Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common solid tumors, and the fourth leading cause of cancer-related mortality worldwide [1]
We evaluated the effects of mortalin on angiogenesis in the three cell lines and found that the tube formation ability of mortalin-plasmidtransfected cells were significantly increased, whereas knockdown of mortalin resulted in the opposite effect (Figures 1A–D and Supplementary Figure S1)
The results revealed a reduction in the phosphorylation of many key components crucial to signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)/Akt (PI3K-p85, AKT1), mitogen-activated protein kinase (MAPK) (MEK1, MKK3/6), nuclear factor kB (NF-kB) (IKKb, IkBa, p65, p105/50), and Janus kinase–signal transducer and activator of transcription (JAKSTAT) (JAK1/2, STAT1)
Summary
Hepatocellular carcinoma (HCC) is one of the most common solid tumors, and the fourth leading cause of cancer-related mortality worldwide [1]. Hematogenous metastasis represents a major shift in HCC biology: tumor angiogenesis, which plays a critical role in providing oxygen and nutrients, is necessary for HCC growth, intrahepatic and extrahepatic metastasis, and postsurgical recurrence [3]. In addition to the curative therapies, resection, or transplantation (for the treatment of early-stage HCC, minority), antiangiogenesis strategies, such as sorafenib, have become the main approach for the treatment of advanced and recurrent HCC (which forms the majority of cases) [4]. The therapeutic effects of these treatments are less than satisfactory. This is largely due to angiogenesis and the development of sorafenib resistance [5, 6]. The identification of novel therapeutic strategies for HCC is a priority
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