miR-506 inhibits cell proliferation and invasion by targeting TET family in colorectal cancer

Document Type : Original Article


1 Department of Gastroenterology, The Hunan Provincial People’s Hospital, Changsha, China

2 Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China


Objective(s): Ten-eleven translocation (TET) family members have been shown to be involved in the development of many tumors. However, the biological role of the TET family and its mechanism of action in colorectal carcinogenesis and progression remain poorly understood.
Materials and Methods:We measured the expression levels of TET family members in colorectal cancer (CRC) specimens, in the corresponding normal tissues and in cell lines using quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Both the protein function and the protein-independent role of TETs were investigated by cell viability assays and cell invasion assays using                  in vitro and in vivo models.
Results: We found that all three TET genes were strongly up-regulated at the transcript level in CRC samples compared to matched normal tissues. The same results were observed in colorectal cancer cell lines. Knockdown of TETs by shTET1/2/3 showed that TET family members inhibited CRC growth and metastasis. We showed that TET family member degradation by miR-506 inhibits cell proliferation and invasion in colorectal cancer.
Conclusion: Through this study, we advance our understanding of the expression levels TETs and miR-506 in CRC and further clarify the internal regulatory mechanism of miR-506 by targeting TET during CRC processes. These findings may contribute to a novel avenue for researching and developing targeted therapies for CRC.


1. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011; 333:1303-1307.
2. Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 2011; 9:193-204.
3. Chen Q, Chen Y, Bian C, Fujiki R, Yu X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 2013; 493:561-564.
4. Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A, et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell 2013; 49:645-656.
5. Malcovati L, Papaemmanuil E, Ambaglio I, Elena C, Galli A, Della Porta MG, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 2014; 124:1513-1521.
6. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers.  N Engl J Med 2009; 360:2289-2301.
7. Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009; 23:905-911.
8. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009; 114:144-147.
9. Yamazaki J, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Shen L, et al. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 2012; 7:201-207.
10. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011; 118:4509-4518.
11. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 2013; 32:663-669.
12. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012; 150:1135-1146.
13. Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, et al. TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene 2015; 34:4168-4176.
14. Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S, et al. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA 2013; 110:9920-9925.
15. Huang H, Jiang X, Li Z, Li Y, Song CX, He C, et al. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci U S A 2013; 110:11994-1199.
16. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136:215-233.
17. Slack FJ, Weidhaas JB. MicroRNA in cancer prognosis. N Engl J Med 2008; 359:2720-2722.
18. Leskela S, Leandro-Garcia LJ, Mendiola M, Barriuso J, Inglada-Perez L, Munoz I, et al. The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer 2011; 18:85-95.
19. Frank D, Gantenberg J, Boomgaarden I, Kuhn C, Will R, Jarr KU, et al. MicroRNA-20a inhibits stress-induced cardiomyocyte apoptosis involving its novel target Egln3/PHD3. J Mol Cell Cardiol 2012; 52:711-717.
20. Dill H, Linder B, Fehr A, Fischer U. Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes Dev 2012; 26:25-30.
21. Ye F, Tang H, Liu Q, Xie X, Wu M, Liu X, et al. miR-200b as a prognostic factor in breast cancer targets multiple members of RAB family. J Translat Med 2014; 12:17.
22. Song C, Liu LZ, Pei XQ, Liu X, Yang L, Ye F, et al. miR-200c inhibits breast cancer proliferation by targeting KRAS. Oncotarget 2015; ;6:34968-34978
23. Wen SY, Lin Y, Yu YQ, Cao SJ, Zhang R, Yang XM,    et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene 2015; 34:717-725.
24. Sun Y, Hu L, Zheng H, Bagnoli M, Guo Y, Rupaimoole R, et al. MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer. J Pathol 2015; 235:25-36.
25. Zhang Z, Ma J, Luan G, Kang L, Su Y, He Y, et al. MiR-506 suppresses tumor proliferation and invasion by targeting FOXQ1 in nasopharyngeal carcinoma. PloS One 2015; 10:e0122851.
26. Deng L, Liu H. MicroRNA-506 suppresses growth and metastasis of oral squamous cell carcinoma via targeting GATA6. Int J Clin Exp Med 2015; 8:1862-1870.
27. Yu F, Lv M, Li D, Cai H, Ma L, Luo Q, et al. MiR-506 over-expression inhibits proliferation and metastasis of breast cancer cells. Med Sci Monit 2015; 21:1687-1692.
28. Deng J, Lei W, Xiang X, Zhang L, Yu F, Chen J, et al. MicroRNA-506 inhibits gastric cancer proliferation and invasion by directly targeting Yap1. Tumour Biol  2015; 36:6823-6831.