Frontiers in Oncology (Jul 2021)

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
https://doi.org/10.3389/fonc.2021.687871
Journal volume & issue
Vol. 11

Abstract

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ObjectivesTo reveal the mechanisms of the effects of mortalin in hepatocellular carcinoma (HCC) and to identify potential novel chemical inhibitors of mortalin.Materials and MethodsFor 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.ResultsMortalin 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.ConclusionsMortalin, 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.

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