Human cytomegalovirus protein UL136 activates the IL-6/STAT3 signal through MiR-138 and MiR-34c in gastric cancer cells
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ORIGINAL ARTICLE
Human cytomegalovirus protein UL136 activates the IL‑6/STAT3 signal through MiR‑138 and MiR‑34c in gastric cancer cells Li Shi1 · Bo Fan1 · Dan Chen1 · Cunguo Guo1 · Hua Xiang1 · Ying Nie1 · Dingfu Zhong1 · Xiaoying Shi1 Received: 9 March 2020 / Accepted: 13 July 2020 © Japan Society of Clinical Oncology 2020
Abstract 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 Abbreviations CCK-8 Cell Counting Kit-8 DMEM Dulbecco Modified Eagle Medium DPBS Dulbecco’s phosphate-buffered saline FBS Fetal Bovine Serum GC Gastric Cancer HCMV Human Cytomegalovirus PVDF Polyvinylidene Fluoride Li Shi and Bo Fan authors contributed equally to this work. Dingfu Zhong and Xiaoying Shi are co-corresponding author to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10147-020-01749-z) contains supplementary material, which is available to authorized users. * Dingfu Zhong [email protected] * Xiaoying Shi [email protected] 1
Department of Gastroenterology, Jinhua People’s Hospital, Jinhua 321000, Zhejiang Province, China
RIPA buffer Radioimmunoprecipitation assay buffer SDS-PAGE Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis
Introduction Amount of studies have demonstrated that that several virus infections contribute as a cause of approximately 20% of all human cancers. Hepatitis B and C viruses (HBV and HCV), for instance, trigger hepatocellular carcinoma (HCC) [1]. Human p
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