Association of miR-193b Down-regulation and miR-196a up-Regulation with Clinicopathological Features and Prognosis in Gastric Cancer

  • Mu, Yong-Ping (Department of Clinical Laboratory Center, The Affiliated People's Hospital of Inner Mongolia Medical University) ;
  • Tang, Song (School of Environment and Sustainability, University of Saskatchewan) ;
  • Sun, Wen-Jie (Department of Global Health and Environmental Sciences, School of Public Health and Tropical Medicine) ;
  • Gao, Wei-Min (The Institute of Environmental and Human Health, Texas Tech University) ;
  • Wang, Mao (Department of Preventive Medicine, School of Public Health, Sun Yat-sen University) ;
  • Su, Xiu-Lan (Clinical Medicine Research Center, The Affiliated People’s Hospital of Inner Mongolia Medical University)
  • Published : 2014.11.06


Dysregulated expression of microRNAs (miRNAs) has been shown to be closely associated with tumor development, progression, and carcinogenesis. However, their clinical implications for gastric cancer remain elusive. To investigate the hypothesis that genome-wide alternations of miRNAs differentiate gastric cancer tissues from those matched adjacent non-tumor tissues (ANTTs), miRNA arrays were employed to examine miRNA expression profiles for the 5-pair discovery stage, and the quantitative real-time polymerase chain reaction (qRTPCR) was applied to validate candidate miRNAs for 48-pair validation stage. Furthermore, the relationship between altered miRNA and clinicopathological features and prognosis of gastric cancer was explored. Among a total of 1,146 miRNAs analyzed, 16 miRNAs were found to be significantly different expressed in tissues from gastric cancer compared to ANTTs (p<0.05). qRT-PCR further confirmed the variation in expression of miR-193b and miR-196a in the validation stage. Down-expression of miR-193b was significantly correlated with Lauren type, differentiation, UICC stage, invasion, and metastasis of gastric cancer (p<0.05), while over-expression of miR-196a was significantly associated with poor differentiation (p=0.022). Moreover, binary logistic regression analysis demonstrated that the UICC stage was a significant risk factor for down-expression of miR-193b (adjusted OR=8.69; 95%CI=1.06-56.91; p=0.043). Additionally, Kaplan-Meier survival curves indicated that patients with a high fold-change of down-regulated miR-193b had a significantly shorter survival time (n=19; median survival=29 months) compared to patients with a low fold-change of down-regulated miR-193b (n=29; median survival=54 months) (p=0.001). Overall survival time of patients with a low fold-change of up-regulated miR-196a (n=27; median survival=52 months) was significantly longer than that of patients with a high fold-change of up-regulated miR-196a (n=21; median survival=46 months) (p=0.003). Hence, miR-193b and miR-196a may be applied as novel and promising prognostic markers in gastric cancer.


Supported by : Inner Mongolia Medical University, National Natural Science Foundation of Chian


  1. Cho WC (2010). MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol, 42, 1273-81.
  2. Bandres E, Bitarte N, Arias F, et al (2009). microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res, 15, 2281-90.
  3. Bindea G, Mlecnik B, Hackl H, et al (2009). ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics, 25, 1091-3.
  4. Calin GA, Sevignani C, Dumitru CD, et al (2004). Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA, 101, 2999-3004.
  5. Camargo MC, Goto Y, Zabaleta J, et al (2012). Sex hormones, hormonal interventions, and gastric cancer risk: a metaanalysis. Cancer Epidemiol Biomarkers Prev, 21, 20-38.
  6. Chen G, Shen ZL, Wang L, et al (2013). Hsa-miR-181a-5p expression and effects on cell proliferation in gastric cancer. Asian Pac J Cancer Prev, 14, 3871-5.
  7. Chen J, Feilotter HE, Pare GC, et al (2010). MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma. Am J Pathol, 176, 2520-9.
  8. Chun-Zhi Z, Lei H, An-Ling Z, et al (2010). MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer, 10, 367.
  9. Crew KD, Neugut AI (2006). Epidemiology of gastric cancer. World J Gastroenterol, 12, 354-62.
  10. Guan Y, Mizoguchi M, Yoshimoto K, et al (2010). MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance. Clin Cancer Res, 16, 4289-97.
  11. Guo J, Miao Y, Xiao B, et al (2009). Differential expression of microRNA species in human gastric cancer versus nontumorous tissues. J Gastroenterol Hepatol, 24, 652-7.
  12. Guo L, Zhao Y, Yang S, et al (2013). Genome-wide screen for aberrantly expressed miRNAs reveals miRNA profile signature in breast cancer. Mol Biol Rep, 40, 2175-86.
  13. Inoue T, Iinuma H, Ogawa E, et al (2012). Clinicopathological and prognostic significance of microRNA-107 and its relationship to DICER1 mRNA expression in gastric cancer. Oncol Rep, 27, 1759-64.
  14. Hou T, Ou J, Zhao X, et al (2014). MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27. Br J Cancer, 110, 1260-8.
  15. Hsu SD, Lin FM, Wu WY, et al (2011). miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res, 39, D163-9.
  16. Hu H, Li S, Liu J, et al (2012). MicroRNA-193b modulates proliferation, migration, and invasion of non-small cell lung cancer cells. Acta Biochim Biophys Sin, 44, 424-30.
  17. Jemal A, Center MM, DeSantis C, et al (2010). Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev, 19, 1893-907.
  18. Jia W, Wu Y, Zhang Q, et al (2013). Identification of four serum microRNAs from a genome-wide serum microRNA expression profile as potential non-invasive biomarkers for endometrioid endometrial cancer. Oncol Lett, 6, 261-7.
  19. Kozinn SI, Harty NJ, Delong JM, et al (2013). MicroRNA profile to predict gemcitabine resistance in bladder carcinoma cell lines. Genes Cancer, 4, 61-9.
  20. Kozomara A, Griffiths-Jones S (2011). miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res, 39, 152-7.
  21. Kutmon M, Kelder T, Mandaviya P, et al (2013). CyTargetLinker: a cytoscape app to integrate regulatory interactions in network analysis. PLoS One, 8, 82160.
  22. Lee Y, Ahn C, Han J, et al (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature, 425, 415-9.
  23. Link A, Kupcinskas J, Wex T, et al (2012). Macro-role of microRNA in gastric cancer. Dig Dis, 30, 255-67.
  24. Li X, Luo F, Li Q, et al (2011). Identification of new aberrantly expressed miRNAs in intestinal-type gastric cancer and its clinical significance. Oncol Rep, 26, 1431-9.
  25. Li XF, Yan PJ, Shao ZM (2009). Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene, 28, 3937-48.
  26. Liang S, He L, Zhao X, et al (2011). MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One, 6, 18409.
  27. Liu M, Du Y, Gao J, et al (2013). Aberrant expression miR-196a is associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells. Pancreas, 42, 1169-81.
  28. Liu R, Zhang C, Hu Z, et al (2011). A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer, 47, 784-91.
  29. Liu XH, Lu KH, Wang KM, et al (2012). MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer, 12, 348.
  30. Ma GJ, Gu RM, Zhu M, et al (2013). Plasma post-operative miR-21 expression in the prognosis of gastric cancers. Asian Pac J Cancer Prev, 14, 7551-4.
  31. Mattick JS, Makunin IV (2006). Non-coding RNA. Hum Mol Genet, 15, 17-29.
  32. Montalban E, Mattugini N, Ciarapica R, et al (2014). MiR-21 is an Ngf-modulated microRNA That Supports Ngf Signaling and Regulates Neuronal Degeneration in PC12 Cells. Neuromolecular Med, 16, 415-30.
  33. Presneau N, Eskandarpour M, Shemais T, et al (2013). MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer, 108, 964-72.
  34. Nishida N, Mimori K, Fabbri M, et al (2011). MicroRNA-125a-5p is an independent prognostic factor in gastric cancer and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab. Clin Cancer Res, 17, 2725-33.
  35. Otsubo T, Akiyama Y, Hashimoto Y, et al (2011). MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One, 6, 16617.
  36. Parkin DM (2001). Global cancer statistics in the year 2000. Lancet Oncol, 2, 533-43.
  37. Peng S, Kuang Z, Sheng C, et al (2010). Association of microRNA-196a-2 gene polymorphism with gastric cancer risk in a Chinese population. Dig Dis Sci, 55, 2288-93.
  38. Ratert N, Meyer HA, Jung M, et al (2013). miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome. J Mol Diagn, 15, 695-705.
  39. Saito K, Inagaki K, Kamimoto T, et al (2013). MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer. PLoS One, 8, 71480.
  40. Severino P, Bruggemann H, Andreghetto FM, et al (2013). MicroRNA expression profile in head and neck cancer: HOX-cluster embedded microRNA-196a and microRNA-10b dysregulation implicated in cell proliferation. BMC Cancer, 13, 533.
  41. Shannon P, Markiel A, Ozier O, et al (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 13, 2498-504.
  42. Siegel R, Naishadham D, Jemal A (2012). Cancer statistics, 2012. CA Cancer J Clin, 62, 10-29.
  43. Shen J, Wang A, Wang Q, et al (2013a). Exploration of genomewide circulating microRNA in hepatocellular carcinoma: MiR-483-5p as a potential biomarker. Cancer Epidemiol Biomarkers Prev, 22, 2364-73.
  44. Shen L, Shan YS, Hu HM, et al (2013b). Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol, 14, 535-47.
  45. Shin VY, Jin H, Ng EK, et al (2011). NF-kappaB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Carcinogenesis, 32, 240-5.
  46. Sobin LH, Fleming ID (1997). TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer, 80, 1803-4.<1803::AID-CNCR16>3.0.CO;2-9
  47. Solcia E, Kloppel G, Sobin LH, et al Histological typing of endocrine tumours; World Health Organization, Germany, Berlin ; New York : Springer, c2000.
  48. Sun M, Liu XH, Li JH, et al (2012). MiR-196a is upregulated in gastric cancer and promotes cell proliferation by downregulating p27 (kip1). Mol Cancer Ther, 11, 842-52.
  49. Tang S, Allagadda V, Chibli H, et al (2013a). Comparison of cytotoxicity and expression of metal regulatory genes in zebrafish (Danio rerio) liver cells exposed to cadmium sulfate, zinc sulfate and quantum dots. Metallomics, 5, 1411-22.
  50. Tang S, Cai Q, Chibli H, et al (2013b). Cadmium sulfate and CdTe-quantum dots alter DNA repair in zebrafish (Danio rerio) liver cells. Toxicol Appl Pharmacol, 272, 443-52.
  51. Tsai KW, Liao YL, Wu CW, et al (2012). Aberrant expression of miR-196a in gastric cancers and correlation with recurrence. Genes Chromosomes Cancer, 51, 394-401.
  52. Wang HJ, Ruan HJ, He XJ, et al (2010). MicroRNA-101 is downregulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer, 46, 2295-303.
  53. Tsuchiya S, Okuno Y, Tsujimoto G (2006). MicroRNA: biogenetic and functional mechanisms and involvements in cell differentiation and cancer. J Pharmacol Sci, 101, 267-70.
  54. Ueda T, Volinia S, Okumura H, et al (2010). Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol, 11, 136-46.
  55. Wan HY, Guo LM, Liu T, et al (2010). Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma. Mol Cancer, 9, 16.
  56. Wang Z, Wang J, Yang Y, et al (2013). Loss of has-miR-337-3p expression is associated with lymph node metastasis of human gastric cancer. J Exp Clin Cancer Res, 32, 76.
  57. Wu JH, Yao YL, Gu T, et al (2014a). MiR-421 regulates apoptosis of BGC-823 gastric cancer cells by targeting caspase-3. Asian Pac J Cancer Prev, 15, 5463-8.
  58. Wu K, Yang L, Li C, et al (2014b). MicroRNA-146a enhances Helicobacter pylori induced cell apoptosis in human gastric cancer epithelial cells. Asian Pac J Cancer Prev, 15, 5583-6.
  59. Xi Y, Nakajima G, Gavin E, et al (2007). Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. RNA, 13, 1668-74.
  60. Xu C, Liu S, Fu H, et al (2010). MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. Eur J Cancer, 46, 2828-36.
  61. Yanaihara N, Caplen N, Bowman E, et al (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9, 189-98.
  62. Zha R, Guo W, Zhang Z, et al (2014). Genome-wide screening identified that Mir-134 acts as a metastasis suppressor by targeting integrin beta1 in hepatocellular carcinoma. PLoS One, 9, 87665.
  63. Yang L (2006). Incidence and mortality of gastric cancer in China. World J Gastroenterol, 12, 17-20.
  64. Yang Y, Li H, Hou S, et al (2013). The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS One, 8, 65309.
  65. Yin Y, Li J, Chen S, et al (2012). MicroRNAs as Diagnostic Biomarkers in Gastric Cancer. Int J Mol Sci, 13, 12544-55.
  66. Zhong Q, Wang T, Lu P, et al (2014). miR-193b promotes cell proliferation by targeting Smad3 in human glioma. J Neurosci Res, 92, 619-26.

Cited by

  1. Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer vol.16, pp.1, 2015,
  2. MicroRNAs May Serve as Emerging Molecular Biomarkers for Diagnosis and Prognostic Assessment or as Targets for Therapy in Gastric Cancer vol.16, pp.12, 2015,
  3. Network Analysis of microRNAs, Genes and their Regulation in Mantle Cell Lymphoma vol.16, pp.2, 2015,
  4. miR-193b acts as a cisplatin sensitizer via the caspase-3-dependent pathway in HCC chemotherapy vol.34, pp.1, 2015,
  5. MicroRNA-199a-3p suppresses glioma cell proliferation by regulating the AKT/mTOR signaling pathway vol.36, pp.9, 2015,
  6. MiR-193b promotes autophagy and non-apoptotic cell death in oesophageal cancer cells vol.16, pp.1, 2016,
  7. Identification of miR-30b as an oncogene in renal cell carcinoma vol.15, pp.4, 2017,
  8. MicroRNA-196a as a Potential Diagnostic Biomarker for Esophageal Squamous Cell Carcinoma vol.35, pp.2, 2017,
  9. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer vol.17, pp.6, 2016,
  10. Deregulation of miR-193b affects the growth of colon cancer cells via transforming growth factor-β and regulation of the SMAD3 pathway vol.13, pp.4, 2017,
  11. miR-193: A new weapon against cancer pp.00219541, 2019,