Background: Accumulating evidences have indicated that human cytomegalovirus (HCMV) may link to multiple human malignancies, including gastric cancer. However, the mechanistic role of HCMV in GC remains largely unknown.
Methods: In this study, we have successfully established HCMV latent gene UL-136-expressing gastric cancer cells. We measured cell proliferation of GC cells, MNK-45 and SGC-7901, with stable UL136 expression or paired control cells by using CCK-8 assay. We have showed that GC cells with stable UL136 expression had a rapid cell growth. Furthermore, our data from matrigel-coated transwell assay have demonstrated that UL136 expressing GC cells showed an enhanced invasion capacity compared to control cells. Furthermore, ectopic expression of UL136 inhibits tumorigenicity in an animal model.
Results: We observed that IL-6/STAT3 was stimulated by UL136 overexpression. Also, miR-138 is consistently up-regulated, while miR-34 down-regulated by UL136 in either MNK-45 or SGC-7901 cells. Our mechanistic study showed that treatment of miR-138 mimics in MNK-45 cells indeed inhibited SIRT1 expression to increase phosphorylation level of STAT3. MiR-34c suppressed expression of IL6R through direct binding with the putative 3'UTR binding sites of this gene. UL136 regulate IL6/STAT3 pathway, at least in part, through down-regulation of miR-34c in GC cells.
Conclusion: In conclusion, HCMV-induced miR-34c or miR-138 involves in the activation of IL6/STAT3 signaling. Targeting the IL6-STAT3 axis or miRNAs represent a promising strategy for HCMV-related tumor formation.
Keywords: Gastric cancer; MiR-138; UL136.