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Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF-β/SMAD signaling
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  • Wu Yin,
  • zhirui zhang,
  • Wei Wu,
  • Hao Jiao,
  • Yuzhong Chen,
  • Xiaojun Ji,
  • Jing Cao,
  • Fangzhou Yin
Wu Yin
Nanjing University
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zhirui zhang
The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing
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Wei Wu
Organ Transplantation Center, Southern District, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital)
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Hao Jiao
Department of Pharmacy, Fuyang People’s Hospital
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Yuzhong Chen
Department of Surgical Oncology,First Affiliated Hospital of Bengbu Medical College
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Xiaojun Ji
Department of Innovation, Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd
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Jing Cao
Department of Pharmacy, Women's Hospital of Nanjing Medical University/Nanjing Maternity and Child Health Care Hospital
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Fangzhou Yin
School of Pharmacy, Nanjing University of Chinese Medicine
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Abstract

Background and Purpose Squalene epoxidase (SQLE) is a key enzyme involved in cholesterol biosynthesis, but increasing evidence reveals that SQLE is abnormally expressed in some types of malignant tumors, and the underlying mechanism remains poorly understood. Experimental Approach Bioinformatics analysis and RNA sequencing were applied to detect to differentially expressed genes in clinical HCC tumors. AnnexinV-FITC/PI, EdU assay, transwell, IHC staining, cytoskeleton F-actin filaments assay, RNA sequencing, dual-luciferase reporters and HE staining were evaluated to investigate the pharmacological effects and possible mechanisms of SQLE. Key Results We found that SQLE expression is specifically elevated in HCC tumors, correlating with poor clinical outcomes. SQLE promoted HCC growth, EMT, and metastasis both in vitro and in vivo. In contrast, silencing of SQLE expression prevented HCC development. Both RNA-seq and functional experiments revealed that the protumorigenic effect of SQLE on HCC is closely related to the activation of cellular TGF-β/SMAD signaling, but interestingly, the stimulatory effect of SQLE on TGF-β/SMAD signaling and HCC development is also critically dependent on STRAP, a serine and threonine kinase. SQLE expression is well correlated with STRAP in HCC, and further, to amplify TGF-β/SMAD signaling, SQLE even transcriptionally increased STRAP gene expression mediated by the trans-acting factor AP-2α. Finally, as a chemical inhibitor of SQLE, NB-598 markedly inhibited HCC cell growth and tumor development in mouse models. Conclusions and Implications Taken together, SQLE serves as an oncogene in HCC development by activating TGF-β/SMAD signaling, and targeting SQLE could be useful in drug development and therapy for HCC.
29 Dec 2021Submitted to British Journal of Pharmacology
29 Dec 2021Assigned to Editor
29 Dec 2021Submission Checks Completed
12 Jan 2022Reviewer(s) Assigned
01 Mar 2022Review(s) Completed, Editorial Evaluation Pending
01 Mar 2022Editorial Decision: Revise Minor