2. Academic Validation
  3. PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway

PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway

  • J Mol Med (Berl). 2018 Feb;96(2):119-133. doi: 10.1007/s00109-017-1605-6.
Anjian Xu 1 2,  Yanmeng Li 3 4,  Wenshan Zhao 3 4,  Fei Hou 5,  Xiaojin Li 3 4,  Lan Sun 6,  Wei Chen 3,  Aiting Yang 3,  Shanna Wu 7,  Bei Zhang 3 4,  Jingyi Yao 3,  Huan Wang 3,  Jian Huang 8 9
Affiliations

Affiliations

  • 1 Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • 2 National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 3 Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 4 National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 5 Department of Infection Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 6 Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 7 Clinical Laboratory Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 8 Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • 9 National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
PMID: 29098317 DOI: 10.1007/s00109-017-1605-6
Abstract

Hepatic fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Migration of the activated HSCs to the site of injury is one of the key characteristics during the wound healing process. We have previously demonstrated that 14 kDa phosphohistidine Phosphatase (PHP14) is involved in migration and lamellipodia formation of HSCs. However, the role of PHP14 in liver fibrosis remains unknown. In this study, we first assessed PHP14 expression and distribution in liver fibrotic tissues using western blot, immunohistochemistry, and double immunofluorescence staining. Next, we investigated the role of PHP14 in liver fibrosis and, more specifically, the migration of HSCs by Transwell assay and 3D collagen matrices assay. Finally, we explored the possible molecular mechanisms of the effects of PHP14 on these processes. Our results show that the PHP14 expression is up-regulated in fibrotic liver and mainly in HSCs. Importantly, TGF-β1 can induce PHP14 expression in HSCs accompanied with the activation of HSCs. Consistent with the previous study, PHP14 promotes HSCs migration, especially, promotes 3D floating collagen matrices contraction but inhibits stressed-released matrices contraction. Mechanistically, the PI3Kγ/Akt/Rac1 pathway is involved in migration regulated by PHP14. Moreover, PHP14 specifically mediates the TGF-β1 signaling to PI3Kγ/Akt pathway and regulates HSC migration, and thus participates in liver fibrosis. Our study identified the role of PHP14 in liver fibrosis, particularly HSC migration, and suggested a novel mediator of transducting TGF-β1 signaling to PI3Kγ/Akt/Rac1 pathway.

Key messages: PHP14 is up-regulated in fibrotic liver and activated hepatic stellate cells. The expression of PHP14 is induced by TGF-β1. The migration of hepatic stellate cells is regulated by PHP14. PHP14 is a mediator of TGF-β1 signaling to PI3Kγ/Akt/Rac1 pathway in hepatic stellate cells.

Keywords

Hepatic stellate cell; Liver fibrosis; Migration; PHP14; PI3Kγ/AKT/Rac1 pathway.

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