Expression of MiR200a, miR93, Metastasis-related Gene RECK and MMP2/MMP9 in Human Cervical Carcinoma - Relationship with Prognosis

  • Wang, Ling (Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Jilin University) ;
  • Wang, Qiang (Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Jilin University) ;
  • Li, He-Lian (Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Jilin University) ;
  • Han, Li-Ying (Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Jilin University)
  • Published : 2013.03.30


Aim and Background: Cervical cancer remains the third most common cancer in women globally after breast and colorectal cancer. Well-characterized biomarkers are necessary for early diagnosis and to predict metastatic progression and effective therapy. MiRNAs can regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or degradation in tumor cells. The present study was conducted to assess expression of miR93, miR200a, RECK, MMP2, MMP9 in invasive cervical carcinoma, and analyze their clinical significance. Method: A total of 116 patients with invasive cervical carcinoma and 100 patients undergoing hysterectomy for benign lesions were retrospectively examined. Quantitative real-time PCR was performed to determine expression of miR93 and miR200a while RECK, MMP2, MMP9 and MVD were assessed by immunohistochemical staining. Results: Cervical carcinoma patients demonstrated up-regulation of miR-93, miR-200a, MMP2 and MMP9, with down-regulation of RECK as compared to benign lesion tissues. RECK was significantly inversely related to invasion and lymphatic metastasis. The 5-year survival rate for patients with strong RECK expression was significantly higher than that with weakly expressing tumors. Conclusion: MiR-93 and miR-200a are associated with metastasis and invasion of cervical carcinoma. Thus together with RECK they are potential prognostic markers for cervical carcinoma. RECK cooperating with MMP2, MMP9 expression is a significant prognostic factor correlated with long-term survival for patients with invasive cervical carcinoma.



  1. Arbyn M, Andersson K, Bergeron C, et al (2011). Cervical cytology biobanks as a resource for molecular epidemiology. Methods Mol Biol, 675, 279-98.
  2. Bartel DP (2009). MicroRNAs, target recognition and regulatory functions. Cell, 136, 215-33.
  3. Chang CK, Hung WC, Chang HC (2008). The Kazal motifs of RECK protein inhibit MMP-9 secretion and activity and reduce metastasis of lung cancer cells in vitro and in vivo. J Cell Mol Med, 12, 12-6.
  4. Cong N, Du P, Zhang A, et al (2013). Downregulated microRNA-200a promotes EMT and tumor growth through the wnt/$\beta$-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma. Oncol Rep, 10, 3892-7.
  5. Curran S, Murray GI (2000). Matrix metalloproteinases, molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer, 36, 1621-30
  6. Dai Y, Xia W, Song T, et al (2013). MicroRNA-200b is overexpressed in endometrial adenocarcinomas and enhances MMP2 activity by downregulating TIMP2 in human endometrial cancer cell line HEC-1A cells. Nucleic Acid Ther, 23, 29-34.
  7. Denny Lynette (2012). Cervical cancer, prevention and treatment. Discov Med, 14, 125-11.
  8. Eissa S, Ali-Labib R, Swellam M, et al (2007). Noninvasive diagnosis of bladder cancer by detection of matrix metalloproteinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) in urine. Eur Urol, 52, 1388-96.
  9. Fang L, Deng Z, Shatseva T, et al (2011). MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-${\beta}8$. Oncogene, 30, 806-21.
  10. Figueira RC, Gomes LR, Neto JS, et al (2009). Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential. BMC Cancer, 9, 20-5.
  11. Liu S, Patel SH, Ginestier C, et al (2012). MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet, 8, e1002751.
  12. Kim VN, Han J, Siomi MC (2009). Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol, 10, 126-39.
  13. Kodate M, Kasai T, Hashimoto H, et al (1997). Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. Pathol Int, 47, 461-9.
  14. Lee JH, Welch DR (1997). Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res, 57, 2384-7.
  15. Liabakk NB, Talbot I, Smith RA, et al (1996). Matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) type IV collagenase in colorectal cancer. Cancer Res, 56, 190-6.
  16. Lim LP, Lau NC, Garrett-Engele P, et al (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature, 433, 769-73.
  17. Long NK, Kato K, Yamashita T, et al (2008). Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas. Oral Oncol, 44, 1052-8.
  18. Lu J, Getz G, Miska EA, et al (2005). MicroRNA expression profiles classify human cancers. Nature, 435, 834-8.
  19. Lui WO, Pourmand N, Patterson BK, Fire A (2007). Patterns of known and novel small RNAs in human cervical cancer. Cancer Res, 67, 6031-43.
  20. Ma D, Zhang YY, Guo YL, Li ZJ, Geng L (2012). Profiling of microRNA-mRNA reveals roles of microRNAs in cervical cancer. Chin Med J, 125, 4270-76.
  21. Mori T, Moriuchi R, Okazaki E, et al (2007). Tgat oncoprotein functions as a inhibitor of RECK by association of the unique C-terminal region. Biochem Biophys Res Commun, 355, 937-43.
  22. Namwat N, Puetkasichonpasutha J, Loilome W, et al (2011). Downregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is associated with enhanced expression of matrix metalloproteinases and cholangiocarcinoma metastases. J Gastroenterol, 46, 664-75.
  23. Oh J, Takahashi R, Kondo S, et al (2001). The membrane anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell, 107, 789-800.
  24. Pereira PM, Marques JP, Soares AR, Carreto L, Santos MA (2010). MicroRNA expression variability in human cervical tissues. PLoS One, 5, e11780.
  25. Perry SV (2001). Vertebrate tropomyosin, distribution, properties and function. J Muscle Res Cell Motil, 22, 5-49.
  26. Rasheed SA, Teo CR, Beillard EJ, Voorhoeve M, Casey PJ (2013). MicroRNA-182 and microRNA-200a control G-protein subunit alpha-13 (GNA13) expression and cell invasion synergistically in prostate cancer. Cells J Biol Chem, 10, 1074-7.
  27. Rodriguez-Paredes M, Esteller M (2011). Cancer epigenetics reaches mainstream oncology. Nat Med, 17, 330-9.
  28. Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, et al (2008). MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol, 26, 462-9.
  29. Reis ST, Leite KR, Piovesan LF, et al (2012). Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer. BMC Urol, 12, 18-23.
  30. Takagi S, Simizu S, Osada H (2009). RECK negatively regulates matrix metalloproteinase-9 transcription. Cancer Res, 69, 1502-8.
  31. Miki T, Shamma A, Kitajima S, et al (2010). TThe ${\beta}1$-integrindependent function of RECK in physiologic and tumor angiogenesis. Mol Cancer Res, 8, 665-76.
  32. TChung TT, Yeh CB, Li YC, et al (2012). Effect of RECK gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features. Plos one, 7, e33517.
  33. Toi M, Ishigaki S, Tominaga T(1998). Metalloproteinases and tissue inhibitors of metallo-proteinases. Breast Cancer Res Treat, 52, 113-24.
  34. Wang X, Tang S, Le SY, et al(2008). Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One, 3, e2557.
  35. Welch DR, Steeg PS, Rinker-Schaeffer CW (2000). Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. Breast Cancer Res, 2, 408-16.
  36. Wu L, Belasco JG (2008). Let me count the ways, mechanisms of gene regulation by miRNAs and siRNAs. Mol Cell, 29, 1-7.
  37. Yang J, Mani SA, Donaher JL, et al (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117, 927-39.
  38. Yang L, Parkin DM, Li L, Chen Y (2003). Time trends in cancer mortality in China, 1987-1999. Int J Cancer, 106, 771-83.
  39. Yu SJ, Hu JY, Kuang XY, et al (2013). MicroRNA-200a Promotes Anoikis Resistance and Metastasis by Targeting YAP1 in Human Breast Cancer. Clin Cancer Res, 10, 1158-63.
  40. Yu XF, Zou J, Bao ZJ, Dong J (2011). miR-93 suppresses proliferation and colony formation of human colon cancer stem cells. World J Gastroenterol, 17, 4711-7.
  41. Zhang B, Zhang J, Xu ZY, Xie HL (2009). Expression of RECK and matrix metalloproteinase-2 in ameloblastoma. BMC Cancer, 9, 427-35.
  42. Zhang C, Ling Y, Zhang C, et al (2012). The silencing of RECK gene is associated with promoter hypermethylation and poor survival in hepatocellular carcinoma. Int J Biol Sci, 8, 451-8.

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