
| miR-210-3p | Human | BEAS-2B, A549, H358, H1650, H1299 | SIN3A, Bcl-2, Caspase-3 | miR-210-3p via targeting SIN3A could regulate apoptosis in NSCLC. | (36) |
| miR-216a-3p | Human | HBE, H1299 A549, H1975, PC9 | COPB2, Bax, Bcl-2, Caspase-3 | miR-216a-3p by targeting COPB2 could regulate apoptosis in LC. | (37) |
| miR-221 | Human | BEAS-2B, A549, H322, H1299 | HOTAIR | miR-221 via negative regulation of lncRNA HOTAIR could promote apoptosis in NSCLC. | (38) |
| miR-222-3p | Human | BEAS-2B, AH1299, SPC-A1, A549, 95D, 293T | BBC3 | miR-222-3p via targeting PUMA (BBC3) could inhibit apoptosis in NSCLC. | (39) |
| miR-323-3p | – | A549, NCI-H3255, H1299 | AKT, ERK, TMEFF2, Akt, ERK1/2 | miR-323-3p by regulating AKT/ERK pathway via targeting transmembrane protein with EGF-like and 2 follistatin domain (TMEFF2) could inhibit apoptosis in NSCLC. | (40) |
| Hsa-miR-329 | Human | A549, H1299 | c-Met | Hsa-miR-329 via targeting oncogenic MET could promote apoptosis in NSCLC. | (41) |
| miR-377 | Human | A549, H460, 95D, HCC82 | CDK6 | miR-377 by directly targeting CDK6 could promote apoptosis in NSCLC. | (42) |
| miR-379-5p | Human | BEAS-2B, A549, PG49, DMS-114 | ARRB1, Bcl-2, Bax, Akt, P13K, Caspase-3 | miR-379-5p via targeting β-rrestin-1 could promote apoptosis in NSCLC. | (43) |
| miR-384 | Gene database (GEO) | BEAS-2B, A549, GLC82, MES-1, LTEP-s | COL10A1, Survivin, Bcl-2, Bax, Bcl-xl, Beclin1, LC3B | miR-384 via negative regulation of Collagen α-1(X) chain gene could induce apoptosis in NSCLC. | (44) |
| miR-425 | Mice | BEAS-2B, A549, SK-MES-1 | AMPH-1, Bcl-2, Caspase-3 | miR-425 via targeting AMPH-1 could regulate apoptosis in NSCLC. | (45) |
| miR-484 | Human | BEAS–2 B, A549, H1650, PC9 | Apaf-1, PARP, Caspase-3 | miR-484 via inhibiting Apaf-1 could suppress apoptosis in NSCLC | (46) |
| miR-503-3p | – | H292, H358, H1975 | p21, CDK4 | miR-503-3p via regulating p21 and CDK4 expression could induce apoptosis in LC. | (47) |
| miR-512-5p | Human | A549, H1299 | p21 | miR-512-5p through targeting p21 could induce apoptosis in NSCLC. | (48) |
| miR-512-5p | Human | 16HBE, A549, H1299 | ETS1, Bcl-2, Bax, Caspase-3/7, MMP-2/9 | miR-512-5p via targeting ETS1 could induce apoptosis in NSCLC. | (49) |
| miR-513b | Human | A549, H460 | HMGB3 | miR-513b via targeting HMGB3 through regulation of the mTOR signaling pathway could regulate apoptosis in NSCLC. | (50) |
| miR-516a-3p | Human | 16HBE, BEAS-2B, H1299, SPC-A1, A549 | PTPRD | miR-516a-3p via targeting PTPRD could inhibit apoptosis in LUAD. | (51) |
| miR-593 | Human | A549, H1299, H358, H1993 | SLUG, Cyclin-D1, Akt, CDK4, CDK6, Bcl-2, Bax, E-cadherin, Vimentin | miR-593 via targeting SLUG−associated signaling pathways could promote apoptosis in NSCLC. | (52) |
| miR-608 | Human | A549, HCC4006, 293T | TFAP4, Caspase-3 | miR-608 via the inhibiting TFAP4 could promote apoptosis in NSCLC. | (53) |
| miR-654-3p | Human | A549 | RASAL2, Bax, Bcl-2 | miR-654-3p by targeting RASAL2 could promote apoptosis in NSCLC. | (54) |
| miR-875 | Human | A549 | SOCS2, Wnt, β-catenin | miR-875 by targeting SOCS2 could regulate apoptosis in NSCLC. | (55) |
| miR-1260b | Human | 16HBE, H1299, SPCA1 | Cyclin-D1, Bcl-2, p21, Caspase-3, | miR-1260b via targeting SOCS6 could regulate apoptosis in NSCLC. | (56) |
| miR-hsa-let-7g | Human | A549, H1944 | HOXB1 | miR-hsa-let-7g via targeting HOXB1 could inhibit apoptosis in LC. | (57) |
miRNAs regulating apoptosis in lung cancer.
Apoptosis-related miRNAs have been shown to influence survival of lung cancer patients. For instance, expression of miR-21 predicts lower OS of patients with NSCLC (12). Moreover, over-expression of miR-125b has been associated with poor prognosis in NSCLC (24).
LncRNAs and Apoptosis in Lung Cancer
Expression of FER1L4 has been remarkably decreased in plasma and tissue samples of patients with NSCLC as well as related cell lines. Forced over-expression of this lncRNA has reduced cell proliferation, migratory aptitude and invasiveness. FER1L4 has been shown to up-regulate PTEN and p53 expressions, suppress AKT phosphorylation expression, therefore enhancing the fraction of apoptotic cells. Functionally, these effects are mediated through the PTEN/AKT/p53 pathway (58). On the other hand, expression of PCAT1 has been increased in NSCLC tissues and cell lines. In vitro studies have shown that PCAT1 stimulates cell proliferation and invasion while suppressing cell apoptosis. In addition, PCAT1 has been shown to interact with the RNA-binding protein DKC1. PCAT1 and DKC1 exert synergistic effects in NSCLC. They enhance activity of VEGF/AKT/Bcl-2/caspase9 pathway in these cells (59). WT1-AS is a down-regulated lncRNA in NSCLC cell lines which is shown to sponge miR-494-3p. Up-regulation of WT1-AS has increased apoptosis of lung cancer cells and attenuated progression of NSCLC through up-regulation of PTEN and subsequent inactivation of PI3K/AKT pathway (60). GACAT1 is another regulator of apoptosis which has been found to be up-regulated in NSCLC tissues in association with poor survival of patients. Functionally, GACAT1 enhances proliferation and cell cycle progression and inhibits apoptosis through sponging miR-422a and increasing expression of YY1 transcription factor (61). HOXC-AS2 is another up-regulated in NSCLC samples which increases proliferation, migration, and EMT, while suppressing apoptosis. HOXC13 has been identified as functional target of HOXC-AS2. Notably, HOXC-AS2 and HOXC13 can enhance expression of each other (62). Expression of SNHG1 has been found to be increased in NSCLC parallel with up-regulation of FRAT1. SNHG1 knock down has suppressed proliferation, increased cell apoptosis and precluded migration and invasiveness of these cells. Mechanistically, SNHG1 sponges miR-361-3p and to release FRAT1 from inhibitory effects of this miRNA (63). Table 2 shows the role of lncRNAs in regulation of apoptosis in lung cancer.
Table 2
| LncRNA | Sample | Cell line | Target/Pathway | Function | Ref |
|---|---|---|---|---|---|
| FER1L4 | Human | – | PTEN, AKT, p53, Ki67, PCNA, MMP2/9, Bcl-2, Bax, Caspase-3/9 | FER1L4 through the PTEN/AKT/p53 signaling pathway could promote cell apoptosis in NSCLC. | (58) |
| PCAT1 | Rat | BEAS-2B, A549, A427, H460 | VEGF, AKT, Bcl-2, Vimentin, N-cadherin, Caspase-3/8/9/12, DKC1, PARP, Cyclin-D, E-cadherin | PCAT1 through the VEGF/AKT/Bcl2/Caspase-9 pathway could regulate apoptosis in NSCLC cells. | (59) |
| WT1-AS | Human | 16-HBE, A549, NCI-H1975, SK-MES-1 | miR-494-3p, PTEN, PI3K, AKT, Bcl-2, Bax, Caspase-3, CDK2, Cyclin-E1 | WT1-AS/miR-494-3p through the PTEN/PI3K/AKT Signaling Pathway could regulate apoptosis in NSCLC cells. | (60) |
| GACAT1 | Human | NHBE, A549, H1299, H460, SK-MES-1 | YY1, miR-422a | GACAT1 via sponging miR-422a could induce apoptosis in NSCLC cells. | (61) |
| HOXC-AS2 | – | – | – | HOXC-AS2 via combining with the HOXC13 gene could mediate apoptosis in NSCLC. | (62) |
| SNHG1 | Human | BEAS‐2B, H23, H1299 | FRAT1 | SNHG1 through the miR‐361‐3p/FRAT1 axis could influence cell apoptosis in NSCLC. | (63) |
| ASB16-AS1 | Human | 16HBE, A549, NCI-H266, NCI-H1299, SK-MES-1 | p21, β-catenin, Cyclin-D1 | ASB16-AS1 via activating the Wnt/β catenin signaling pathway could promote apoptosis of NSCLC. | (37) |
| PVT1 | Human, mice | BEAS-2B, A549, PC-9, H157, H460 | ITGB8, MEK, ERK | PVT1 via targeting miR-145-5p could regulate cell apoptosis in NSCLC. | (64) |
| LEF1-AS1 | human | NCIH1993, NCI-H1581 | miR-221, PTEN | LEF1-AS1 via regulating miR-221/PTEN Signaling could induce apoptosis in NSCLC. | (65) |
| MALAT1 | Human, mice | BEAS-2B, H460, A549, H661, H358 | miR-374b-5p, SRSF7 | Knockdown of MALAT1 through miR-374b-5p/SRSF7 axis could regulate apoptosis in NSCLC. | (66) |
| MIR503HG | human | BEAS-2B, A549, NCI-H1299, NCI-H1975, NCI-H2170 | Cyclin-D1/E, PCNA, p16, p21, Bcl-2, Bax, Caspase-3/9 | MIR503HG via regulating miR-489-3p and miR-625-5p could promote apoptosis in NSCLC. | (67) |
| NEAT1 | Human | BEAS-2B, A549, H292 | SULF1, MAPK, Akt | NEAT1 via targeting has-miR-376b-3p/SULF1 axis could regulate apoptosis in NSCLC. | (25) |
| NEAT1 | – | A549 | miR-1224, KLF3 | Knockdown of NEAT1 by sponging the miR-1224 could enhance the apoptosis in lung cancer | (68) |
| PRNCR1 | Human | BEAS-2B, SPC-A1, A549 | E-cadherin, N-cadherin, Vimentin, MTDH | Knockdown of PRNCR1 through sponging miR-126-5p could inhibit cell apoptosis in NSCLC treatment. | (69) |
| HCG11 | Human, mice | A549, SPC-A1, H1299, H1650, H1975, PC-9 | Caspase-3 | HCG11 by Sponging miR-224-3p could promote apoptosis in NSCLC. | (70) |
| SNHG6 | Human | BEAS-2B, A549, H460, H1299 | Bcl-2, Bax, Caspase-3, RSF1 | SNHG6 via regulating miR-490-3p/RSF1could inhibit apoptosis in NSCLC. | (71) |
| SNHG7 | Human | BEAS-2B, H125, 95D, A594 | FAIM2 | SNHG7 via enhancing the FAIM2 expression could inhibit apoptosis in LC. | (72) |
| SNHG12 | Human, mice | 16-HBE, H1299, A549, H358, H1975, SPC-A1 | miR-138 | Knockdown of SNHG12 via Upregulating miR-138 could induce apoptosis in NSCLC. | (73) |
| SNHG14 | Human, mice | PC9, PC9/GR | ABCB1, miR-206-3p | Knockdown of SNHG14 by sponging miR-206-3p via upregulating ABCB1 could induce apoptosis in NSCLC. | (13) |
| SNHG20 | Human, mice | A549, H32, H1299, GLC-82, SPC-A1 | ZEB2, RUNX2 | Knockdown of SNHG20 by acting as a miR-154 sponge could promote apoptosis in NSCLC. | (45) |
| Human | 16HBE, A549, H1299 | E2F3, P13k, Akt | Knockdown of SNHG20 via regulating miR-2467-3p/E2F3 could induce apoptosis in NSCLC. | (74) | |
| Human | 16HBE, A549, NCI-H520, H1299 | TCF4, LEF1, Wnt/β-catenin | SNHG20 via Wnt/β-catenin signaling pathway by targeting miR-197 could inhibit the apoptosis of NSCLC cells. | (75) | |
| SNHG20 | Human | 16HEB, A549, H1299 | DDX49, miR-342 | Knockdown of SNHG20 by sponging miR-342 and upregulating DDX49 could promote cell apoptosis in lung adenocarcinoma. | (76) |
| HAND2-AS1 | Human | BEAS-2B, NCI-H23, NCI-H522 | PI3K, Akt | HAND2-AS1 via inactivating PI3K/Akt pathway could promote cell apoptosis in NSCLC. | (77) |
| PANDAR | Human | 16HBE, L78, PC9, 95D, NCI-H460, A549 | Beclin-1, LC3-I, LC3-II | PANDAR by upregulation of BECN1 expression via activating autophagy and apoptosis pathways could inhibit the development of lung cancer. | (14) |
| LINC00460 | Murine | A549 | miR-539 | LINC00460 via targeting miR-539 could inhibit apoptosis in NSCLC. | (78) |
| ATB | – | NCI-H838, BEAS-2B | Bcl-2, Caspase-3, CytC | ATB via suppressing the expression of miR-200a and up-regulating the expression of β-catenin could promote apoptosis in NSCLC. | (79) |
| AWPPH | Human | WI-38, NCI-H23, NCI-H522 | Wnt, β-catenin | AWPPH via activating the Wnt/β−catenin signaling pathway could inhibit apoptosis in NSCLC. | (80) |
| DLX6-AS1 | Human, mice | 16HBE, H1975, A549 | PRR11 | Knockdown of DLX6-AS1 via downregulating PRR11 expression and upregulating miR-144 could promote apoptosis in NSCLC. | (53) |
| BANCR | Human, mice | A549, SPC-A1, H1299, H1650, H1975, PC-9 | Bcl-2, Bax | Overexpression of BANCR could increase apoptotic level. | (81) |
| TSLNC8 | Human | HBE, A549, H441, H1975 | CDK2, Cyclin-E1, p21, MMP9, Bcl-2, Bax, Caspase-3 | TSLNC8 via targeting the IL-6/STAT3/HIF-1α signaling pathway could accelerate apoptosis in NSCLC. | (82) |
| AFAP1-AS1 | Human, mice | BEAS-2B, H1975, PC-9, A549, SPCA-1 | RRM2, EGFR, Akt | AFAP1-AS1 via Competitively upregulating RRM2 by sponging miR-139-5p could reduce apoptosis in NSCLC. | (83) |
| PCAT-1 | Human | 16HBE, H1299, SK‐MES‐1 | PCAT‐1, LRIG2 | Knockdown of PCAT‐1 via regulating miR‐149‐5p/LRIG2 axis could induce apoptosis promotion in NSCLC. | (84) |
| HULC | Human | NCI-H23, NCI-H522 | PI3K, Akt, SPHK1 | HULC via upregulating sphingosine kinase 1(SPHK1) and its downstream PI3K/Akt pathway could inhibit apoptosis in NSCLC. | (85) |
| EPB41L4A-AS2 | Human | 16HBE, SK-MES-1, HCC827, A549, NCI-H1975 | PCNA | Overexpression of EPB41L4A-AS2 could promote apoptosis in NSCLC. | (86) |
| NBAT-1 | Human | A549 | RAC1 | NBAT-1 by downregulating RAC1 could promote Cell Apoptosis in NSCLC. | (87) |
| PICART1 | Human | BEAS-2B, A549, SPC-A-1, NCI-H358, NCI-H1975, HCI-H292 | Twist1, MMP2/9, E-cadherin, Cyclin D1, p21, Bcl-2, Bax, Caspase-3, STAT3, JAK2 | PICART1 via inhibiting JAK2/STAT3 signaling could promote apoptosis in NSCLC. | (30) |
| CASC2 | Human | 16HBE, A549, H1299 | p62,Atg-5, LC3-I, LC3-II, LC3-II/I, TRIM16, | CASC2 by regulating the miR-214/TRIM16 axis could promote apoptosis in NSCLC. | (88) |
| LINC00961 | Database | A549, H226 | PCNA, Bax | LINC00961 via regulating PCNA could induce cell apoptosis in NSCLC. | (89) |
| LINC02418 | 16HBE, A549, PC-9 | miR-4677-3p, SEC61G | LINC02418 via regulating miR-4677-3p/SEC61G could regulate apoptosis in NSCLC. | (90) | |
| 00312 | Human, mice | A549, SPC-A1, H1299, H1975, PC9, H1703, H520, SK-MES | HOXA5 | lncRNA00312 via inhibiting HOXA5 could promote apoptosis in NSCLC. | (91) |
| TRPM2-AS | Human | A549, H1299 | SHC1 | Knockdown of TRPM2-AS could increase cell apoptosis in NSCLC. | (92) |
| MEG3 | Human, mice | A549 | miR-205-5p, LRP1, p53,p21, Caspase-3 | MEG3 through the miR-205-5p/LRP1 pathway could regulate apoptosis in NSCLC. | (46) |
| TUG1 | Human | 16HBE, A549, SPC-A1, PC-9, H1299, H1975 | EZH2, Bax, BCL2, BCL2A1, PARP2, BIRC3, MCL1, BAK1, CASP9, CASP3 | TUG1 through the epigenetic silencing of BAX could suppress apoptosis in LUAD. | (21) |
| LINC00857 | Human | BEAS-2B, H1229, H838 | miR-1179, SPAG5 | LINC00857 via targeting the miR-1179/SPAG5 axis could regulate apoptosis in lung adenocarcinoma. | (93) |
| LINC00472 | Human | BEAS-2B, A549, H1299, H460, H446 | miR-24-3p, DEDD | LINC00472 by regulating miR-24-3p/DEDD could promote Apoptosis of LUAD, | (94) |
| AFAP1-AS1 | Murine | A549 | miR-545-3p, HDGF | Knockdown of AFAP1-AS1 by regulating the miR-545-3p/HDGF axis could promote apoptosis in lung cancer. | (95) |
| ZEB2-AS1 | Human | MRC-5, 95D, H-125, A549, NCI-H292, H1975 | Bcl-2, Bax, Caspase-3/9 | In A549 and NCI−H292 cells, knockdown of ZEB2-AS1 could inhibit cell proliferation, while in H-125 and H1975 cells overexpression of ZEB2-AS1 could inhibit cell apoptosis. | (96) |
| NORAD | Human | H460, H1299, A549, HBE, SCLC-21H | ADAM19, miR-30a-5p | Knockdown of NORAD via regulating miR-30a-5p/ADAM19 could promote cell apoptosis in LC | (97) |
LncRNAs regulating apoptosis in lung cancer.
Among lncRNAs which regulate apoptosis in lung cancer cells, over-expression of LINC00460, AWAPPH, SNHG20, HULC, ZEB2-AS1 and TRPM2-AS has been associated with poor prognosis of patients, while EPB41L4A-AS2 has the opposite effect (Table 3).
Table 3
| Sample | Kaplan-Meier Analysis | Ref |
|---|---|---|
| 483 NSCLC tissues and 347 paracancerous tissues were TCGA | Higher expression of LINC00460 was associated with poor prognosis of NSCLC | (78) |
| 88 patients with NSCLC including 56 males and 32 females, aged 23–71 years (average age, 46 ± 8.9 years) | Higher expression of AWPPH was associated with poor prognosis of NSCLC | (80) |
| 42 paired NSCLC tumor and adjacent normal tissue samples from Wenzhou Central Hospital | Higher expression of SNHG20 was associated with a poor prognosis of NSCLC | (45) |
| 102 patients (61 males and 51 females) with NSCLC aged from 21-76 years, with an average age of 48 ± 7.7 years. | Higher expression of HULC was associated with poor prognosis of NSCLC | (85) |
| 100 lung cancer tissues and their adjacent non-cancerous tissues from patients (67 males and 33 females; mean age, 62; age range, 48–79) | Higher expression of ZEB2-AS1was associated with higher proliferation of NSCLC. | (96) |
| 56 NSCLC and adjacent tissues | Lower levels of EPB41L4A-AS2 was associated with poor prognosis in NSCLC | (86) |
| 60 NSCLC patients | Higher expression of TRPM2-AS was associated with poor prognosis in NSCLC | (92) |
Prognostic role of apoptosis-related lncRNAs in lung cancer.
ncRNAs, Cell Apoptosis and Immunotherapy
Since immunotherapy has an emerging role in the treatment of lung cancer (98), identification of the role of ncRNAs in immune regulation and response of lung cancer to immunotherapy is important. A number of apoptosis-regulating ncRNAs have essential roles in this regard. For instance, miR-155 and miR-17~ 92 are involved in differentiation regulatory T cells (Tregs) and their function (99). miR-21 and miR-26 through down-regulation of TAP1 and reduction in expression of HLA class I antigens affect response to immunotherapies (100). miR-138, miR-155, miR-34 and miR-146a have been found to affect immune checkpoints (101). MALAT1 is an lncRNA which is possibly involved in the immunotherapy resistance through induction of immunosuppressive phenotypes in stem cells (102). NEAT1 can affect response to immunotherapy through modulation of miR-155/Tim-3 (103). The exact roles of these ncRNAs in conferring resistance to immunotherapeutic approaches have not been elucidated in lung cancer; yet based on the results obtained from similar studies in other cancer types, these ncRNAs are expected to simultaneously affect apoptosis and response to immunotherapy in lung cancer.
Discussion
Cell apoptosis, as one of the major dysregulated processes in the carcinogenesis of lung cancer has been shown to be regulated by ncRNAs. In the current review, we have explained the impact of miRNAs and lncRNAs on apoptosis in lung cancer. These ncRNAs interact with PI3K/Akt, NF-κB, Wnt/β-catenin, EGFR, TGF-β and other cancer-related pathways. Therefore, they not only regulate apoptosis, but also influence other aspects of lung carcinogenesis. Figure 3 depicts the role of ncRNAs in modulating apoptosis through Wnt/β-catenin cascade in human lung cancer.
Figure 3
Manipulation of expression of apoptosis-regulating lncRNAs and miRNAs represent a strategy for combating carcinogenesis as well as resistance to chemo/radiotherapy. Some of the apoptosis-regulating miRNAs/lncRNAs have been shown to influence prognosis of lung cancer. The observed correlation between their expression and patients’ survival is due to their impact on disease progression as well as response of patients to EGFR inhibitors and chemotherapeutic agents. EMT is another important feature of lung cancer cells which is regulated by a number of apoptosis-regulating miRNAs/lncRNAs indicating the intercalation between cancer-related processes.
An acknowledged route of function of lncRNAs in the regulation of apoptosis in lung cancer is their impact on expression of miRNAs. In fact, they can sequester miRNAs and release miRNA targets from their inhibitory effects. WT1-AS/miR-494-3p, LEF1-AS1/miR-221, NEAT1/miR-1224, SNHG12/miR-138, LINC02418/miR-4677-3p, MEG3/miR-205-5p, LINC00857/miR-1179, LINC00472/miR-24-3p, AFAP1-AS1/miR-24-3p and NORAD/miR-30a-5p are examples of lncRNAs/miRNAs interactions with verified roles in the control of lung cancer cells apoptosis.
Based on the importance of apoptotic pathways in determination of response of lung cancer patients to conventional as well as targeted therapies, identification of the impacts of lncRNAs/miRNAs on apoptosis and prior profiling of these ncRNAs in clinical samples would help in prediction of response of patients to each therapeutic regimen and design of personalized treatment strategies. The advent of high throughput sequencing strategies has facilitated conduction of this approach in the clinical settings.
Finally, the possibility of lncRNAs/miRNAs tracing in the peripheral blood of patients has opened a new opportunity for early detection of emergence of resistance to conventional or targeted therapies and modulation of therapeutic regimens to enhance the survival of affected individuals.
Statements
Author contributions
MT and SG-F wrote the draft and revised it. HS, AA, JM, and MM collected the data, designed the tables and figures. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
lncRNA, miRNA, apoptosis, lung cancer, expression
Citation
Ghafouri-Fard S, Aghabalazade A, Shoorei H, Majidpoor J, Taheri M and Mokhtari M (2021) The Impact of lncRNAs and miRNAs on Apoptosis in Lung Cancer. Front. Oncol. 11:714795. doi: 10.3389/fonc.2021.714795
Received
25 May 2021
Accepted
08 July 2021
Published
21 July 2021
Volume
11 - 2021
Edited by
Yan Gu, National Key Laboratory of Immunology, China
Reviewed by
Dan Qi, Baylor Scott and White Health, United States; Tupa Basuroy, Massachusetts General Hospital and Harvard Medical School, United States
Updates
Copyright
© 2021 Ghafouri-Fard, Aghabalazade, Shoorei, Majidpoor, Taheri and Mokhtari.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohammad Taheri, mohammad_823@yahoo.com; Majid Mokhtari, majimokh@gmail.com
This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology
Disclaimer
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