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Long Non-Coding RNAs in Lung Cancer: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Oncology
Contributor: Weidong Yu

Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. 

  • lncRNAs
  • cancer
  • metastasis

1. LncRNAs Definition and Functions

LncRNAs are a class of RNA transcripts with a length greater than 200 bp, characterized by more spatial and temporal specificity and lower interspecific conservation when compared with mRNAs [1]. LncRNAs had been previously considered to be the by-products of the transcription process. However, it has been widely accepted now that lncRNAs are involved in the process of cell differentiation and growth and the pathogenesis of many diseases, including cancer [2]. According to the relative location of lncRNAs to protein-encoding genes in the genome, they have been classified into sense lncRNA, antisense lncRNA, bidirectional lncRNA, intron lncRNA, intergenic lncRNA, and enhancer lncRNA [3]. So far, lncRNAs have been revealed to play an important role in regulating gene expression at the epigenetic, transcription, and post-transcriptional levels [4].
Firstly, lncRNAs play a crucial role in regulating gene expression though chromatin modification and remodeling, histone modification, and nucleosome localization changes [5]. Among the mechanisms regulating chromosome remodeling, SWItch/Sucrose Non-Fermentable (SWI/SNF) complex is a chromosome reconstitution complex composed of multiple subunits, which drive the change of nucleosome localization [6][7]. LncRNAs can interact with SWI/SNF complexes to alter chromosome structure and regulate gene expression [8][9][10][11]. In addition, lncRNAs also regulate chromatin remodeling by affecting the DNA methylation with S-adenosylhomocysteine hydrolase [12], DNA demethylation with growth arrest and DNA-damage-inducible alpha (GADD45A) [13], and acetylation of histone with Sirtuin 6 (SIRT6) [14]. Histone is an important basic unit of the nucleosome, which plays an important role in the formation of structure and function of chromosomes. Many lncRNAs modulate histone methylation by interacting with polycomb repressive complex 2 (PRC2), altering the structure and function of chromosomes [15][16].
Furthermore, microRNAs (miRNAs) inhibit the translation efficiency and/or induce mRNA degradation of the target gene by complementary pairing with the target RNA, regulating gene expression at the post-transcriptional level. There is a type of competitive endogenous RNA (ceRNA) that can indirectly regulate the expression of target genes via competitively binding with miRNAs; this competitive binding of miRNAs is also called microRNA sponges [17][18]. Many lncRNAs can work as miRNA sponges to influence gene expression and the development of cancer [19].

2. LncRNAs in Lung Cancer (LC)

LC is the leading cause of cancer-related deaths, accounting for 18.4% of total cancer-related deaths and taking the first place with an incidence rate of 11.6% among males and females [20]. It was estimated that there were 2,093,876 newly diagnosed LC cases and 1,761,007 cases that died from LC worldwide in 2018 [20][21]. LC is pathologically divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which accounts for 80–85% of all LC cases. NSCLC is further divided into lung squamous cell carcinoma (LSCC), lung adenocarcinoma (LAD), and large cell carcinoma (LCC) [22][23]. Although many advances had been made in the treatment of LC, such as surgical resection and chemotherapy in the past decades, the five-year survival rate is only 15% [22] due to its late-stage diagnosis, metastasis, insensitivity to chemotherapy, and recurrence [22][24]. Clearly, to explore new targets and biomarkers for early diagnosis and more effective treatment of LC is of great significance. In particular, several lncRNAs have been shown to have the potential of serving as novel biomarkers and targets for LC diagnosis and treatment [25].

2.1. Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1)

MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2), is an 8.7 kb intergenic lncRNA located on chromosome 11q13 [25], and is one of the most abundantly expressed lncRNAs in normal tissues [26]. MALAT1 is involved in post-transcriptional regulation of gene expression and mRNA splicing [27]. It has been reported that MALAT1 is involved in the pathogenesis of LC and other human cancers, including liver, breast, colon, uterus, prostate, ovarian, and hematological malignancies and neuroblastoma [22][28][29][30].
Several studies have suggested that MALAT1 could serve as a potential prognostic biomarker and therapeutic target for patients with early-stage LC due to its specificity and stability [22][26][31][32][33]. It has been shown that the expression of MALAT1 in NSCLC tissues is higher than that in adjacent tissues, and NSCLC patients with high MALAT1 expression have poor overall survival (OS) [32][34][35]. Moreover, the expression of MALAT1 in NSCLC tissues with bone metastasis is higher than that in NSCLC tissues without bone metastasis [36]. MALAT1 expression level is lower in the peripheral whole blood [37] and cellular fraction of human blood [38] in patients with LC than that in healthy subjects. However, the expression of MALAT1 in the whole blood of LC patients with metastasis is shown to be higher compared with that in patients with non-metastasis [37]. Moreover, MALAT1 level is significantly upregulated in the whole blood of LC patients with metastasis such as bone or brain metastasis than that in LC patients with lymph node or pleura metastasis [37].
Functionally, MALAT1 is considered as an oncogenic lncRNA because of its role in promoting tumor differentiation, proliferation, migration, invasion, EMT, and chemoresistance [25][22]. Silencing of MALAT1 inhibits cell proliferation and colony formation in NSCLC cell lines [31][39][40]. MALAT1 promotes cell migration and invasion process by sponging miR-206 in A549 and H1299 cell lines [41]. In addition, MALAT1 can promote EMT and invasion of A549 and H1299 cells by upregulating the expression of snail family transcriptional repressor 2 (SLUG) through competitively sponging miR-204 [42]. C-X-C motif chemokine ligand 5 (CXCL5) is a downstream gene of MALAT1, and knockdown of CXCL5 in vitro could inhibit MALAT1-induced cell migration and invasion [34]. In nude mice, the total number and area of lung tumor nodules are significantly reduced in the injection of A549 MALAT1 KO cells compared to A549 MALAT1 wild-type (WT) cells [32]. MALAT1 also directly binds with miR-200a to promote cell proliferation and induce gefitinib resistance in A549 cells [43]. An additional study showed that MALAT1 could promote cisplatin (DDP) resistance by sequestering miR-101-3p and upregulating the expression of myeloid cell leukemia 1 (MCL1) in LC cells [44]. Overall, MALAT1 plays an important role in the progression of LC through multiple mechanisms, and it could serve as a potential biomarker and target for the diagnosis and treatment of LC. However, the role of MALAT1 in regulating cancer stemness and post-translational modifications needs to be further studied. In particular, the mechanisms for MALAT1 activation in LC tissues still need further exploration.

2.2. H19

H19 is a 2.3 kb intergenic and maternally-expressed lncRNA located on chromosome 11p15.5, which is also one of the first identified imprinting lncRNA [21][22][28][45]. H19 includes five exons and four introns, and plays an important role in embryonic and tumor development [28][45][46]. H19 is reported to be associated with multiple cancers such as LC, GC, CRC, pancreatic cancer (PC), ovarian cancer (OC), neuroblastoma (NB), and bladder cancer [28][47].
Studies have revealed that the expression of H19 is significantly increased in LC tissues when compared with that in adjacent tissues [21][48]. H19 overexpression is associated with carcinogenesis from early stages to metastasis, reduced disease-free survival (DFS) time, and poor prognosis in LC [25][22][28][49]. Plasma level of H19 is also significantly increased in NSCLC patients, which could be a clinical serological biomarker for complementary diagnosis of NSCLC [50]. In the Chinese population, it has been reported that H19 rs2107425 is significantly related to LC susceptibility [51], and H19 SNP rs217727 is strongly associated with susceptibility to LSCC and LAD [51]. Kaplan–Meier analysis was used to evaluate that higher expressions of H19 and miR-21 are correlated with shorter OS in NSCLC patients, suggesting that H19 and miR-21 together may be involved in the development of LC [52].
H19 plays an important role in promoting cell proliferation and differentiation, cell migration and invasion, and EMT [21]. Zhou et al. reported that knockout of H19 obviously inhibits the proliferation of LC cells in vitro and in vivo [52]. Zhao et al. indicated that the overexpression of H19 sponged and inhibited miR-200a function to upregulate zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2), thereby promoting proliferation, migration, invasion, and EMT in LC [21]. It has been demonstrated that upregulation of H19 can induce cell proliferation, invasion, and EMT occurrence by acting as an miRNA sponge and regulating miRNA-203-mediated EMT [48]. Additionally, H19 can induce cell proliferation by promoting the expression of pro-oncogene lin-28 homolog B (LIN28B) via the inhibition of miR-196b expression in A549 and H1299 LC cell lines [53]. H19 can also compete with miR-107 to bind neurofibromin 1 (NF1), which stimulates the development of NSCLC [23][54]. Additionally, H19/miR-29b-3p/signal transducer and activator of the transcription 3 (STAT3) signaling pathway is also considered to be involved in cell proliferation, viability, apoptosis, and EMT of LAD Calu-3 and NCI-H1975 cell lines [55]. H19 also promotes NSCLC metastasis by activating some cellular signaling pathway proteins, including metastasis associated in colon cancer 1 (MACC1), epidermal growth factor receptor (EGFR), β-catenin, and extracellular-signal-regulated kinase 1/2 (ERK1/2) [46]. Overexpression of H19 promotes cell proliferation, migration, and invasion by upregulating the expression of EMT markers, including snail family transcriptional repressor 1 (SNAI1), N-cadherin, and Vimentin [23][45][46][48][56]. Moreover, upregulation of H19 can induce A549 cells resistance to DDP [56][57]. SNP rs2107425 in H19 is also reported to be associated with resistance to platinum-based chemotherapy in SCLC [51]. Oncogene c-Myc has been shown to be associated with H19 regulation in NSCLC [58]. c-Myc induces H19 expression and then downregulates miR-107 to promote mitotic progression of the NSCLC cell line [58]. The in vivo and in vitro experiments revealed that c-Myc can bind to the promoter of H19 and then activate its transcription [59]. Collectively, activation of H19 promotes the progression of LC and it could also serve as a serological biomarker in diagnosing LC. Further studies might concentrate on the role in cancer stemness. Particularly, how to repress the expression of H19 in LC tissues represents a novel strategy for treating LC.

2.3. Taurine Upregulated Gene 1 (TUG1)

TUG1 is a 7.1 kb intergenic lncRNA located on chromosome 22q12 [60][61][62]. TUG1 was firstly discovered to play a crucial role in mouse retinal development [60][61][63]. After that, TUG1 was found to have an important role in other cancers such as LC, HCC, BC, OC, GC, CRC, esophageal squamous cell carcinoma (ESCC), osteosarcoma, glioma, and bladder cancer [60][64].
TUG1 is upregulated in the majority of the above cancer tissues but downregulated in LSCC and LAD tissues [60][61][62][64][65][66], suggesting that it may have tissue-specific expression patterns and a role in different human tumors [22]. NSCLC patients with high expression of TUG1 have a better prognosis [60]. In support, lower expression of TUG1 is associated with larger tumor size, advanced tumor lymph node metastasis (TNM) stage, and poorer OS in NSCLC patients [62]. Moreover, univariate and multivariate analysis revealed that TUG1 can serve as an independent predictor for OS in NSCLC patients [62]. However, TUG1 is found to be upregulated in SCLC tissues compare with that in adjacent normal tissues and its upregulation is associated with poor prognosis [67]. An additional study also revealed that TUG1 is upregulated in LAD cells and serum samples, and a high level of TUG1 is positively correlated with tumor size, TNM stage, lymph node metastases, and distant metastasis [68].
TUG1 expression is induced by the wild-type p53 in three NSCLC cell lines (A549, SK-MES-1, and NCI-H1299), and TUG1 knockdown increases cell proliferation in vitro and in vivo [62][66]. Additionally, TUG1 can bind with PRC2 in the promotor region of Elav-like family member 1 (CELF1) to inhibit the expression of the genes involved in cell cycle [69]. Moreover, TUG1/PRC2 complex could also bind to the homeobox B7 (HOXB7) promoter and activate its expression, thereby activating the Akt and mitogen-activated protein kinase (MAPK) pathways in NSCLC tissues [62]. However, TUG1 knockdown significantly inhibits cell proliferation, migration, and invasion and promotes cell apoptosis and cell cycle arrest in three SCLC cell lines (NCI-H69, NCI-H446, NCIH69AR) by regulating LIMK2b (a splice variant of LIM-kinase 2) expression via binding with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) [67]. TUG1 can also induce SCLC cell resistance to chemotherapeutic drugs, including DDP, adriamycin (ADM), and vepeside (VP-16) in vitro and in vivo [67]. In general, TUG1 plays an important role in the development of LC. However, further studies are needed to clarify the distinct mechanisms of TUG1 in NSCLC and SCLC.

2.4. Maternally Expressed Gene 3 (MEG3)

MEG3 is 6.9 kb in length and acts as a tumor suppressor gene located on chromosome 14q32.2 within the DLK1-MEG3 locus [22][70][71]. MEG3 is expressed in many normal tissues and is considered to be involved in many cellular processes [72]. Compared with adjacent non-tumor lung tissues, MEG3 is significantly downregulated in NSCLC tissues [72]. A meta-analysis declared that overexpression of MEG3 exhibited better prognosis in NSCLC patients, suggesting that MEG3 could serve as a prognostic factor of NSCLC patients [73]. Additionally, the MEG3 rs4081134 SNP is strongly associated with LC susceptibility in the Chinese population [70]. Moreover, MEG3 is also considered to be inhibited in other cancers, including HCC, NB, glioma, meningioma, bladder cancer, and hematological malignancies [25][70][74][75].
MEG3 is significantly downregulated in LC cell lines A549 and HCC823 [76]. Upregulation of MEG3 inhibits the viability, proliferation, and autophagy in H292 and A549 cells [72][77]. Upregulation of MEG3 increases cell apoptosis by suppressing the expression of apoptosis inhibitory protein B-cell lymphoma-2 (Bcl-2) and promoting apoptosis-promoting factor BCL2 associated X (Bax) in A549 cells [76]. MEG3 overexpression suppresses cell proliferation and induces apoptosis by activating the expression of p53 in vitro [71][72]. The retinoblastoma tumor suppressor (pRb) pathway, which is important in regulating cell cycle progression and cell proliferation, is revealed to inhibit cell proliferation by activating MEG3 expression in A549 and SK-MES-1 in LC cells [78]. In addition, the MEG3/microRNA-7-5p/BRCA1 regulatory network is also verified to be essential in NSCLC [76].
The drug resistance to chemotherapy drug vincristine is negatively associated with the expression of MEG3 in vitro [77]. Upregulation of MEG3 improves the sensitivity of DDP-resistant NSCLC cells to DDP treatment via inhibiting cell proliferation and inducing cell apoptosis modulated by the miR-21-5p/SRY-box transcription factor 7 (SOX7) axis [79]. MEG3 knockdown could also induce DDP resistance in A549/DDP cells by activating the Wnt/β-catenin signaling pathway [80]. Overall, these findings suggest that MEG3 could repress the development of LC, and it may also act as a therapeutic target for LC. Further study is also needed to clarify the mechanism(s) of MEG3 repression in LC tissues.

2.5. Actin Filament Associated Protein 1 Antisense RNA 1 (AFAP1-AS1)

AFAP1-AS1 is a 6.8 kb antisense lncRNA, which is located on chromosome 4p16.1. AFAP1-AS1 is transcribed from AFAP1 in the antisense direction and can also affect the expression of AFAP1 [24]. AFAP1-AS1 plays an important role in the progression of LC and other cancers, including LC, HCC, GC, PC, CRC, OC, and gallbladder cancer (GBC) [24].
AFAP1-AS1 expression is positively correlated with tumor pathological grade, TNM staging, smoking history, infiltration degree, distant metastasis, and clinical outcomes in NSCLC patients [73][81][82][83]. High expression of AFAP1-AS1 is correlated with advanced lymph node metastasis and reduced survival time [84]. A meta-analysis report showed that increased expression level of AFAP1-AS1 is a strong predictor of poor OS in NSCLC patients [73]. These findings suggest that AFAP1-AS1 could serve as a prognostic biomarker for NSCLC.
AFAP1-AS1 is upregulated in NSCLC tissues and cell lines [73][81][82][83][84][85][86][87][88][89]. Inhibition of AFAP-AS1 suppresses cell growth and migration and promotes apoptosis of NSCLC cells in vitro [85][86]. AFAP1-AS1 knockdown leads to a significant increase in keratin 1 (KRT1) expression in vitro, suggesting that the oncogenic activity of AFAP1-AS1 is mediated by suppressing KRT1 expression [86]. Moreover, AFAP1-AS1 knockdown also inhibits tumor growth of LC in BALB/c nude mice [86]. In contrast, overexpression of AFAP1-AS1 promotes proliferation, migration, and invasion, and inhibits apoptosis of NSCLC cell lines by upregulating the interferon regulatory factor (IRF) 7 and retinoid-inducible protein (RIG)-I-like receptor signaling pathways [87]. AFAP-AS1 can also promote NSCLC cell growth by recruiting EZH2 to epigenetically downregulate p21 expression [83]. In general, AFAP-AS1 promotes LC cell proliferation and migration, and inhibits cell apoptosis via multiple signaling pathways.

This entry is adapted from the peer-reviewed paper 10.3390/cells8091015

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