miR-202 functions as a tumor suppressor in non-small cell lung cancer by targeting STAT3.

MicroRNAs (miRNAs) are a group of non-protein‑coding, short single-stranded RNAs, which are considered as promising molecular markers and therapeutic targets in several cancers. The present study explored the expression patterns and functional roles of miR‑202 in non‑small cell lung cancer (NSCLC). The expression levels of miR‑202 were determined in NSCLC tissues and cell lines using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The functional impact of miR‑202 overexpression on NSCLC cell viability, migration and invasion were evaluated using Cell Counting Kit‑8 reagent and Transwell migration and invasion assays, respectively. The molecular mechanism underlying the tumor suppressive roles of miR‑202 on NSCLC was examined using bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blot analysis. In addition, signal transducer and activator of transcription (STAT) 3 was overexpressed to investigate the impact on miR‑202‑mediated tumor suppression in NSCLC. The results indicated that miR‑202 was downregulated in NSCLC tissues and cell lines, and was associated with tumor node metastasis stage and lymph node metastasis. Exogenous miR‑202 expression reduced NSCLC cell viability, migration and invasion. Furthermore, STAT3 was identified as a direct target gene of miR‑202 in NSCLC. STAT3 overexpression improved miR‑202‑impaired cell viability, migration and invasion. In conclusion, the present study revealed novel anticancer effects induced by miR‑202 upregulation in NSCLC, and indicated that STAT3 may be a molecular target of miR‑202.

[1]  S. Ju,et al.  miRNA-202 in bone marrow stromal cells affects the growth and adhesion of multiple myeloma cells by regulating B cell-activating factor , 2016, Clinical and Experimental Medicine.

[2]  Q. Fan,et al.  MicroRNA-202 inhibits tumor progression by targeting LAMA1 in esophageal squamous cell carcinoma. , 2016, Biochemical and biophysical research communications.

[3]  X. Niu,et al.  MicroRNA-335 is downregulated in bladder cancer and inhibits cell growth, migration and invasion via targeting ROCK1. , 2016, Molecular medicine reports.

[4]  Guoliang Ma,et al.  Low expression of microRNA-202 is associated with the metastasis of esophageal squamous cell carcinoma. , 2016, Experimental and therapeutic medicine.

[5]  Y. Li,et al.  Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer , 2016, Cancer biology & therapy.

[6]  Robert A. Smith,et al.  MicroRNA-126 suppresses proliferation of undifferentiated (BRAF(V600E) and BRAF(WT)) thyroid carcinoma through targeting PIK3R2 gene and repressing PI3K-AKT proliferation-survival signalling pathway. , 2015, Experimental cell research.

[7]  Yanyun Li,et al.  MiR-202 promotes endometriosis by regulating SOX6 expression. , 2015, International journal of clinical and experimental medicine.

[8]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[9]  Shuo Zhang,et al.  MicroRNA-15a induces cell apoptosis and inhibits metastasis by targeting BCL2L2 in non-small cell lung cancer , 2015, Tumor Biology.

[10]  Qun Qian,et al.  MicroRNA-133a suppresses colorectal cancer cell invasion by targeting Fascin1 , 2014, Oncology letters.

[11]  Huanyu Hong,et al.  miR-202 suppresses proliferation and induces apoptosis of osteosarcoma cells by downregulating Gli2 , 2014, Molecular and Cellular Biochemistry.

[12]  Weina Li,et al.  Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer. , 2014, Biochemical and biophysical research communications.

[13]  Q. Ye,et al.  miR‐202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post‐transcriptionally , 2014, FEBS letters.

[14]  Xiaoming Hou,et al.  The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis , 2014, Journal of Molecular Histology.

[15]  Rafael Rosell,et al.  Genetics and biomarkers in personalisation of lung cancer treatment , 2013, The Lancet.

[16]  K. Rabe,et al.  Management of non-small-cell lung cancer: recent developments , 2013, The Lancet.

[17]  A. Cossu,et al.  Lung cancer epidemiology in North Sardinia, Italy , 2013, Multidisciplinary Respiratory Medicine.

[18]  W. Hung,et al.  STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells , 2013, British Journal of Cancer.

[19]  M. Ginsberg,et al.  Epidemiology of Lung Cancer , 2013, Seminars in Interventional Radiology.

[20]  J. Gimferrer,et al.  Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer , 2012, European Respiratory Journal.

[21]  Y. Li,et al.  Prognostic significance of STAT3 expression and its correlation with chemoresistance of non-small cell lung cancer cells. , 2012, Acta histochemica.

[22]  K. Wagner,et al.  The two faces of Janus kinases and their respective STATs in mammary gland development and cancer , 2011, Journal of carcinogenesis.

[23]  A. Nicholson,et al.  Non-small-cell lung cancer , 2011, The Lancet.

[24]  Hong-cheng Wang,et al.  [The expressions of STAT3, WWOX and c-myc in human non small cell lung cancer tissue and correlativity analysis]. , 2010, Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology.

[25]  Y. Akao,et al.  MicroRNAs and their therapeutic potential for human diseases: microRNAs, miR-143 and -145, function as anti-oncomirs and the application of chemically modified miR-143 as an anti-cancer drug. , 2010, Journal of pharmacological sciences.

[26]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[27]  K. Kelnar,et al.  Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. , 2010, Cancer research.

[28]  R. Kurzrock,et al.  Targeted therapy in non-small-cell lung cancer—is it becoming a reality? , 2010, Nature Reviews Clinical Oncology.

[29]  W. Dempke,et al.  Targeted therapies for non-small cell lung cancer. , 2010, Lung cancer.

[30]  C. Compton,et al.  The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the Future of TNM , 2010, Annals of Surgical Oncology.

[31]  A. Pesatori,et al.  MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer , 2010, Clinical Cancer Research.

[32]  George A Calin,et al.  Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  Andrea Ventura,et al.  MicroRNAs and Cancer: Short RNAs Go a Long Way , 2009, Cell.

[34]  Hongbing Shen,et al.  Genetic variants of miRNA sequences and non-small cell lung cancer survival. , 2008, The Journal of clinical investigation.

[35]  B. Leiby,et al.  Stat3 promotes metastatic progression of prostate cancer. , 2008, The American journal of pathology.

[36]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[37]  G. Tang,et al.  [Effects of STAT3 antisense oligonucleotide on proliferation and apoptosis of non-small cell lung cancer cell line A549]. , 2007, Ai zheng = Aizheng = Chinese journal of cancer.

[38]  Witold Zatonski,et al.  Lung cancer mortality at ages 35-54 in the European Union: ecological study of evolving tobacco epidemics , 2005, BMJ : British Medical Journal.

[39]  R. Shiekhattar,et al.  MicroRNA biogenesis and cancer. , 2005, Cancer Research.

[40]  Zhenfa Zhang,et al.  [STAT3 and ras-MAPK signal transduction pathway in non-small cell lung cancer]. , 2005, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[41]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[42]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[43]  Fredrik Nyberg,et al.  Contribution of environmental factors to cancer risk. , 2003, British medical bulletin.

[44]  R. Matthay,et al.  Epidemiology, etiology, and prevention of lung cancer. , 2002, Clinics in chest medicine.

[45]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[46]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[47]  Jianru Xiao,et al.  TGF-β1-induced miR-202 mediates drug resistance by inhibiting apoptosis in human osteosarcoma , 2015, Journal of Cancer Research and Clinical Oncology.

[48]  S. Srivastava,et al.  STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells. , 2015, Carcinogenesis.

[49]  P. Fan,et al.  Plasmid-based STAT3-siRNA efficiently inhibits breast tumor growth and metastasis in mice. , 2011, Neoplasma.