한빛사 논문
Youn-Sang Jung,1,2 Sabrina A. Stratton,3 Sung Ho Lee,1 Moon-Jong Kim,1 Sohee Jun,1 Jie Zhang,1 Biyun Zheng,1 Christopher L Cervantes,1 Jong-Ho Cha,4 Michelle C. Barton,3,5 Jae-Il Park1,5,6,*
1Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Department of Life Science, Chung-Ang University, Seoul, 06974, South Korea
3Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, South Korea
5Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
*Corresponding author
Abstract
How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. TMEM9 facilitates v‐ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein (CV) and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased Apc and reduced Wnt signaling. Mechanistically, TMEM9 downregulates APC through lysosomal protein degradation via v‐ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β‐catenin hyperactivation. TMEM9‐upregulated APC binds to and inhibits nuclear translocation of β‐catenin, independent of HCC‐associated β‐catenin mutations. Pharmacological blockade of TMEM9‐v‐ATPase or lysosomal degradation suppresses Wnt/β‐catenin through APC stabilization and β‐catenin cytosolic retention. Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis via lysosomal degradation of APC.
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