MiR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression.

Ya-Ping Ye,Jun-Feng Qiu,Ting-Ting Li,Yan-Ru Chen,Wen-Ting Liao,Wen-Ting Wei,Li Liang,Chun-Cai Gu,Run-Wei Yang,Yong-Xia Wang,Jie Lin,Zhi-Yuan Xiao,Yan-Qing Ding,Ping Wu,Shu-Yang Wang,Hong-Li Jiao,Dan-Ling Deng

doi:10.18632/oncotarget.11016

Abstract

The development and progression of CRC are regarded as a complicated network and progressive event including genetic and/or epigenetic alterations. Recent researches revealed that MicroRNAs are biomarkers and regulators of CRC progression. Analyses of published microarray datasets revealed that miR-450b-5p was highly up-regulated in CRC tissues. In addition, high expression of miR-450b-5p was significantly associated with KRAS mutation. However, the role of miR-450b-5p in the progression of CRC remains unknown. Here, we sought to validate the expression of miR-450b-5p in CRC tissues and investigate the role and underlying mechanism of miR-450b-5p in the progression of CRC. The results revealed that miR-450b-5p was up-regulated in CRC tissues, high expression level of miR-450b-5p was positively associated with poor differentiation, advanced TNM classification and poor prognosis. Moreover, miR-450b-5p was especially high in KRAS-mutated cell lines and could be up-regulated by KRAS/AP-1 signaling. Functional validation revealed that overexpression of miR-450b-5p promoted cell proliferation and tumor growth while inhibited apoptosis of CRC cells. Furthermore, we demonstrated that miR-450b-5p directly bound the 3′-UTRs of SFRP2 and SIAH1, and activated Wnt/β-Catenin signaling. In conclusion, miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression. Collectively, our work helped to understand the precise role of miR-450b-5p in the progression of CRC, and might promote the development of new therapeutic strategies against CRC.

Highlights

Colorectal cancer (CRC) is one of the most commonly digestive malignant tumor worldwide and the incidence of which increases rapidly among different kinds of cancer in recent decades [1]
The results revealed that miR-450b-5p was up-regulated in CRC tissues, high expression level of miR-450b-5p was positively associated with poor differentiation, advanced TNM classification and poor prognosis
Further investigations revealed that miR-450b-5p directly bound the 3′-untranslated region (UTR) of SFRP2 and SIAH1, which function as regulators of Wnt/β-Catenin signaling, boosting the activation of Wnt/β-Catenin signaling, and promoting the progression of CRC

Summary

Introduction

Colorectal cancer (CRC) is one of the most commonly digestive malignant tumor worldwide and the incidence of which increases rapidly among different kinds of cancer in recent decades [1]. MiR-450b-5p has been shown to be associated with proliferation, differentiation as well as chemo-resistance of some cancer cells [26, 27], and our preliminary work and published microarray analysis indicated that the expression of miR-450b-5p was up-regulated, and it can induce activation of Wnt/βCatenin signaling in CRC. The role of miR-450b-5p in CRC progression and the molecular mechanisms about regulating the activation of Wnt/β-Catenin signaling are unclear.

Results

Conclusion