MicroRNA-645 is an oncogenic regulator in colon cancer

S T Guo,C C Jiang,H Hondermarck,X Y Li,Y F Wang,C Y Wang,J Wang,X D Zhang,R H Yang,R F Thorne,X Y Guo,L Jin,F H Wang

doi:10.1038/oncsis.2017.37

S T Guo, C C Jiang + Show 11 more

Open Access

https://doi.org/10.1038/oncsis.2017.37

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Abstract

Despite advances in early diagnosis and the development of molecularly targeted therapy, curative treatment of colon cancer once it has metastasized is yet to be accomplished. This is closely associated with deregulated CRC cell proliferation and resistance to apoptosis. Here we reveal that upregulation of microRNA-645 (miR-645) through DNA copy number gain is responsible for enhanced proliferation and resistance to apoptosis in colon cancer. MiR-645 was upregulated in most colon cancer tissues related to adjacent normal mucosa. This appeared to be associated with amplification of a section of chromosome 20q13.13, where miR-645 is located. Inhibition of miR-645 reduced proliferation and enhanced sensitivity to apoptosis triggered by the chemotherapeutic drugs 5-fluorouracil and cisplatin in CRC cells, and retarded colon cancer xenograft growth. Conversely, overexpression of miR-645 in normal colon epithelial cells enhanced proliferation and triggered anchorage-independent cell growth. Although SRY-related HMG-box 30 (SOX30) was identified as a miR-645 target, its expression was only partially affected by miR-645, suggesting that miR-645 is a fine-tuning mechanism of SOX30 expression. Moreover, overexpression of SOX30 only moderately inhibited promotion of CRC cell proliferation by miR-645, indicating that miR-645 may have more targets that contribute to its pro-proliferation effect in colon cancer. Together, this study reveals that miR-645 can regulate oncogenesis in colon cancer with SOX30 being one of its targets.

Highlights

Colon cancer is among the most deadly cancers and has a high incidence rate.[1,2] Despite recent advances in early diagnosis and the development of molecularly targeted therapeutic approaches, the survival of metastatic colon cancer patients remains disappointing.[3]
We show that SRY-related HMG-box 30 (SOX30) is targeted by miR-645, its expression is only moderately affected by the levels of miR-645 expression, and that it is only partially responsible for the oncogenic effect of miR-645 on CRC cells
The data are presented as average fold changes of miR-645 level in CRC tissues normalized to their corresponding controls. *P o0.05, Student's t-test. (c) qPCR analysis showing that miR-645 is upregulated in the majority of colon cancers

Summary

INTRODUCTION

Colon cancer is among the most deadly cancers and has a high incidence rate.[1,2] Despite recent advances in early diagnosis and the development of molecularly targeted therapeutic approaches, the survival of metastatic colon cancer patients remains disappointing.[3]. Regulation of protein coding gene expression by miRs is sequence specific and occurs mostly through binding of miRs to the 3′-UTR (untranslated region) regions of their target This functions to either target the transcripts for degradation, or to block the transcript from being translated.[10,11] The functional significance and target selectivity is highly specific to each miR, and the expression status and function of miRs can be critically dependent on the tissue and cell type involved.[12]. We show that SOX30 is targeted by miR-645, its expression is only moderately affected by the levels of miR-645 expression, and that it is only partially responsible for the oncogenic effect of miR-645 on CRC cells

RESULTS

DISCUSSION

MATERIALS AND METHODS