Abstract
Acquired resistance towards sorafenib treatment was found in HCC patients, which results in poor prognosis. To investigate the enhanced metastatic potential of sorafenib resistance cells, sorafenib-resistant (SorR) cell lines were established by long-term exposure of the HCC cells to the maximum tolerated dose of sorafenib. Cell proliferation assay and qPCR of ABC transporter genes (ABCC1-3) were first performed to confirm the resistance of cells. Migration and invasion assays, and immunoblotting analysis on the expression of epithelial to mesenchymal transition (EMT) regulatory proteins were performed to study the metastatic potential of SorR cells. The expression of CD44 and CD133 were studied by flow cytometry and the gene expressions of pluripotency factors were studied by qPCR to demonstrate the enrichment of cancer stem cells (CSCs) in SorR cells. Control (CTL) and SorR cells were also injected orthotopically to the livers of NOD-SCID mice to investigate the development of lung metastasis. Increased expressions of ABCC1-3 were found in SorR cells. Enhanced migratory and invasive abilities of SorR cells were observed. The changes in expression of EMT regulatory proteins demonstrated an activation of the EMT process in SorR cells. Enriched proportion of CD44+ and CD44+CD133+ cells were also observed in SorR cells. All (8/8) mice injected with SorR cells demonstrated lung metastasis whereas only 1/8 mouse injected with CTL cells showed lung metastasis. HCC cells with sorafenib resistance demonstrated a higher metastatic potential, which may be due to the activated EMT process. Enriched CSCs were also demonstrated in the sorafenib resistant cells. This study suggests that advanced HCC patients with acquired sorafenib resistance may have enhanced tumor growth or distant metastasis, which raises the concern of long-term sorafenib treatment in advanced HCC patients who have developed resistance of sorafenib.
Highlights
Hepatocellular carcinoma (HCC) is the fifth leading cancer in men and the seventh leading cancer in women with a total of 0.7 million new cases worldwide [1]
Recent reports on patients with long-term treatment of sorafenib demonstrated that only manageable adverse effects with mild-tomoderate in severity were reported in patients with advanced nonsmall-cell lung cancer [12], advanced renal cell carcinoma [13], and advanced HCC [14]
This study suggests that a higher metastatic potential of HCC cells might be developed in HCC patients with acquired sorafenib resistance, which brings out the concern of sorafenib treatment in advanced HCC patients
Summary
Hepatocellular carcinoma (HCC) is the fifth leading cancer in men and the seventh leading cancer in women with a total of 0.7 million new cases worldwide [1]. Enrichment of CD44+ and CD44+CD133+ subpopulations of CSCs and enhanced expression of pluripotency factors further suggested the possibility of tumor recurrence or metastasis caused by SorR cells. This study suggests that a higher metastatic potential of HCC cells might be developed in HCC patients with acquired sorafenib resistance, which brings out the concern of sorafenib treatment in advanced HCC patients.
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