Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic behavior. We aimed to clarify the mechanism(s) underlying this observation and transfected vectors carrying CD147, a glycoprotein enriched on the surface of tumor cells that stimulates the production of matrix metalloproteinases (MMPs), and specific shCD147 into MCF7 and MCF7/Adr cells, respectively. Using quantitative real-time polymerase chain reaction and Western blot, we found that overexpression of CD147 in MCF7 cells up-regulated MDR1, MMP2, and MMP9 on both transcription and expression levels, which promoted tumor cells metastasis and conferred them multidrug resistance to P-gp substrate drugs, as determined by in vitro invasion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. On the other hand, silencing of CD147 in MCF7/Adr cells led to the opposite effect. Moreover, Erk1/2 in CD147-overexpressing clones were observed to be highly activate and after treatment with U0126, an Erk1/2-specific inhibitor, the expression of MDR1, MMP2 and MMP9 were decreased significantly. Thus, CD147 may assume a dual role, since it had intrinsic stimulative effects on tumor invasion in vitro as well as increasing resistance to P-gp substrate drugs. M ultidrug resistance (MDR) and tumor metastasis are the two main causes of treatment failure and mortality in cancer patients. These two properties of malignant tumors have been studied extensively and there are evidences suggesting functional linkage between the two phenotypes.(1-3) Up-regulation of CD147 has been reported in many MDR cancers.(4) CD147 (EMMPRIN or extracellular matrix metallo-proteinase inducer) is the major stimulator of MMPs. They congregate on the surfaces of most tumor cells to produce elevated levels of several MMPs.The greatly increased expression or activity of distinct MMPs observed in MDR cancer cells could be attributed to the elevated expression of CD147.(4) Morever, Misra et al. (8) have demonstrated that CD147 is also involved in resistance of cancer cells to some chemotherapeutic agents. Inhibition of CD147 gene expression via RNAi could increase chemosensitivity to paclitaxel in the human ovarian cancer cell line.(9) As we know, more than one mechanism participates in MDR to chemotherapeutic drugs, the detailed mechanisms underlying these observations have not been clarified yet. MDR is often associated with overexpression of P-glycoprotein (P-gp), a transmembrane, adenosine triphosphate (ATP)-dependent transporter encoded by the MDR1 gene. (10,11) Our main purpose in the current research was to explore whether CD147 participated in the regulation of both MDR1 and MMPs. Additional, tyrosine kinases have been confirmed to be required not only for CD147 induction of MMPs, (12)(13)(14)(15) but for mediation of the expression of MDR1 as well.(16) Since tyrosine kinases are integrally involved in MAP kinase (MAPK) signaling pathways, we attempted to further clarify whether MMPs and MDR1 expression...
The reason for and consequences of BCL2L10 down-regulation in gastric carcinoma are poorly understood. Our aim was to investigate the function of the protein BCL2L10 in gastric carcinoma. We investigated BCL2L10 expression using quantitative real-time PCR and immunoblotting. The methylation status of the BCL2L10 gene promoter was examined by bisulphite sequencing in fresh gastric normal and carcinoma tissues. We studied apoptosis and proliferation regulation in gastric cancer cell lines using flow cytometry, fluorescence staining, murine xenografting and immunoblotting. Pathway inhibitors were applied to confirm the major pathways involved in apoptosis or proliferation regulation. We observed significant correlations between lower BCL2L10 expression and CpG island hypermethylation of the BCL2L10 gene promoter in gastric carcinoma, apoptosis induced by over-expressed BCL2L10 through mitochondrial pathways, and proliferation accelerated by BCL2L10 siRNA via the PI3K-Akt signalling pathway in gastric cancer cell lines. The pro-apoptotic effect of BCL2L10 and growth promotion by BCL2L10 siRNA in gastric cancer cells suggest that it may be a tumour suppressor.
Loss of BCL2L10 protein expression predicts poor clinical outcome in gastric carcinoma.
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