Int J Med Sci 2021; 18(14):3112-3124. doi:10.7150/ijms.60610

Research Paper

HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma

Suhong Xia1,2*, Jingwen Wu1,2*, Wangdong Zhou1,2, Mingyu Zhang1,2, Kai Zhao1,2, Dean Tian1,2, Jingmei Liu1,2✉, Jiazhi Liao1,2✉

1. Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
2. Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
* These authors contributed equally to this work.

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Citation:
Xia S, Wu J, Zhou W, Zhang M, Zhao K, Tian D, Liu J, Liao J. HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma. Int J Med Sci 2021; 18(14):3112-3124. doi:10.7150/ijms.60610. Available from https://www.medsci.org/v18p3112.htm

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Abstract

Histidine-rich calcium binding protein (HRC) is markedly overexpressed in hepatocellular carcinoma (HCC) and is significantly correlated with metastasis. Anoikis resistance and endoplasmic reticulum (ER) stress may have a critical effect on survival before metastasis. However, the potential functions of HRC in anoikis resistance in HCC remain unknown. Here, we uncovered the clinical value of HRC and its functional significance on anoikis in HCC. The positive expression of HRC was observably correlated with tumor size, tumor encapsulation, and tumor-node-metastasis (TNM) stage. The expression of HRC increased in HCC cells cultured in suspension. HRC enhanced the anoikis resistance of HCC, and promoted the HCC metastasis in vivo. Mechanistically, the anoikis resistance was probably dependent on endoplasmic reticulum stress. Modulating HRC level changed the ERS to affect anoikis resistance by acting protein kinase RNA-like ER kinase (PERK)-eIF2a-ATF4-CHOP signaling axis. In conclusion, we define HRC as a novel candidate oncogene involved in anoikis resistance and HCC metastasis, and provide a new potential therapeutic target for HCC.

Keywords: hepatocellular carcinoma, metastasis, HRC, endoplasmic reticulum stress, anoikis resistance