Abstract
Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson’s correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is a highly malignant tumor with very poor prognosis
Compared with parental cell line, we found that USP22 and ABCC1 was highly expressed in sorafenib resistant cells
Our results revealed the positive correlation among USP22, SIRT1, and ABCC1 expression that were observed in all 6 HCC cell lines
Summary
Hepatocellular carcinoma (HCC) is a highly malignant tumor with very poor prognosis. It is the fourth leading cause of cancer mortality worldwide and accounts for>700,000 deaths every year. Hepatocellular carcinoma (HCC) is a highly malignant tumor with very poor prognosis. It is the fourth leading cause of cancer mortality worldwide and accounts for. Recommended treatment modalities are curative therapies (e.g., surgical resection, local ablation therapy, and liver transplantation) at early stage, transarterial chemoembolization (TACE) at intermediate stage, and systemic therapy at advanced stage (characterized by major vascular invasion or extrahepatic metastasis). Many HCC patients experience tumor progression to advanced stage following curative therapy or TACE. Such patients are often recommended to receive systemic therapy, e.g., molecular target therapy or immune checkpoint inhibitors. HCC patients often discontinue sorafenib treatment because of the appearance of serious adverse effects, or resumption of tumor progression resulting from development of drug resistance [4]. To improve outcomes of such HCC patients, we need to elucidate the mechanism of sorafenib resistance with a purpose of developing novel compounds that overcome the resistance
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