LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma

Jianping Liao; Jiahong Wang; Yu Xu; Yong Wu; Meifeng Wang; Qiudong Zhao; Xiaodan Tan; Yan Meng; Lixin Wei; Aimin Huang

doi:10.1016/j.isci.2023.106754

LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma

iScience. 2023 Apr 27;26(6):106754. doi: 10.1016/j.isci.2023.106754. eCollection 2023 Jun 16.

Authors

Jianping Liao^{1

2}, Jiahong Wang¹, Yu Xu¹, Yong Wu¹, Meifeng Wang¹, Qiudong Zhao³, Xiaodan Tan¹, Yan Meng^{3

4}, Lixin Wei³, Aimin Huang¹

Affiliations

¹ Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China.
² Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
³ Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
⁴ Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China.

Abstract

Hepatocellular carcinoma (HCC) is highly heterogeneous, and stemness signatures are frequently elevated in HCC tumor cells to generate heterogeneous subtypes via multidirectional differentiation. However, the mechanisms affecting the regulation of stemness in HCC remain unclear. In this study, we identified that lysosome-associated protein transmembrane-4β (LAPTM4B) was significantly overexpressed in stem-like tumor cell populations with multidirectional differentiation potential at the single cell level, and verified that LAPTM4B was closely related to stemness of HCC using in vitro and in vivo experiments. Mechanistically, elevated LAPTM4B suppresses Yes-associated protein (YAP) phosphorylation and ubiquitination degradation. In turn, stabilized YAP localizes to the nucleus and binds to cAMP responsive element binding protein-1 (CREB1), which promotes transcription of LAPTM4B. Overall, our findings suggest that LAPTM4B forms a positive feedback loop with YAP, which maintains the stemness of HCC tumor cells and leads to an unfavorable prognosis for HCC patients.

Keywords: Cancer; Cancer systems biology; Cell biology; Stem cells research.