Effects of human chorion- and placenta-derived mesenchymal stem cells on the proliferation, migration, and invasion of cholangiocarcinoma cell lines

Cholangiocarcinoma (CCA) is aggressive cancer that originates from damaged epithelial cells of the bile duct. The incidence and mortality rate of CCA is increasing worldwide due to its aggressiveness, late diagnosis, and limited treatment options. Previous studies have revealed that mesenchymal stem cells (MSCs), are multipotent stem cells, that can release various cytokines to activate a series of tumor signaling pathways to influence the development of tumor cells. However, the role of human chorion-and placenta-derived MSCs (CH-MSCs and PL-MSCs) in CCA progression has not been clarified. This study aimed to examine the effects and underlying molecular mechanisms of the conditioned media from the human chorion- and placenta-derived MSCs (CH-CM and PL-CM) in three CCA cell lines, namely KKU100, KKU213A, and KKU213B. The results demonstrated that CH-CM and PL-CM inhibited the proliferation of CCA cell lines analyzed by MTT assay and colony formation assay as well as can induce CCA apoptosis as assessed by Annexin V/PI analysis. Moreover, JC-1 staining showed that CH-CM and PL-CM induced loss of mitochondrial membrane potential (∆Ψm) in CCA cell lines. Mechanistically, CH-CM and PL-CM could inhibit JAK2/STAT3 signaling, resulting in suppression of Bcl-2 anti-apoptotic protein expression and increasing the expression of pro-apoptotic protein including Bax, cleaved caspase 3, and cleaved PARP, leading to promoting apoptosis in CCA cell lines. Furthermore, CH-CM and PL-CM had inhibitory effects on cell migration and invasion as analyzed by wound healing assay and Transwell assay, respectively. In addition, CH-CM and PL-CM were able to inhibit the PI3K/AKT signaling pathway involved in the downregulation of the ZEB1 and ZEB2 and also MMP-2, resulting in induction of E-cadherin expression and inhibition of EMT markers including N-cadherin and vimentin and leading to inhibiting cell migration and invasion in CCA cells. In conclusion, these studies suggest that CH-CM and PL-CM have anti-cancer potential effects on CCA cell lines through suppressing the JAK2/STAT3 and PI3K/AKT signaling pathways and could provide a promising additional and/or alternative therapeutic target for CCA patients.