Voltage-dependent calcium channel α2δ1 subunit is a specific candidate marker for identifying gastric cancer stem cells
Received 23 December 2018
Accepted for publication 3 April 2019
Published 23 May 2019 Volume 2019:11 Pages 4707—4718
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Beicheng Sun
Ziran Zhang,1 Wei Zhao,2 Xiaoting Lin,1 Jing Gao,1 Zhiqian Zhang,2 Lin Shen1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, People’s Republic of China
Purpose: Cancer stem cells (CSCs) are a subpopulation of cancer cells with self-renewal property and responsible for tumor malignancy, progression and drug resistance. Researches on CSC-specific markers in gastric cancer remain limited. Our current study explored the expression of voltage-dependent calcium channel α2δ1 subunit and the potential of using α2δ1 as a CSC marker in gastric cancer. We also compared the specificity of α2δ1 and CD44 in identifying gastric cancer stem cells (GCSCs).
Materials and methods: Expression of α2δ1 was analyzed in gastric cancer cell lines, patient-derived xenograft (PDX) models and clinical samples of malignant ascites of gastric cancer patients. α2δ1+, gastric cancer cells were isolated from gastric cancer cell lines. CSC properties of α2δ1+, gastric cancer cells were then verified by subsequent tests both in vitro and in vivo.
Results: The expression level of α2δ1 was found to differ drastically among gastric cancer cell lines, PDX models and clinical samples of malignant ascites. α2δ1+, gastric cancer cells sorted from HGC-27 and SGC-7901 cell lines demonstrated significant self-renewal properties, including tumorigenic capacity, sphere-formation capacity and asymmetric differentiation potential. Knockdown of α2δ1 in α2δ1+, HGC-27 significantly inhibited CSC properties and rendered HGC-27 more sensitive to chemotherapy. Flow cytometry showed that α2δ1+, gastric cancer cells accounted for a small fraction of CD44+, gastric cancer cells. Isolated CD44+,α2δ1+, HGC-27 cells displayed more significant tumorigenic capacity and sphere-forming capacity compared with their CD44+,α2δ1−, counterparts.
Conclusion: α2δ1+, gastric cancer cells possessed CSC properties. α2δ1 could be a proper marker in identifying GCSCs with superior specificity than CD44. The combination of α2δ1 and CD44 could be used to identify GCSCs with improved accuracy. Knockdown of α2δ1 combined with chemotherapy displayed higher therapeutic efficacy on gastric cancer cells, suggesting that α2δ1 could be a potential target for anticancer treatment.
Keywords: α2δ1, gastric cancer, cancer stem cell, HGC-27
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