Tmub1 Negatively Regulates Liver Regeneration via Inhibiting STAT3 Phosphorylation

Hangwei Fu  ¹ , Rui Dong  ¹ , Yida Zhang  ¹ , Jianhua Xu  ¹ , Menggang Liu  ² , Ping Chen  ³

• ¹ Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China.
• ² Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China. Electronic address: menggang_liu@hotmail.com.
• ³ Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China. Electronic address: chenpingsyd@126.com.

Abstract

Tmub1 (transmembrane and ubiquitin-like domain-containing 1) plays negative roles in rat hepatocyte proliferation, but its underlying molecular mechanisms in liver regeneration regulation have yet to be revealed. Here, we show that in vivo transfection of Tmub1 overexpression vectors impaired mouse liver regeneration after partial hepatectomy (PHx). Loss- and gain-of-function analyses in human hepatocyte Lo2 cells indicated that Tmub1 inhibits the phosphorylation of STAT3 and the activation of STAT3 signaling. Furthermore, the inhibitory effect of Tmub1 overexpression on hepatocyte proliferation can be reversed by the STAT3 activator OSM, while the promotive effect of Tmub1 knockdown can be abolished by the STAT3 inhibitor stattic. Coimmunoprecipitation assays revealed interaction between Tmub1 and STAT3. Finally, we present data from chromatin immunoprecipitation and luciferase reporter gene assays and report that STAT3 binds to and activates the promoter of Tmub1, suggesting a putative negative feedback loop between Tmub1 and STAT3 signaling. Taken together, the results of our study suggest that Tmub1 is an important negative regulator of hepatocyte proliferation in liver regeneration through STAT3 signaling. These findings provide a potential strategy for the management of liver regeneration.

Keywords: Cell cycle; Cell proliferation; Liver regeneration; STAT3 transcription factor; Transmembrane and ubiquitin-like domain containing 1 protein.