Tumor Biology

, Volume 37, Issue 2, pp 1651–1662 | Cite as

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

  • Manqing Cao
  • Junrong Gao
  • Hongyuan Zhou
  • Jiafei Huang
  • Abin You
  • Zhigui Guo
  • Feng Fang
  • Wei Zhang
  • Tianqiang Song
  • Ti Zhang
Research Article


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-2α in clear cell renal carcinoma (CC-RCC). However, considering the role of HIF-2α in the progression of HCC is highly controversial, it is necessary to figure out whether HIF-2α and CDCP1 play a significant part in the metastasis of HCC. Our results showed that HIF-2α and CDCP1 were both induced by hypoxia, and the activation of CDCP1 was HIF-2α dependent. CDCP1 was governed by HIF-2α at mRNA and protein levels in HCC cell lines. Moreover, knocking down of HIF-2α not only inhibited cell invasion but also impaired the expression of Tyr311 phosphorylation of protein kinase Cδ (PKCδ) 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-2α could promote HCC cell migration by regulating CDCP1, and targeting HIF-2α-CDCP1-PKCδ pathway might be effective to inhibit HCC metastasis.


HIF-2α CDCP1 PKCδ Hepatocellular carcinoma Metastasis 



We thank Prof. Ning Zhang (the vice president of Tianjin Medical University, PhD of the Medical College of Johns Hopkins University) for experimental support. This work was supported by the National Natural Science Foundation of China (No.81372635; No.81101871 and No.81201644) and Major Program of National Natural Science Foundation of Tianjin (No. 11JCZDJC18800).

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Manqing Cao
    • 1
  • Junrong Gao
    • 2
  • Hongyuan Zhou
    • 1
  • Jiafei Huang
    • 1
  • Abin You
    • 1
  • Zhigui Guo
    • 1
  • Feng Fang
    • 1
  • Wei Zhang
    • 1
  • Tianqiang Song
    • 1
  • Ti Zhang
    • 1
  1. 1.Department of Hepatobiliary Surgery, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and TherapyTianjin Medical University Cancer Institute and HospitalHexi DistrictPeople’s Republic of China
  2. 2.Academy of Medical ImageTianjin Medical UniversityTianjinPeople’s Republic of China

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