MAEL Augments Cancer Stemness Properties and Resistance to Sorafenib in Hepatocellular Carcinoma through the PTGS2/AKT/STAT3 Axis

Cancers

Chaoran Shi¹  Xiaona Fang¹  Dora Lai-Wan Kwong¹  Ying Tang¹  Liangzhan Sun¹  Xin-Yuan Guan¹  Shan-Shan Li²  Xia Wang³  Xue Li⁴ 

[1] Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China;Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518058, China;Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China;Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China;

关键词: Maelstrom;    MAEL;    PTGS2;    HCC;    drug resistance;    cancer stemness;   

DOI  :  10.3390/cancers14122880

来源: DOAJ

【 摘 要 】

Cancer stem cells (CSCs) are responsible for tumorigenesis, therapeutic resistance, and metastasis in hepatocellular cancer (HCC). Cancer/testis antigen Maelstrom (MAEL) is implicated in the formation of CSC phenotypes, while the exact role and underlying mechanism remain unclear. Here, we found the upregulation of MAEL in HCC, with its expression negatively correlated with survival outcome. Functionally, MAEL promoted tumor cell aggressiveness, tumor stem-like potentials, and resistance to sorafenib in HCC cell lines. Transcriptional profiling indicated the dysregulation of stemness in MAEL knockout cells and identified PTGS2 as a critical downstream target transactivated by MAEL. The suppression effect of MAEL knockout in tumor aggressiveness was rescued in PTGS2 overexpression HCC cells. A molecular mechanism study revealed that the upregulation of PTGS2 by MAEL subsequently resulted in IL-8 secretion and the activation of AKT/NF-κB/STAT3 signaling. Collectively, our work identifies MAEL as an important stemness regulation gene in HCC. Targeting MAEL or its downstream molecules may provide a novel possibility for the elimination of CSC to enhance therapeutic efficacy for HCC patients in the future.

【 授权许可】

Unknown