hsa-miR-93 regulates MUCIN family gene expression via WNT/?-catenin pathway in intrahepatic stone disease - 27/04/18

Doi : 10.1016/j.clinre.2018.03.013

Hua Ma ^a, Wenyi Li ^b, Pinduan Bi ^b, Qiang Wang ^b, Jian Li ^c, Bin Yang ^b,^⁎
^a Scientific Research Experiment Center, Kunming Medical University, No. 295, Xichang Road, 65, Kunming, China
^b Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
^c Kunming biological diversity regional center of instruments, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

^⁎Corresponding author.

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Highlights

•	Mucins family, miR-93 and wnt pathway play an important role in the pathogenesis of intrahepatic stone.
•	Mucin3/4/5ac/B levels were found increased in patients with intrahepatic bile duct stones, and miR-93 levels were decreased.
•	Beta-catenin and wnt4 levels were higher also in subjects with intrahepatic bile duct stones.
•	Activition of wnt pathway up-regulated the expression of MUC4 and MUC5B, not MUC3 and MUC5ac.
•	miR-93 directly targeted TCF7 and repressed the activation of non-canonical, not canonical Wnt pathway.
•	miR-93 decreases the expression of MUC4/5ac/5B induced by wnt4.

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Summary

Background

Mucin plays an essential role in the intrahepatic stone formation, but the mechanism of mucin regulation is unclear.

Objective

To investigate the potential implication of miR-93 and WNT pathway in the regulation of intrahepatic bile duct mucin expression.

Methods

Thirty patients with or without intrahepatic bile duct stones are involved; Reverse-transcription polymerase chain reaction was performed to evaluate the expression of MUC3, MUC4, MUC5B, MUC5AC mRNA and miR-93 levels. miR-NC or miR-93 mimics was transfected into intrahepatic biliary epithelial cells. Then mucins and Wnt pathway proteins were detected by the immunoblotting, and the target gene TCF7 were validated using the dual luciferase assay. β-catenin, wnt4, and mucins were an immunohistochemical stain of the intrahepatic biliary epithelial tissues.

Results

The expression levels of MUC3, MUC4, MUC5B, and MUC5AC in patients with intrahepatic bile duct stones are higher than control, as well as Wnt pathway proteins (especially β-catenin and wnt4). Mucins levels increased in wnt4, wnt5a or SB216763-treated HIBECs, and reduced by miR-93 mimics transfection. miR-93 directly targeted TCF7 and repressed Wnt pathway protein expression, which reversed the upregulation of mucin levels induced by wnt4 or wnt5a, but not SB216763.