Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear.MethodsTissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down.ResultsHypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo.ConclusionsHypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC
We show that supervillin promotes extracellular signal-regulated kinase (ERK)/p38 signal transduction as a downstream of the Ras homolog gene family (RhoA)/ROCK signaling pathway, enhances the expression of epithelial-mesenchymal transition (EMT) genes in HCC cells, and accelerates metastasis of HCC in vivo
A higher expression of supervillin was significantly correlated with the presence of portal vein tumor thrombus (PVTT) (χ2 = 15.44, p < 0.01), occurrence of serosal infiltration (χ2 = 12.64, p < 0.01), and distant metastasis (χ2 = 9.79, p < 0.01), which indicated the potential important roles of supervillin played in HCC metastasis (Table 1)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Investigation of the mechanisms driving tumor EMT and cell migration/invasion is essential for the development of treatments for malignancies in HCC patients. Several molecular players and pathways contribute to the modulation of the actin cytoskeleton, which affect EMT and metastasis during hypoxia [17]. The effects of hypoxia on Rho GTPases and their activation vary greatly, which in turn control actin dynamics directly or by activating downstream signaling modules leading to activation of the RhoA/ROCK/cofilin or MLC/MLCK signal-transduction pathways [21,22,23]. The ERK or p38 signaling pathways play a key role in cancer development by stimulating cell proliferation and metastasis
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