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miR-204-5p expression in colorectal cancer: an autophagy-associated gene

Abstract

MicroRNAs (miRNAs) are important factors during tumorigenesis by affecting posttranscriptional gene expression. miRNA 204 (miR-204) is a miRNA frequently investigated in different types of cancers. According to literature, autophagy has dual roles in cancer, acting as both a tumor suppressor and cell survival agent. Also, the current data suggests that autophagy is activated in human colorectal cancer cells and enhances the aggressiveness of human colorectal cancer cells. So, our aim is to investigate potential effect of miR-204-5p on colorectal cancer by associating its expression with autophagy-related targets of miR-204-5p. This is the first miRNA study conducted on patients with colorectal cancer and healthy subjects and also to search the relation of miR-204-5p with clinicopathological factors and survival. Sixty-six patients with colorectal cancer and healthy subjects without any known chronic disease were enrolled into our study. Total miRNA was isolated from paraffin-embedded tissues of all patients’ cancerous and normal tissues, and healthy subjects. cDNAs were obtained from this miRNAs by reverse transcriptase method, and miR-204-5p relative expression levels were detected by qRT-PCR method. Patients were divided into two groups according to median relative expression levels of miR-204-5p, as low- and high-expression group. Relation of miR-204-5p with clinicopathological factors and overall survival was also investigated. Medians of miR-204-5p relative expression levels in cancerous and normal tissues of patients were found as 0.00235 and 0.00376, respectively. The difference between two groups was not statistically significant (p = 0.11). Nonetheless, median of miR-204-5p relative expression levels in healthy subjects were found as 0.00135, and the difference between patient with cancer and healthy subjects and between normal tissues of patients and healthy subjects were statistically significant (p = 0.021 and p = 0.0005, respectively). There were 32 patients (48.5 %) showing high expression and 34 patients (51.5 %) showing low expression according to miR-204-5p relative expression levels. There were no statistically significant relation between clinicopathologic features and miR-204-5p relative expression levels. We also investigated the relation between miR-204-5p relative expression levels and overall survival, and no statistically significant relation was found between them (p = 0.462). The absence of any significant difference between tumor and non-tumor samples, low sample size, and performance at just one center are the limitations of our study. In opposition to literature, miR-204-5p is overexpressed in colorectal cancer patients as compared with healthy subjects and this situation is not associated with clinicopathological factors and overall survival. This may be explained by the fact that miR-204-5p increases in colorectal cancer cases in order to inhibit increased activity of LC3B-II in autophagy and Bcl2 against apoptosis posttranscriptionally and to take role as tumor suppressor.

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References

  1. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137(6):1062–75.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.

    PubMed  Article  Google Scholar 

  3. Yoshimori T. Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun. 2004;313(2):453–8.

    CAS  PubMed  Article  Google Scholar 

  4. Shibutani ST, Tamotsu Y. A current perspective of autophagosome biogenesis. Cell Res. 2014;24(1):58–68.

    CAS  PubMed  Article  Google Scholar 

  5. Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 2007;67(20):9677–84.

    CAS  PubMed  Article  Google Scholar 

  6. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.

    CAS  PubMed  Article  Google Scholar 

  7. Waldman SA, Terzic A. Translating MicroRNA discovery into clinical biomarkers in cancer. JAMA. 2007;297(17):1923–5.

    CAS  PubMed  Article  Google Scholar 

  8. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    CAS  PubMed  Article  Google Scholar 

  9. Esquela-Kerscher A, Slack FJ. Oncomirs–microRNAs with a role in cancer. Nat Rev Cancer. 2006; 259–269.

  10. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma, JAMA. 2008; 425–436.

  11. Saadi JI, Plyler JR, Hima B, Suresh P, Sanjay B, Jennifer R, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and ınvasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS One. 2012;7(12):e52397.

    Article  Google Scholar 

  12. Li G, Luna C, Qiu J, Epstein DL, Gonzalez P. Role of miR-204-5p in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2011;52:2999–3007.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  13. Cui RR, Li SJ, Liu LJ, Yi L, Liang QH, et al. MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo. Cardiovasc Res. 2012;96:320–9.

    CAS  PubMed  Article  Google Scholar 

  14. Gong M, Ma J, Li M, Zhou M, Hock JM, et al. MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors. Neuro Oncol. 2012;14:1007–17.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  15. Chung TK, Lau TS, Cheung TH, Yim SF, Lo KW, et al. Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1. Int J Cancer. 2012;130:1036–45.

    CAS  PubMed  Article  Google Scholar 

  16. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 2003;113(1):25–36.

    CAS  PubMed  Article  Google Scholar 

  17. Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432(7014):226–30.

    CAS  PubMed  Article  Google Scholar 

  18. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316(5824):604–8.

    CAS  PubMed  Article  Google Scholar 

  19. He L, Thomson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–33.

    CAS  PubMed  Article  Google Scholar 

  20. Voorhoeve PM, le Sage C, Schrier M, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124(6):1169–81.

    CAS  PubMed  Article  Google Scholar 

  21. Johnson SM, Grosshans H, Shingara J. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–47.

    CAS  PubMed  Article  Google Scholar 

  22. Chao-Jie W, Zong-Guang Z, Ling W, Lie Y, Bin Z, Jun G, et al. Clinicopathological significance of microRNA-31, −143 and −145 expression in colorectal cancer. Dis Markers. 2009;26:27–34.

    Article  Google Scholar 

  23. Zhou T, Zhang G, Liu Z, Xia S, Tian H. Overexpression of miR-92a correlates with tumor metastasis and poor prognosis in patients with colorectal cancer. Int J Colorectal Dis. 2013;28:19–24.

    CAS  PubMed  Article  Google Scholar 

  24. Liu H, Du L, Wen Z, Yang Y, Li J, Wang L, et al. Up-regulation of miR-182 expression in colorectal cancer tissues and its prognostic value. Int J Colorectal Dis. doi:10.1007/s00384-013-1674-0.

  25. Zhou T, Zhang G-J, Zhou H, Xiao H-X, Li Y. Overexpression of microRNA-183 in human colorectal cancer and its clinical significance. Eur J Gastroenterol Hepatol 2014, 26 No 2.

  26. Zhang G, Xia S, Tian H, Liu Z, Zhou T. Clinical significance of miR-22 expression in patients with colorectal cancer. Med Oncol. 2012;29:3108–12.

    CAS  PubMed  Article  Google Scholar 

  27. Toiyama Y, Hur K, Tanaka K, Inoue Y, Kusunoki M, Boland CR, et al. Serum miR-200c is a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer. Ann Surg. 2013 (epub ahead print).

  28. Yu H, Gao G, Jiang L, Guo L, Lin M, Jiao X, et al. Decreased expression of miR-218 is associated with poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 2013;15;6(12):2904–11.

  29. Chen Z, Sangwan V, Banerjee S, Mackenzie T, Dudeja V, Li X, et al. miR-204-5p mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death. Mol Cancer. 2013;12(1):105.

    PubMed Central  PubMed  Article  Google Scholar 

  30. Ying Z, Li Y, Wu J, Zhu X, Yang Y, Tian H, et al. Loss of miR-204-5p expression enhances glioma migration and stem cell-like phenotype. Cancer Res. 2013;73(2):990–9.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  31. Sacconi A, Biagioni F, Canu V, Mori F, Di Benedetto A, Lorenzon L, et al. miR-204-5p targets Bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 2012;3:e423.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. Lee Y, Yang X, Huang Y, Fan H, Zhang Q, Wu Y, et al. Network modeling identifies molecular functions targeted by miR-204-5p to suppress head and neck tumor metastasis. PLoS Comput Biol. 2010;6(4):e1000730.

    PubMed Central  PubMed  Article  Google Scholar 

  33. Zheng H, Zhang X, Wang X, Sun B. Autophagy enhances the aggressiveness of human colorectal cancer cells and their ability to adapt to apoptotic stimulus. Cancer Biol Med. 2012;9:105–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Drullion C, Trégoat C, Lagarde V, Tan S, Gioia R, Priault M, et al. Apoptosis and autophagy have opposite roles on imatinib-induced K562 leukemia cell senescence. Cell Death Dis. 2012;3:e373.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  35. Xu D, Wang C, Shen X, Yu Y, Rui Y2, Zhang D, et al. Apoptotic block in colon cancer cells may be rectified by lentivirus mediated overexpression of caspase-9. Acta Gastroenterol Belg. 2013;76(4):372–80.

    CAS  PubMed  Google Scholar 

  36. Mikhaylova O, Stratton Y, Hal D, Kellner E, Ehmer B, Drew AF, et al. VHL-regulated miR-204-5p suppresses tumor growth through ınhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell. 2012;21(4):532–46.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. Wang X, Wang J, Ma H, Zhang J, Zhou X. Downregulation of miR-195 correlates with lymph node metastasis and poor prognosis in colorectal cancer. Med Oncol. 2012;29:919–27.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This study was performed with a grant taken from the Turkish Medical Oncology Society.

Conflicts of interest

The authors of this manuscript have no conflicts of interest to disclose. The authors have full control of all the primary data and agree to allow the journal to review the data if requested.

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Correspondence to Ahmet Taner Sümbül.

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Sümbül, A.T., Göğebakan, B., Ergün, S. et al. miR-204-5p expression in colorectal cancer: an autophagy-associated gene. Tumor Biol. 35, 12713–12719 (2014). https://doi.org/10.1007/s13277-014-2596-3

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  • DOI: https://doi.org/10.1007/s13277-014-2596-3

Keywords

  • Colorectal cancer
  • miR-204-5p
  • LC3B-II
  • Bcl2
  • Clinicopathological factors