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
Affiliations
Jianping Liao
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China
Jiahong Wang
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China
Yu Xu
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China
Yong Wu
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China
Meifeng Wang
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China
Qiudong Zhao
Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
Xiaodan Tan
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China
Yan Meng
Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China; Corresponding author
Lixin Wei
Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; Corresponding author
Aimin Huang
Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China; Corresponding author
Summary: 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.
