Abstract
c‐Myc overexpression has been implicated in several malignancies including gastric cancer. Here, we report that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer via c‐Myc activation both in vivo and in vitro. c‐Myc mRNA and protein levels were assessed in ten primary and five local recurrent gastric cancer samples by quantitative real‐time polymerase chain reaction and western blotting analysis. The gastric cancer cell line MGC803 was exposed to bile salts (100 μmol/L glycochenodeoxycholic acid and deoxycholic acid) in an acid medium (pH 5.5) for 10 min daily for 60 weeks to develop an MGC803‐resistant cell line. Control MGC803 cells were grown without acids or bile salts for 60 weeks as a control. Cell morphology, proliferation, colony formation and apoptosis of MGC803‐resistant cells were analyzed after 60 weeks. To determine the involvement of c‐Myc in tumor progression and telomere aging in MGC803‐resistant cells, we generated xenografts in nude mice and measured xenograft volume and in vivo telomerase activity. The c‐Myc and hTERT protein and mRNA levels were significantly higher in local recurrent gastric cancer samples than in primary gastric cancer samples. MGC803‐resistant cells showed a marked phenotypic change under normal growth conditions with more clusters and acini, and exhibited increased cell viability and colony formation and decreased apoptosis in vitro. These phenotypic changes were found to be dependent on c‐Myc activation using the c‐Myc inhibitor 10058‐F4. MGC803‐resistant cells also showed a c‐Myc‐dependent increase in xenograft growth and telomerase activity in vivo. In conclusion, these observations support the hypothesis that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer and that these effects are dependent on c‐Myc activity. These findings suggest that acidified bile acids play an important role in the malignant progression of local recurrent gastric cancer.
Highlights
Reflux of duodenal contents–acidified bile acids, have been proved to be involved in the pathogenesis of Barrett’s esophagus [1, 2] and promote the occurrence of intestinal metaplasia and gastric cancer [3]
We found that MGC803-resistant cells showed progressive morphological, molecular, and biological changes associated with a more malignant phenotype. These changes were observed as enhanced cell viability, colony formation, xenograft formation, telomerase activity, and decreased apoptosis capacity, which were dependent on c-Myc expression
Our results show that c-M yc and hTERT expression in local recurrent gastric cancer tissues was much higher than in primary gastric cancer tissues at the protein and mRNA levels
Summary
Reflux of duodenal contents–acidified bile acids, have been proved to be involved in the pathogenesis of Barrett’s esophagus [1, 2] and promote the occurrence of intestinal metaplasia and gastric cancer [3]. Acidified Bile Acids Enhance Tumor Progression and Telomerase Activity Of Gastric Cancer. Bile acids under acidified media (known as acidified bile acids) were reported to upregulate the mRNA and protein expression of the proto-oncogene c-Myc in Barrett’s metaplasia and esophageal adenocarcinoma [9]. We previously confirmed that acidified bile acids can upregulate hTERT transcription by activating c-Myc in gastric cancer cells [11]. To further confirm the in vitro effects of acidified bile acids, we used an animal model to systemically study the role of bile acids in gastric cancer. The purpose of this study was to evaluate whether acidified bile acids contribute to gastric cancer progression via c-M yc activation
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