Tumor suppressor activity of miR-451: Identification of CARF as a new target

Ling Li,Zeenia Kaul,Renu Wadhwa,Jia Wang,Yue Yu,Ran Gao,Sunil C Kaul,Rajkumar S Kalra,Zhenya Zhang

doi:10.1038/s41598-017-18559-5

Abstract

microRNAs (miRs) have recently emerged as small non-coding regulators of gene expression. We performed a loss-of-function screening by recruiting retrovirus mediated arbitrary manipulation of genome coupled with escape of cells from 5-Aza-2′-deoxycytidine (5-Aza-dC)-induced senescence. miRNA pool from cells that emerged from 5-Aza-dC-induced senescence was subjected to miR-microarray analysis with respect to the untreated control. We identified miR-451 as one of the upregulated miRs and characterized its functional relevance to drug resistance, cell growth, tumor suppressor proteins p53 and pRb, and stress response. We report that miR-451 caused growth arrest in cells leading to their resistance to 5-Aza-dC-induced senescence. Decrease in cyclin D1, CDK4 and phosphorylated pRB supported the growth arrest in miR-451 transfected cells. We demonstrate that Collaborator of ARF (CARF) protein is a new target of miR-451 that intermediates its function in tumor suppressor and stress signaling.

Highlights

Cancer known as malignant neoplasm is a group of diseases involving abnormal cell growth and is extremely complex to understand and treat
Consistent with other reports, we found that all cancer cells possessed low level (~2–6 fold) of expression of miR-451 as compared to the normal cells (Fig. 1)
It has been established that Collaborator of ARF (CARF) is essential for cell survival; its knockdown causes apoptosis

Summary

Introduction

Cancer known as malignant neoplasm is a group of diseases involving abnormal cell growth and is extremely complex to understand and treat. Downregulation of miR-451 has been reported in a variety of tumors including glioma[8,9,10,11], breast carcinoma[12], gastrointestinal carcinoma[13], non-small cell lung carcinoma (NSCLC)[14,15,16,17], hepatoma[18,19,20,21], nasopharyngeal[22], esophageal[23,24], bladder[25], osteosarcoma[26,27], epithelial ovarian[28], renal[29] and thyroid[30] carcinomas. It was shown to correlate with clinical stages of tumor including metastasis and poor response to neoadjuvant chemotherapy and recurrence[26,27]. Transfection of the MCF-7/DOX-resistant cells with miR-451 sensitized them to DOX suggesting its implication for treatment of drug resistant cancer cells[12]

Methods

Results

Conclusion