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Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma

Ji Yu Wang1, Meng Fang1, Alex Boye1

  • 1Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China.

Oncotarget
|November 22, 2017
PubMed

Insights

MicroRNA-21 promotes Hepatocellular carcinoma (HCC) progression via MAPK signaling, while microRNA-145 suppresses it by regulating Smad3 phosphorylation. Targeting Smad3 phosphorylation offers a potential therapeutic strategy for HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • MicroRNAs (miRNAs) 21 and 145 show inverse expression in Hepatocellular carcinoma (HCC).
  • The relationship between these miRNAs and Smad3 phosphorylation (pSmad3C, pSmad3L) in TGF-β/MAPK signaling in HCC is unclear.

Purpose of the Study:

  • To elucidate the roles of microRNA-21 and microRNA-145 in HCC progression.
  • To investigate their interaction with Smad3 phosphorylation downstream of TGF-β/MAPK signaling.

Main Methods:

  • Utilized HepG2 cell lines and xenograft models.
  • Administered microRNA-21 antagomir and microRNA-145 agomir.
  • Inhibited TGF-β receptor type I (TβRI) and MAPK pathway components (ERK, JNK, p38).
  • Analyzed Smad3 phosphorylation and miRNA expression levels.

Main Results:

  • MicroRNA-145 targets Smad3 in HepG2 cells.
  • MicroRNA-21 antagomir and microRNA-145 agomir reduced tumor volume and increased apoptosis.
  • Inhibition of TβRI and MAPK decreased miR-21 and increased miR-145 expression.
  • MicroRNA-145 agomir increased pSmad3C and decreased pSmad3L; microRNA-21 antagomir decreased MAPK phosphorylation.
  • Smad3 phosphorylation changes correlated with miRNA expression in xenografts.

Conclusions:

  • MicroRNA-21 promotes HCC via MAPK signaling; microRNA-145 suppresses HCC through Smad3 phosphorylation.
  • Increased pSmad3C/3L upregulates microRNA-145/21, respectively.
  • The interplay between pSmad3C/3L and miRNAs regulates HCC; Smad3 phosphorylation switch is a potential therapeutic target.
Keywords:
hepatocellular carcinomamicroRNA-145microRNA-21pSmad3CpSmad3L

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