MALT1 paracaspase is overexpressed in hepatocellular carcinoma and promotes cancer cell survival and growth

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, therapeutic management of HCC remains a challenge, emphasizing the importance of exploring novel targets. MALT1 paracaspase is a druggable signaling molecule whose dysregulation has been linked to hematological and solid tumors. However, the role of MALT1 in HCC remains poorly understood, leaving its molecular functions and oncogenic implications unclear. Here we provide evidence that MALT1 expression is elevated in human HCC tumors and cell lines, and that correlates with tumor grade and differentiation state, respectively. Our results indicate that ectopic expression of MALT1 confers increased cell proliferation, 2D clonogenic growth, and 3D spheroid formation in well differ-entiated HCC cell lines with relatively low MALT1 levels. In contrast, stable silencing of endogenous MALT1 through RNA interference attenuates these aggressive cancer cell phenotypes, as well as migration, invasion, and tumor-forming ability, in poorly differentiated HCC cell lines with higher paracaspase expression. Consistently, we find that pharmacological inhibition of MALT1 proteolytic activity with MI-2 recapitulates MALT1 depletion phenotypes. Finally, we show that MALT1 expression is positively correlated with NF-kB activation in human HCC tissues and cell lines, suggesting that its tumor promoting functions may involve functional interaction with the NF-kB signaling pathway. This work unveils new insights into the molecular implications of MALT1 in hepatocarcinogenesis and places this paracaspase as a potential marker and druggable liability in HCC.

Automated summary

This study shows that MALT1 expression is elevated in human HCC tumors and cell lines, and is correlated with tumor grade and differentiation state. Ectopic expression of MALT1 promotes cell proliferation, clonogenic growth, and spheroid formation in well differentiated HCC cell lines, while silencing of MALT1 attenuates aggressive cancer cell phenotypes in poorly differentiated HCC cell lines. The study also suggests that MALT1 is positively correlated with NF-kB activation in HCC tissues, indicating its potential involvement in tumor promotion through the NF-kB signaling pathway.