title: The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+breast cancer stem cells.
abstract: The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147+cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147+cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147+BCSCs was enhanced compared with that in differentiated adherent progeny of CD147+BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147+BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147+BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147+BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147+BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Lv
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: 2 Biotecan Medical Diagnostics Co. Ltd., Zhangjiang Center for Translational Medicine, Shanghai, People's Republic of China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Juliang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 2 Biotecan Medical Diagnostics Co. Ltd., Zhangjiang Center for Translational Medicine, Shanghai, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhao
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: He
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Meng
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: 3 Department of Orthopaedic, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 4 Institute of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, People's Republic of China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Jianghao
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1 Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D051926:Basigin / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000502:physiology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000032:analysis / Q000502:physiology*
chemical_list: C497886:BSG protein, human; C493557:SLC34A2 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D051926:Basigin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer stem cells; CD147; PI3K/AKT pathway; SLC34A2; SOX2; stem cell-like phenotypes