Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma

Ye Yang; Ming Jin; Yi Dai; Wenqi Shan; Shuai Chen; Rong Cai; Haojun Yang; Liming Tang; Lei Li

doi:10.3389/fonc.2021.687871

Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma

Front Oncol. 2021 Jul 29:11:687871. doi: 10.3389/fonc.2021.687871. eCollection 2021.

Authors

Ye Yang¹, Ming Jin¹, Yi Dai², Wenqi Shan¹, Shuai Chen², Rong Cai¹, Haojun Yang², Liming Tang², Lei Li¹

Affiliations

¹ Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
² Department of General Surgery, The Affiliated Changzhou No. 2 Hospital of Nanjing Medical University, Changzhou, China.

Abstract

Objectives: To reveal the mechanisms of the effects of mortalin in hepatocellular carcinoma (HCC) and to identify potential novel chemical inhibitors of mortalin.

Materials and methods: For the experiments, three HCC cell lines (HepG2 cells, Hep3B cells, and sorafenib-resistant HuH7 cells) and xenografted nude mice were used. For the clinical analysis, cohorts of 126 patients with HCC and 34 patients with advanced recurrent HCC receiving sorafenib therapy were examined.

Results: Mortalin regulated the phosphorylation-modification of cancer-associated proteins and also regulated angiogenesis-related secretome to cause angiogenesis and sorafenib resistance in HCC cells. Two molecular mechanisms were identified. In one, via phosphatidylinositol 3-kinase (PI3K)/Akt signaling, mortalin regulated nuclear factor (NF)-κB and then activated vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to neovascularization. In the other, mortalin regulated PI3K/Akt/β-catenin and then regulated Bcl-XL and Bcl-2, leading to the antiapoptosis effect of HCC. Treatment of the sorafenib-resistant xenografts with sorafenib in combination with mortalin knockdown facilitated the sorafenib-mediated inhibition of tumor growth and angiogenesis and increased apoptosis. Mortalin was a potential risk factor for HCC, predicting poor prognosis and sorafenib resistance. Finally, we showed that caffeic acid (C₉H₈O₄) could bind to and induce the ubiquitination-mediated degradation of mortalin, which in turn blocked the abovementioned signaling pathways, leading to the inhibition of angiogenesis and the reversal of sorafenib resistance.

Conclusions: Mortalin, which regulates the phosphorylation of cancer-associated proteins, caused angiogenesis and sorafenib resistance, and was a competitive risk factor for HCC. Caffeic acid can therefore be considered a novel chemical inhibitor that targets the action of mortalin and a potential treatment for HCC.

Keywords: angiogenesis and sorafenib resistance; hepatocellular carcinoma; mortalin; proteome phosphorylated-modification; targeted intervention.