Hepatic Stellate Cells Promote Intrahepatic Cholangiocarcinoma Progression Via NR4A2/osteopontin/Wnt Signaling Axis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 Mar 20

PMID 33742120

Citations 12

Authors

Chu-Yu Jing

Yi-Peng Fu

Cheng Zhou

Mei-Xia Zhang

Yong Yi

Jin-Long Huang

Wei Gan

Juan Zhang

Su-Su Zheng

Bo-Heng Zhang

Shuang-Jian Qiu

Affiliations

Soon will be listed here.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.

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