Upregulation of autophagy by hypoxia-inducible factor-1α promotes EMT and metastatic ability of CD133+ pancreatic cancer stem-like cells during intermittent hypoxia

• DOI: 10.3892/or.2014.3298
• Publication Date: 2014-07-02T07:00:00Z
• Authors: HAITAO ZHU; DONGQING WANG; LIRONG ZHANG; XIAODONG XIE; YINGYING WU; YANFANG LIU; GENBAO SHAO; ZHAOLIANG SU
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Up-Regulation; 3. Good health; Pancreatic Neoplasms; 03 medical and health sciences; Antigens, CD; Cell Movement; Cell Line, Tumor; Autophagy; Neoplastic Stem Cells; Humans; AC133 Antigen; Neoplasm Metastasis; Peptides; Glycoproteins

Epithelial-to-mesenchymal transition (EMT) facilitates the escape of pancreatic cancer cells from the primary tumor site, which is a key early event in metastasis. In the present study, we examined if intermittent hypoxia facilitates the invasiveness of human pancreatic cancer cell lines (Panc-1 and BxPC-3) by Transwell assay. We used western blotting and flow cytometry analysis to quantify stem-like cells in the migratory cells during intermittent hypoxia in the human pancreatic cancer cells. Under normoxia or intermittent hypoxia, the expression of autophagy-related proteins (LC3-II and Beclin), hypoxia-inducible factor-1α (HIF-1α) and EMT-related markers (E-cadherin, Vimentin and N-cadherin) was examined by western blotting. siRNA and the autophagic inhibitor were used to access the role of HIF-1α and autophagy in promoting metastasis and EMT. Under intermittent hypoxia, pancreatic cancer cells demonstrated enhanced invasive ability and enriched stem-like cells. The migratory cells displayed stem-like cell characteristics and elevated the expression of LC3-II and Beclin-1, HIF-1α, E-cadherin, Vimentin and N-cadherin under intermittent hypoxia conditions. Moreover, enhanced autophagy was induced by the elevated level of HIF-1α. The metastatic ability and EMT of pancreatic cancer stem cells was associated with HIF-1α and autophagy. This novel finding may indicate the specific role of HIF-1α and autophagy in promoting the metastatic ability of pancreatic cancer stem cells. Additionally, it emphasizes the importance of developing therapeutic strategies targeting cancer stem cells and autophagy to reduce metastasis.