CREB3L4 promotes hepatocellular carcinoma progression and decreases sorafenib chemosensitivity by promoting RHEB-mTORC1 signaling pathway
Zhengchen Jiang,
Bowen Shi,
Yun Zhang,
Tianming Yu,
Yang Cheng,
Jiankang Zhu,
Guangyong Zhang,
Mingwei Zhong,
Sanyuan Hu,
Xiaomin Ma
Affiliations
Zhengchen Jiang
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China; Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310022, China
Bowen Shi
Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
Yun Zhang
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
Tianming Yu
Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
Yang Cheng
Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
Jiankang Zhu
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
Guangyong Zhang
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
Mingwei Zhong
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
Sanyuan Hu
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China; Corresponding author
Xiaomin Ma
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China; Corresponding author
Summary: This study was designed to explore the roles of CREB3L4 in the pathogenesis and drug resistance of hepatocellular carcinoma (HCC). The proliferation of HCC lines was determined in the presence of CREB3L4 over-expression and silencing. Chromatin immunoprecipitation (ChIP) assay and dual-luciferase reporter assay were performed to screen the potential target of CREB3L4 on mTORC1. Xenografted tumor model was established to define the regulatory effects of CREB3L4 in the tumorigenesis. Then we evaluated the roles of CREB3L4 in chemosensitivity to sorafenib treatment. CREB3L4 significantly induced the HCC cell proliferation by modulating the activation of mTROC1-S6K1 signaling pathway via binding with RHEB promoter. Moreover, CREB3L4 dramatically inhibited the chemosensitivity to sorafenib treatment via up-regulating RHEB-mTORC1 signaling. CREB3L4 promoted HCC progression and decreased its chemosensitivity to sorafenib through up-regulating RHEB-mTORC1 signaling pathway, indicating a potential treatment strategy for HCC through targeting CREB3L4.
