Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma
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Ji Yu Wang1,*, Meng Fang1,*, Alex Boye1,*, Chao Wu1, Jia Jun Wu1, Ying Ma1, Shu Hou1, Yue Kan1 and Yan Yang1
1Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
*These authors have contributed equally to this work
Yan Yang, email: [email protected]
Keywords: hepatocellular carcinoma, microRNA-21, microRNA-145, pSmad3C, pSmad3L
Received: November 10, 2016 Accepted: April 02, 2017 Published: May 09, 2017
MicroRNAs 21 and 145 exhibit inverse expression in Hepatocellular carcinoma (HCC), but how they relate to Smad3 C-terminal and Link region phosphorylation (pSmad3C and pSmad3L) downstream of TGF-β/MAPK signaling, remains inconclusive. Our results suggest microRNA-145 targets Smad3 in HepG2 cells. Decreased tumor volume and increased apoptosis were produced in both microRNA-21 antagomir and microRNA-145 agomir groups compared to controls. Inhibition of TβRI and MAPK (ERK, JNK, and p38) activation respectively produced decreased microRNA-21 but increased microRNA-145 expression. Correspondingly, the expression level of pSmad3C obviously increased while pSmad3L decreased in microRNA-145 agomir-group and the expression of pSmad3C/3L were not markedly changed but pERK, pJNK, pp38 decreased in microRNA-21 antagomir-group compared to controls. On the other hand, microRNA-145 and 21 increased respectively in xenografts of HepG2 cells transfected with Smad3 EPSM and 3S-A plasmid, and this correlated with the overexpression of pSmad3C and pSmad3L respectively compared to control. To conclude, microRNA-21 promotes tumor progression in a MAPK-dependent manner while microRNA-145 suppresses it via domain-specific phosphorylation of Smad3 in HCC. Meanwhile, increased pSmad3C/3L lead to the up-regulation of microRNA-145/21 respectively. The interaction between pSmad3C/3L and microRNA-145/21 regulates HCC progression and the switch of pSmad3C/3L may serve as an important target for HCC therapy.
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