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REVIEW ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 5  |  Page : 7-10

Roles of noncoding RNAs in metastasis of nonsmall cell lung cancer: A mini review


1 Department of Interventional Radiology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475001, PR China
2 Department of Oncology, Henan University School of Medicine, Kaifeng, Henan 475001, PR China

Date of Web Publication31-Aug-2015

Correspondence Address:
Dr. Ruimin Sun
Department of Interventional Radiology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475001
PR China
Dr. Zhijun Zhao
Department of Interventional Radiology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475001
PR China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.163831

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 > Abstract 

Recent advances in genome-wide sequencing and gene expression profiling technologies has facilitated the discovery of a huge amount of long noncoding RNA (lncRNA) transcripts. In general, these lncRNAs have been reported to participate in multiple biological processes and human diseases through transcriptional, posttranscriptional and epigenetic pathway. Furthermore, emerging evidence has suggested that dysregulation of lncRNA contributes to the development and progression of human malignancies, notably lung cancer, which is one of the leading causes of cancer-related death. In this review, we will summarize the functions of lncRNAs from recent reports in human nonsmall cell lung cancer (NSCLC) research, especially in the metastasis of NSCLC, and highlight the future opportunities and challenges in diagnostics and therapy of NSCLC patients.

Keywords: HOX antisense intergenic RNA, long noncoding RNA, metastasis, metastasis-associated-in-lung-adenocarcinoma- transcript-1, nonsmall cell lung cancer


How to cite this article:
Wu T, Yin X, Zhou Y, Wang Z, Shen S, Qiu Y, Sun R, Zhao Z. Roles of noncoding RNAs in metastasis of nonsmall cell lung cancer: A mini review. J Can Res Ther 2015;11, Suppl S1:7-10

How to cite this URL:
Wu T, Yin X, Zhou Y, Wang Z, Shen S, Qiu Y, Sun R, Zhao Z. Roles of noncoding RNAs in metastasis of nonsmall cell lung cancer: A mini review. J Can Res Ther [serial online] 2015 [cited 2019 Sep 15];11:7-10. Available from: http://www.cancerjournal.net/text.asp?2015/11/5/7/163831

Tao Wu and Xiaoxiang Yin contribute equallyto this work.



 > Introduction Top


Lung cancer, including nonsmall cell lung cancer (NSCLC) and small cell lung cancer, is one of the leading causes of global cancer-related mortality, with an approximate 5-year survival rate of 16.6%. [1],[2] NSCLC accounts for ~85% of all lung cancer cases, and more than half of NSCLC patients have advanced local invasion and/or distant metastasis. [3],[4] Metastasis is the major cause of cancer recurrence and tumor-related death. [5] Despite much efforts and improvements have been made in early diagnostics and therapy, the overall prognosis and survival time are still limited and unsatisfied. Therefore, keeping on understanding the molecular mechanisms and pathways underlying NSCLC progression, especially metastasis is now essential for achieving better therapy effects and prognosis currently.

An exciting discovery of the ENCODE project is that approximately 90% of the total human genome can be transcribed into noncoding RNAs, and only <3% of the genome encodes proteins. [6] Long noncoding RNAs (lncRNAs) refer to the noncoding RNAs that were not shorter than 200 nt in length, with no or little protein-coding capacity. [7] LncRNAs are predicted to modulate chromatin or to function as genetic expression regulators, which largely depend on their location to the nucleus. [8] Till now, more than 3000 lncRNAs have been identified; however, functions for only 1% of them have been discussed. Aberrant expression of lncRNAs is linked with tumorigenesis, and dysregulation of them participate in tumor initiation, progression, and metastasis in various types of human cancers. [9],[10] Emerging evidence suggests that lncRNAs function as novel master regulators of NSCLC, particularly in the metastasis process. [11],[12],[13] Studying the roles of lncRNAs opens new avenues into the biology of NSCLC and provides novel possibilities for developing more efficient treatments.


 > Long Noncoding Rnas: Crucial Contributors in Metastasis of Nonsmall Cell Lung Cancer Top


LncRNAs, as a novel and important class of noncoding RNAs involved in cancer research, is known to be involved in a variety of basic biological processes, such as epigenetic, transcriptional, and posttranscriptional regulation of gene expression. [14]

Recently, some lncRNAs, including metastasis-associated- in-lung-adenocarcinoma-transcript-1 (MALAT1), HOX antisense intergenic RNA (HOTAIR), colon cancer-associated transcript 2 (CCAT2), BRAF activated noncoding RNA (BANCR), microvascular invasion in HCC (MVIH), SPRY4 intronic transcript 1 (SPRY4-IT1), cancer-associated region long noncoding RNA (CARLo-5), plasmacytoma variant translocation 1 (PVT-1), brain cytoplasmic RNA 1 (BCYRN1), antisense noncoding RNA in the INK4 locus (ANRIL), have been identified as novel modulators in the metastasis of human NSCLC. [15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] Herein, we provide a brief description of these lncRNAs.

Metastasis-associated-in-lung-adenocarcinoma-transcript-1

MALAT-1 is highly conserved among mammals. It was originally identified as a prognostic marker for metastasis, and patient survival in NSCLC. [15] Its elevated level might induce migration and tumor growth of NSCLC cells. [16] On the other hand, reduced MALAT1 expression inhibited cell motility in vitro. [17] Furthermore, a loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis. [17],[18] Recently, researchers proved that MALAT1 could promote lung cancer brain metastasis through inducing epithelial-mesenchymal transition (EMT). [19]

HOX antisense intergenic RNA

A lncRNA located in the HOXC locus is one of the most well-known lncRNAs in NSCLC. It exhibits significantly higher expression in the tumor tissue than the adjacent nontumor tissue in patients with NSCLC. Its upregulation was correlated with NSCLC advanced pathological stage, lymph-node metastasis or lymph-vascular invasion and short disease-free interval. Moreover, brain metastases show significantly higher HOTAIR expression. And patients with high levels of HOTAIR had a relatively poor prognosis. In cultured cells, HOTAIR overexpression induced cell migration, and inhibition of HOTAIR by RNAi limited the migration and invasion of NSCLC cells in vitro and impeded cell metastasis in vivo, which partially through the downregulation of HOXA5, and promotion of EMT by repressing the expression of cell adhesion-related genes. [20],[21],[22]

Colon cancer-associated transcript 2

A novel lncRNA mapping to 8q24 underlies metastatic progression and chromosomal instability in colon cancer. [23] In NSCLC, it was found to be significantly overexpressed, and knockdown of CCAT2 led to inhibition invasion in NSCLC cell lines in vitro. [24]

BRAF activated noncoding RNA

BANCR was reported to be decreased in NSCLC tissues and associated with larger tumor size, advanced pathological stage, metastasis distance, and shorter overall survival of patients. BANCR actively functions as a regulator of EMT during NSCLC metastasis, through the regulation of E-cadherin, N-cadherin, and vimentin expression. [25] Or in another reports, it regulates cell proliferation and migration through p38 and JNK inactivations. [26]

LONG NONCODING RNAS associated with microvascular invasion in HCC

lncRNA MVIH was increased in NSCLC, and its expression level was significantly correlated with tumor node metastases (TNM) stages, tumor size, and lymph-node metastasis. Functionally, silencing MVIH expression by siRNA could inhibit cell proliferation and invasion, while ectopic expression of MVIH promoted cell proliferation and invasion in NSCLC cells partly via regulating matrix metalloproteinase (MMP) 2 and MMP9 protein expression. [27]

SPRY4 intronic transcript 1

SPRY4-IT1, derived from an intron within SPRY4, is transcriptionally repressed by the polycomb group protein enhancer of zeste homolog 2. It was found that SPRY4-IT1 was downregulated and correlated with poor prognosis in NSCLC. Overexpression of SPRY4-IT1 was found to have a key role in the EMT through the regulation of E-cadherin and vimentin expression, which further suppressed NSCLC migration and invasion in vitro and NSCLC metastasis in vivo. [28]

Cancer-associated region long noncoding RNA

A recently identified lncRNA, whose great upregulation was observed in NSCLC tissues compared to their adjacent normal tissues. Inhibition of CARLo-5 by siRNA suppressed the migration, and invasion by reversing the EMT in NSCLC cells. [29]

Plasmacytoma variant translocation 1

PVT-1 was significantly upregulated in NSCLC. Increased PVT-1 expression was significantly correlated with histological grade, lymph-node metastasis, and poorer overall survival.

In vitro
assays indicated that knockdown of PVT1 inhibited cell proliferation, migration, and invasion. [30]

Brain cytoplasmic RNA 1

BCYRN1 is upregulated in NSCLC. ChIP assay found the binding of c-MYC to the promoter region of BCYRN1 gene. In vitro cell metastasis experiments demonstrated that BCYRN1 was necessary in the c-MYC-regulated cell migration and invasion. Besides, the expression levels of MMP9 and MMP13 descended with the decreasing BCYRN1 level and ascended with the upregulation of BCYRN1. In general, cell metastasis of NSCLC was regulated by c-MYC-activated BCYRN1 through promoting the expressions of MMP9 and MMP13. [31]

Antisense noncoding RNA in the INK4 locus

ANRIL, co-clustered mainly with p14/ARF has been reported to be dysregulated in gastric cancer, esophageal squamous cell carcinoma, and lung cancer. Lin et al. proved that its increased expression in NSCLC tissues was associated with higher TNM stage, advanced lymph-node metastasis, and poorer overall survival. Moreover, knockdown of it could inhibit cell proliferation, migration and invasion in vitro. [32]


 > Challenges and Perspectives Top


NSCLC has one of the highest morbidity and mortality rates of all malignant tumors. Intriguingly, as with other solid carcinomas, most of NSCLC related deaths are due to secondary organ metastases and ensuing complications. Activation of migration, invasion, and metastasis is a crucial characteristic of malignancy as one of the hallmark capabilities of NSCLC. Most studies investigating metastasis mechanisms focused on protein-coding genes. With the advances of high-throughput sequencing and gene expression profiling, lncRNAs were recently characterized as a class of ncRNAs that play crucial roles in tumor biology.

In this review, we provide a brief summary of the current understanding of lncRNAs in metastasis phenotypes of human NSCLC. Most of these referred lncRNAs promote or suppress NSCLC metastasis through modulation of EMT. However, there is much research still on the way toward a deeper understanding of regulation processes. Understanding the precise molecular mechanisms of these lncRNAs in the metastasis processes will be a critical step before exploring new strategies in future NSCLC therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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