Open AccessHigh glucose‐ROS conditions enhance the progression in cholangiocarcinoma via upregulation of MAN2A2 and CHD8
Author(s) -
Thonsri Unchalee,
Wongkham Sopit,
Wongkham Chaisiri,
Hino Shinjiro,
Nakao Mitsuyoshi,
Roytrakul Sittiruk,
Koga Tomoaki,
Seubwai Wunchana
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14719
Subject(s) - downregulation and upregulation , gene knockdown , tumor progression , cancer research , reactive oxygen species , biology , cell growth , microbiology and biotechnology , chemistry , cancer , biochemistry , apoptosis , gene , genetics
Abstract Diabetes is a major risk factor in the development and progression of several cancers including cholangiocarcinoma (CCA). However, the molecular mechanism by which hyperglycemia potentiates progression of CCA is not clearly understood. Here, we showed that a high glucose condition significantly increased reactive oxygen species (ROS) production and promoted aggressive phenotypes of CCA cells, including proliferation and migration activities. Mannosidase alpha class 2a member 2 (MAN2A2), was upregulated at both mRNA and protein levels in a high glucose‐ and ROS‐dependent manner. In addition, cell proliferation and migration were significantly reduced by MAN2A2 knockdown. Based on our proteome and in silico analyses, we further found that chromodomain helicase DNA‐binding protein 8 ( CHD8 ) was induced by ROS signaling and regulated MAN2A2 expression. Overexpression of CHD8 increased MAN2A2 expression, while CHD8 knockdown dramatically reduced proliferation and migration as well as MAN2A2 expression in CCA cells. Moreover, both MAN2A2 and CHD8 were highly expressed with positive correlation in CCA tumor tissues. Collectively, these data suggested that high glucose conditions promote CCA progression through ROS‐mediated upregulation of MAN2A2 and CHD8 . Thus, glucose metabolism is a promising therapeutic target to control tumor progression in patients with CCA and diabetes.