Journal
PANCREAS
Volume 45, Issue 3, Pages 443-457Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPA.0000000000000460
Keywords
TERT; CD133; pancreatic cancer; EGFR
Categories
Funding
- NSC [101-2314-B-110-001-MY2, 101-2628-B-110-001-MY2]
- National Science Council, Taiwan, ROC [MOST 103-2314-B-037 -062]
- Kaohsiung Medical University, Kaohsiung, Taiwan [KMU-TP103G00, KMU-TP103G01]
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Objectives The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling. Methods The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo. Results AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion. Conclusion Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance.
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