Abstract
Hepatocellular carcinoma (HCC) is a prevalent problem worldwide. Chemotherapy, especially cisplatin (CDDP)-based systemic chemotherapy, is the best option for advanced liver cancer. However, CDDP resistance is becoming common and hindering the clinical application of CDDP. Meanwhile, no consensus has been reached regarding the chemotherapeutic use of vasohibin 2 (VASH2), which promotes the angiogenesis and proliferation of cancer cells. In this work, a tissue microarray was used to observe VASH2 and its possible role in cancer treatment. Results showed that VASH2 was highly expressed in HCC tissues and was significantly correlated with cancer differentiation. To further investigate the efficacy and mechanism of the combination of VASH2 with anti-cancer drugs in liver cancer cells, we stably built VASH2 overexpression and knockdown cell lines. We found that VASH2 can influence the CDDP sensitivity and that the cell overexpression of VASH2 had a higher cell viability and lower apoptosis rate after CDDP exposure. We also observed that VASH2 overexpression downregulated wild-type p53, as well as suppressed the expression of the pro-apoptotic protein BCL2-associated X protein (Bax) and cleaved caspase-3 (CC-3) after treatment by CDDP. Conversely, the knockdown of VASH2 significantly inhibited these effects. In an in vivo chemosensitivity study, nude mice were subcutaneously injected with tumor cells and received CDDP treatment through intraperitoneal administration every 3 days. We found that VASH2 knockdown markedly limited the tumor growth and enhanced the CDDP toxicity and apoptosis of tumor cells. Western blot analysis revealed that tumor cells with downregulated VASH2 had a higher expression of wild-type p53, Bax, and CC-3 than control cells. Overall, our results indicated the novel roles of VASH2 in the chemoresistance of hepatocarcinoma cells to CDDP and suggested that VASH2 may be a promising anticancer target.
Highlights
Vasohibin 2 (VASH2) belongs to the VASH family along with vasohibin 1 (VASH1)
Apart from surgical treatment, systematic chemotherapy plays an important role in Hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC [32]
Chemotherapy is ineffective for HCC treatment because of the inherent chemoresistance
Summary
VASH2, which was first described by Shibuya et al [1], is located on chromosome 1q32.3 and composed of 355 amino acid residues. The overall homology between human VASH1 and VASH2 is 52.5% at the amino acid level [2]. In contrast to VASH1, VASH2 promotes angiogenesis, and highly expresses in HCC cells and tissues and promotes HCC cell proliferation and tumor growth [8,9,10]. These results indicate that the function of VASH2 is beyond angiogenesis promotion, i.e., it plays a significant role in other aspects of tumor metabolism
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