Abstract
BackgroundPrimary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC.MethodsHepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment.ResultsThe HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib.ConclusionsA novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC.
Highlights
Primary liver cancer is a lethal malignancy with a high mortality worldwide
High mobility group box 1 (HMGB1) is upregulated in response to sorafenib treatment in HepG2 cells The effects of sorafenib on the expression of HMGB1 were explored in the hepatocellular carcinoma (HCC) cell line HepG2
HMGB1 translocates from the mitochondria to the cytoplasm following sorafenib treatment To further examine the relationship between HMGB1 and sorafenib resistance, the HMGB1 distribution in HepG2 cells exposed to sorafenib was examined
Summary
Primary liver cancer is a lethal malignancy with a high mortality worldwide. Sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). Primary carcinoma of the liver is the second most common cause of death from cancer worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of all liver cancers. In patients with advanced HCC, sorafenib (Nexavar), which is a molecular-targeted therapy, significantly helps prolong the median survival time by approximately 3 months. Only approximately 30% of advanced HCC patients benefit from sorafenib, and acquired resistance often develops within 6 months [4]. The extremely high sorafenib resistance rate has raised great concern worldwide, and the epithelial-mesenchymal transition (EMT), cancer stem cells, and tumour microenvironment may be involved [5]. The mechanisms underlying primary and acquired sorafenib resistance in HCC remain unclear. No other chemotherapeutic agent yields the results obtained with sorafenib; understanding and overcoming sorafenib chemoresistance is critical for improving survival in advanced HCC populations [6]
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