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

Simple Summary Hepatocellular cancer (HCC) is the most common and lethal subtype of liver cancer without effective therapeutics. Understanding and targeting cancer stem cells (CSCs), a stem-cell-like subpopulation, which are emerging as effective ways to decipher tumor biology and develop therapies, may help to revolutionize cancer management. Cancer/testis antigen Maelstrom (MAEL) has been implicated in the regulation of CSC phenotypes, while the role of CSCs remains unclear. We demonstrated that MAEL positively regulates cancer stem-cell-like properties in HCC, and MAEL silencing provokes tumor cells' sensitivity to sorafenib. We further discovered that the MAEL-dependent stemness was operated via PGST2/IL8/AKT/STAT3 signaling. Collectively, our study suggests the MAEL/PGST2 axis as a potential therapeutic target against CSC and sorafenib resistance in HCC. 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-kappa B/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.

Automated summary

Hepatocellular cancer (HCC) is a lethal subtype of liver cancer, and effective therapeutics are lacking. Understanding and targeting cancer stem cells (CSCs) can revolutionize cancer management. Maelstrom (MAEL) is implicated in the regulation of CSC phenotypes, and our study demonstrates that MAEL positively regulates cancer stem-cell-like properties in HCC. MAEL silencing enhances tumor cells' sensitivity to sorafenib. Our study also reveals the involvement of the MAEL-dependent PGST2/IL8/AKT/STAT3 signaling pathway in the regulation of stemness. Targeting the MAEL/PGST2 axis may be a potential therapeutic strategy against CSC and sorafenib resistance in HCC.