MiR-449a inhibits colorectal cancer progression by targeting SATB2.

Xiaohua Sun,Jie Mao,Sanhong Liu,Mingliang Wang,Xianling Cong,Yu Tao,Zhanjie Liu,Pengfei Chen,Yufang Shi,Xiaoren Zhang,Cuifeng Li,Yu Zhan,Yingyong Hou,Yuhang Jiang,Jin Hu,Qi Wang,Da Fu,Xinwei Cao,Xi Chen,Lin Zhi ,Y Hu ,Yu‐Shui Ma ,Ryan Sun ,Cheng Cheng

doi:10.18632/oncotarget.10900

Abstract

miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.

Highlights

Colorectal cancer (CRC) is ranked the third most common cancer and the fourth leading cause of death among all human cancers worldwide, with 1.2 million cases identified every year [1, 2]
MiR-449a has been reported to act as a tumor suppressor, and its expression is downregulated in several cancers including ovarian, lung, bladder, prostate and gastric cancers [8,9,10]. miR-449a induces cell cycle arrest at G1 phase by directly targeting CDK6 and CDC25A, which leads to the inhibition of pRb-E2F1 activity in prostate cancer cells and breast cancer cells [11,12,13,14], and directly targets Bcl-2, histone deacetylase 1 (HDAC1) and Sirt1 to promote cell death
We report the existence of a negative feedback loop that maintains reduced levels of miR-449a and miR-34a and that directly promotes CRC cell growth and survival through upregulating a novel target: SATB2

Summary

Introduction

Colorectal cancer (CRC) is ranked the third most common cancer and the fourth leading cause of death among all human cancers worldwide, with 1.2 million cases identified every year [1, 2]. Some miRNAs function as oncogenes or tumor suppressors and are important in cancer development. MiR-449a has been reported to act as a tumor suppressor, and its expression is downregulated in several cancers including ovarian, lung, bladder, prostate and gastric cancers [8,9,10]. MiR-449a induces cell cycle arrest at G1 phase by directly targeting CDK6 and CDC25A, which leads to the inhibition of pRb-E2F1 activity in prostate cancer cells and breast cancer cells [11,12,13,14], and directly targets Bcl-2, HDAC1 and Sirt to promote cell death. The mechanism underlying the regulation of decreased miR-449a expression and tumor suppression in CRC remains largely unknown

Methods

Results

Conclusion