ABSTRACT
Mounting evidence has shown that side population (SP) cells are enriched for cancer stem cells (CSCs) responsible for cancer malignancy.In this study,SP technology was used to isolate a small subpopulation of SP cells in human gallbladder cancer cell line GBC-SD,and SP cells which had superior potential for proliferation in vitro and tumorigenesis in vivo were identified.Importantly,the abundance of GBC-SD SP cells was increased by a transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT),and this effect was accompanied with a strong up-regulation of ABCG2 mRNA expression,and a decreased sensitivity to mitoxantrone.SP cells were restored upon the removal of TGF-β and the reversion of the cells to an epithelial phenotype,and smad3-specific siRNA reduced SP abundance in response to TGF-β.In conclusion,TGF-β-induced EMT by smad-dependent signaling pathway promotes cancer development and anti-cancer drug resistant phenotype by augmenting the abundance of GBC-SD SP cells,and a better understanding of mechanisms involved in TGF-β-induced EMT may provide a novel strategy for preventing cancer progression.
ABSTRACT
Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes.Direct integrin-mediated cell adhesion to ECM components in the space of Disse appears to be required for the successful liver metastatic formation of colon cancer.In the present study,human colon cancer HT-29 cells were transfected by liposome with integrin-β1 antisense oligodeoxynucleotide (ASODN).The integrin-β1 gene expression in HT-29 cells was significantly down-regulated.The migration of HT-29 cells was assayed using transwell cell culture chambers in vitro.The number of migrating HT-29 cells in experimental group was far less than that in control group (P＜0.05).The models of hepatic metastasis in nude mice were established by the intrasplenic injection of transfected HT-29 cells.Thirty days later,the nude mice were killed and the average number of hepatic metastases (4.00±0.93 per mouse),average volume (10.10±6.50 mm3 per mouse),average weight (0.0440±0.0008 g per mouse) in experimental group were remarkably reduced as compared with those in control group (P＜0.05).Integrin-β1 expression in the hepatic metastasis was studied by immunohistochemistry (SP).Positive cell percentage of hepatic metastases in experimental group was markedly decreased as compared with that in control group (P＜0.05).It was concluded that integrin-β1 may take part in hepatic metastasis,and down-regulation of integrin-β1 expression may play a key role in decreasing migration and hepatic metastasis of human colon carcinoma cells (HT-29).