HIF-2α regulates CDCP1 to promote PKCδ-mediated migration in hepatocellular carcinoma

Overexpression of CUB domain-containing protein 1 (CDCP1), a transmembrane glycoprotein and major substrate of Src family kinases (SFKs), always indicates unfavorable outcomes in various cancers. The characteristics of CDCP1 in hepatocellular carcinoma (HCC) have not been assessed. Most recently, CDCP1 was identified as a specific target gene of HIF-2 alpha in clear cell renal carcinoma (CC-RCC). However, considering the role of HIF-2 alpha in the progression of HCC is highly controversial, it is necessary to figure out whether HIF-2 alpha and CDCP1 play a significant part in the metastasis of HCC. Our results showed that HIF-2 alpha and CDCP1 were both induced by hypoxia, and the activation of CDCP1 was HIF-2 alpha dependent. CDCP1 was governed by HIF-2 alpha at mRNA and protein levels in HCC cell lines. Moreover, knocking down of HIF-2 alpha not only inhibited cell invasion but also impaired the expression of Tyr(311) phosphorylation of protein kinase C delta (PKC delta) which is a downstream factor of CDCP1 and has been reported to induce malignant migration in various tumors. Analysis of human HCC samples showed a negative correlation of CDCP1 expression with disease-free survival, and CDCP1 was an independent prognostic factors of disease-free survival. Taken together, these data demonstrated that HIF-2 alpha could promote HCC cell migration by regulating CDCP1, and targeting HIF-2 alpha-CDCP1-PKC delta pathway might be effective to inhibit HCC metastasis.