title: OPCML is frequently methylated in human colorectal cancer and its restored expression reverses EMT via downregulation of smad signaling.
abstract: Emerging evidence has indicated that the expression of OPCML gene is frequently altered in a variety of cancers. We previously demonstrated that the OPCML gene is a target of epigenetic inactivation and its gene product exhibits tumor-suppressive properties. However, little is known regarding the effects and mechanisms of OPCML in colon cancer. We show that the loss or downregulation of OPCML is associated with its promoter hypermethylation. Methylation of the OPCML promoter was detected in all tumors and tumor-adjacent tissues, but lower methylation in normal colon tissues. The drug-induced release of epigenetic silencing was able to restore OPCML expression and the re-expression led to the suppression of cell growth. Furthermore, the increase in OPCML expression reversed a partial epithelial-to-mesenchymal (EMT)-like transition. Cell migration and invasiveness were also inhibited in response to OPCML upregulation. These actions were mediated through the inactivation of TGFβ-Smad signaling pathways. In addition, OPCML expression was associated with two upstream nuclear receptors (ERRa and RORa). Altogether, our study reveals OPCML as a potential tumor suppressor gene epigenetically silenced in colon cancer. Our study will help to elucidate the anti-invasive mechanisms of OPCML and establish new chemotherapeutic strategies for human colon cancer.
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China ; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Tang
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute Hong Kong, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Luo
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Peng
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China ; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Ren
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China ; Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute Hong Kong, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China.
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
keywords: OPCML; Tumor suppressor; cancer; methylation