| 著者 |
Xiao R, Lu X, Huang F, Zhao Y, Jin H, Jia X, Huang B, Wang Y, Chu L.
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| Abstract |
Intrahepatic cholangiocarcinoma (ICCA), the second most prevalent primary liver malignancy, remains poorly understood at the molecular level. Research into the function of N6-methyladenosine (m6A) modification in the formation of ICCA and its potential as a therapeutic approach is being spurred by mounting evidence that it plays a crucial role in tumor biology. Immunohistochemical examination of patient samples in this investigation revealed a significant decrease in m6A methyltransferase METTL3 expression, accompanied by lower levels, which were associated with a lower overall survival rate. Functional assays demonstrated that the enforced expression of METTL3 inhibited ICCA cell proliferation and migration, while concurrently increasing the levels of the long non-coding RNA H19. Mechanistic experiments using RNA-binding protein immunoprecipitation and methylated RNA immunoprecipitation confirmed that METTL3 directly interacted with H19 and enhanced its m6A modification. Importantly, silencing of H19 reversed the growth- and migration-suppressive effects of METTL3, whereas H19 overexpression counteracted the phenotype induced by METTL3 downregulation. Further analysis revealed that the METTL3-H19 regulatory axis suppressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Moreover, an oncolytic adenovirus engineered to overexpress H19, in combination with the PPARγ inhibitor BAY-4931, elicited potent antitumor effects both in vitro and in vivo. Collectively, these findings identify METTL3-mediated m6A modification of H19 as a critical suppressor of ICCA progression through modulation of PPARγ signaling. One interesting treatment option for ICCA may be the use of H19-armed oncolytic adenoviruses, especially when combined with PPARγ suppression.
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