Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent
Zhifeng Ning1,2,5, Hua Zhu8, Feifei Li2,5, Qing Liu2,5, Gefei Liu6, Tao Tan8, Bo Zhang8, Shaobin Chen4, Guanwu Li7, Dongyang Huang6, Stephen J. Meltzer9 and Hao Zhang2,3,5
1 Laboratory for Translational Oncology basic medicine college, Hubei University of Science and Technology, Xianning, Hubei province, China
2 Department of Biotherapy and Gastrointestinal Medical Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
3 Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
4 Department of Thoracic Surgery, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
5 Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
6 Department of Cell Biology, Shantou University Medical College, Shantou, Guangdong, China
7 Department of Biochemistry, Shantou University Medical College, Shantou, Guangdong, China
8 Department of Surgery, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, OH, USA
9 Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Correspondence:
Hao Zhang, email:
Keywords: microRNA, miR-31, p21, esophageal squamous cell cancer, personalized medicine
Received: March 27, 2014 Accepted: October 08, 2014 Published: October 09, 2014
Abstract
microRNA regulation network is important for the cancer genetic heterogeneity. Relative to the increasing numbers of microRNA’s targets identified, upstream regulatory mechanisms that control functional microRNAs are less well-documented. Here, we investigated the function of miR-31, a pleiotropically-acting microRNA, in esophageal squamous cell cancer (ESCC). We demonstrated that miR-31 only exerted tumor-suppressive effects in TE-7 ESCC cells, but not in TE-1 ESCC cells, although both of these cell lines harbor inactive p53. Interestingly, TE-1 cells highly expressed p21, while p21 levels were virtually undetectable in TE-7 cells, suggesting a p21-dependent mechanism of miR-31-mediated tumor suppression. Accordingly, knockdown of p21 in TE-1 cells reversed the tumor suppressive actions of miR-31. In patient ESCC specimens, real-time RT-PCR analysis revealed that expression of E2F2 and STK40, two known miR-31 target oncogenes, was negatively correlated with the expression of miR-31 in a p21-dependent manner, supporting the conclusion that miR-31 only downregulates its target oncogenes when p21 levels are low. Collectively, these data suggest a novel mechanism through which the tumor-suppressive effect of miR-31 is p21-dependent. In addition, we speculate that delivery of miR-31 could provide therapeutic benefit in the personalized management of a subgroup of ESCC patients with p21-deficient tumors.
