Abstract. Resistance to chemotherapeutic agents is the main reason for treatment failure in patients with cancer. The primary mechanism of multidrug resistance (MDR) is the overexpression of drug efflux transporters, including ATP-binding cassette transporter G2 (ABCG2). To the best of our knowledge, the MDR mechanisms of esophageal cancer have not been described. An adriamycin (ADM)-resistant subline, Eca109/ADM, was generated from the Eca109 esophageal cancer cell line by a stepwise selection in ADM from 0.002 to 0.02 ng/µl. The resulting subline, designated Eca109/ADM, revealed a 3.29-fold resistance against ADM compared with the Eca109 cell line. The ABCG2 gene expression in the Eca109/ADM cells was increased compared with that of the Eca109 cells. The cellular properties of the Eca109/ADM cells were detected by reverse transcription polymerase chain reaction (RT-PCR), flow cytometry and western blotting. The ABCG2 expression levels were detected by RT-PCR and flow cytometry, and the drug efflux effect was detected by flow cytometry. The present study detected the correlation between ABCG2 and the multidrug resistance of esophageal cancer. ABCG2 gene expression and the drug efflux effect of the Eca109/ADM cells were increased compared with those of the Eca109 cells. Collectively, the results of this study indicated that the overexpression of ABCG2 in the Eca109/ADM cells resulted in drug efflux, which may be responsible for the development of esophageal cancer MDR.
The overexpression of ATP-binding cassette (ABC) transporters confers multidrug resistance (MDR) to tumor cells. ABCG2 is a member of the ABC superfamily. The present study aimed to investigate the correlation between ABCG2 expression and the MDR of esophageal cancer and to estimate the therapeutic benefit of downregulating ABCG2 expression and reversing chemoresistance in esophageal cells using artesunate (Art). The Eca109/ABCG2 cell line was established by transfecting the ABCG2 gene into Eca109 cells. The Eca109/ABCG2 esophageal cancer cells with ABCG2 gene overexpression were resistant to adriamycin (ADM), daunorubicin (DNR) and mitoxantrone (MIT), which indicated that ABCG2 may be associated with drug resistance in esophageal cancer. Art is a noteworthy antimalarial agent, particularly in severe and drug-resistant cancer cases, as Art is able to reverse drug resistance. In the present study, Art also exerted profound anticancer activity. The mechanism for the reversal of multidrug resistance by Art in esophageal carcinoma was analyzed using cellular experiments, but still remains largely unknown.
The aim of this study was to investigate the effect of short hairpin RNA (shRNA) targeting autotaxin (ATX) on the migratory and invasive capability of AGS human gastric cancer cells and the growth of xenografts in nude mice. pSUPER-ATX and pSUPER-mock (non-specific), which were constructed corresponding to the ATX-shRNA and negative control mock-shRNA synthesized based on gene sequence, were transfected with blank plasmid pSUPER-control into AGS human gastric cancer cells using Lipofectamine. At 24, 48 and 72 h post-transfection, the cells were harvested and analyzed. The endogenous ATX mRNA and protein of the different groups of AGS cells were detected by RT-PCR and western blot assays. Cell proliferation was measured by MTT assay. In vitro Transwell and Matrigel assays were used to detect the cell migratory and invasive capabilities. A tumor xenograft model was generated by subcutaneous injection of AGS cells into the dorsum of nude mice. The growth of xenograft tumors was monitored and measured; changes in tumor morphology and the organs of mice were observed by H&E staining. The expression of ATX, MMP-2 and MMP-9 protein in xenograft tumor tissues was detected by immunohistochemistry and western blotting. In vitro, both the mRNA and protein levels of ATX in the pSUPER-ATX group were significantly downregulated (P<0.01), and the cell proliferative, migratory and invasive capabilities were also significantly decreased. In vivo, no obvious damage to the organs was found. pSUPER-ATX significantly suppressed the tumor volume and weight from the 7th week after cell transplantation, compared to the pSUPER-mock, pSUPER-control and WT groups; the inhibition rates were approximately 50% (P<0.05). However, no significant differences in these parameters were found among the WT, pSUPER-mock and pSUPER-control groups. Furthermore, ATX, MMP-2 and MMP-9 were expressed at significantly lower levels in the pSUPER-ATX group compared to the levels in the other three groups (P<0.05), and a significant correlation between ATX and MMP-2 expression was found (r=0.869, P<0.01). The specific shRNA targeting ATX downregulated the endogenous ATX of AGS human gastric cancer cells, and inhibited AGS cell proliferative, migratory and invasive potentials. Moreover, shRNA targeting ATX inhibited the growth of human gastric cancer xenografts in nude mice.
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