Feedback circuitry via let-7c between lncRNA CCAT1 and c-Myc is involved in cigarette smoke extract-induced malignant transformation of HBE cells.

Lu Lu,Fei Luo,Qizhan Liu,Jiachun Lu,Hong Qi,Chao Chen,Min Ling,Ping Yang,Quanyong Xiang,Qianlei Yang,Hui Xu,Yu Qin,Qian Bian,Junchao Xue,Xinlu Liu

doi:10.18632/oncotarget.15195

Abstract

Cigarette smoking is a primary risk factor for the development of lung cancer, which is regarded as the leading cause of cancer-related deaths. The process of malignant transformation of cells, however, is complex and elusive. The present study investigated the roles of an lncRNA, CCAT1, and a transcriptional factor, c-Myc, in human bronchial epithelial (HBE) cell transformation induced by cigarette smoke extract. With acute and chronic treatment of HBE cells, cigarette smoke extract induced increases of CCAT1 and c-Myc levels and decreases of levels of let-7c, a microRNA. Down-regulation of c-Myc reduced the degree of malignancy and the invasion/migration capacity of HBE cells transformed by cigarette smoke extract. ChIP assays established that c-Myc, increased by cigarette smoke extract, binds to the promoter of CCAT1, activating its transcription. Further, let-7c suppressed the expression of c-Myc through binding to its 3′-UTR. In turn, CCAT1 promoted the accumulation of c-Myc through binding to let-7c and decreasing free let-7c, which influenced the neoplastic capacity of HBE cells transformed by cigarette smoke extract. These results indicate that a positive feedback loop ensures expression of cigarette smoke extract-induced CCAT1 and c-Myc via let-7c, which is involved in cigarette smoke extract-induced malignant transformation of HBE cells. Thus, the present research establishes a new mechanism for the reciprocal regulation between CCAT1 and c-Myc and provides an understanding of cigarette smoke extract-induced lung carcinogenesis.

Highlights

The globalization of tobacco use began centuries ago, the public health response to the consequences that it has caused is less than 50 years old [1]
These results indicate that cigarette smoke extract (CSE) induces increases of c-Myc levels, which enhance neoplastic activity in the CSE-induced malignant transformation of human bronchial epithelial (HBE) cells
To explore the mechanism for c-Myc regulation of CCAT1, Chromatin immunoprecipitation (ChIP) assays were performed for HBE cells exposed to CSE

Summary

Introduction

The globalization of tobacco use began centuries ago, the public health response to the consequences that it has caused is less than 50 years old [1]. Exposure to tobacco is primarily associated with cigarette smoke, which contains carcinogens that cause lung cancers [2, 3]. An aggressive and heterogeneous disease caused mainly by smoking [4], results in more than 1 million deaths annually [5]. The association between lung cancer and cigarette smoke has been studied for several decades, the tumorigenic process caused by cigarette smoke remains largely unclear. The c-Myc protein, often overexpressed in tumors, is essential for various cellular functions and is associated with poor cancer outcomes [7, 8]. It is essential to understand the molecular networks involved, in particular, whether c-Myc participates in the tumorigenic process caused by cigarette smoke

Methods

Results

Conclusion