Abstract
Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
Highlights
The globally cancer statistics of 2018 show that liver cancer is the sixth most commonly diagnosed form of cancer, and a fourth cause of cancer-related deaths worldwide [1]
A previous study reported that miR-486-3p inhibits cell proliferation and induces apoptosis, it was downregulated in sorafenib-resistant hepatocellular carcinoma (HCC) cell lines by up-regulating FGFR4 and Epidermal growth factor receptor (EGFR) activity [67]
Yeh et al showed that galectin-1 is elevated in sorafenib-resistant HCC cells, both in vitro and in vivo, promoting tumor metastasis and increasing tumor invasion, suggesting that galectin-1 plays a role in downstream regulation of the AKT/mTOR/HIF-1 signaling pathway [113]
Summary
The globally cancer statistics of 2018 show that liver cancer is the sixth most commonly diagnosed form of cancer, and a fourth cause of cancer-related deaths worldwide [1]. A previous Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial confirmed that the drug was safe and efficacious in patients with advanced HCC These similar results were corroborated by findings in Asia-Pacific clinical trials [5, 6], in which. Previous studies have shown that the drug activates c-Jun, Akt pathway, epidermal growth factor receptor (EGFR), cancer stem cells enrichment, epithelialmesenchymal transition (EMT) enhancement and reduces autophagy. Other factors, such as dysregulation of miRNAs and lncRNAs in HCC have been implicated in sorafenib resistance [9, 14]. We sought to clarify the underlying mechanism of sorafenib resistance, its relationship with the hypoxia microenvironment and the effect of targeting HIFs on sorafenib resistance in hepatocellular carcinoma
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