Galectin-1 upregulation in PIK3CA induced hepatocarcinogenesis- therapeutic cooperativity

Background Aberrant activation of the PI3K/AKT/mTOR pathway is a hallmark of hepatocarcinogenesis. In mice, hydrodynamic transfection of phosphatidylinositol 3-kinase catalytic alpha polypeptide (PIK3CA) mutant forms elicits hepatocellular carcinoma development. The induced tumors are characterized by an early and consistent upregulation of Galectin1 (Gal1). This study aimed to elucidate putative Gal1 effectors in addition to strategies for therapeutic intervention.

Methods PIK3CA H1047R and E545K mutant forms were delivered to the mouse liver by tail vein hydrodynamic injection. Gene expression microarray analyses identified Gal1 as a key effector in hepatocarcinogenesis. A compound library including 315 approved anti-cancer drugs identified drugs synergistic with the Gal1 inhibitor OTX008. Gal1 function was studied in vitro and by the use of proteomics.

Results Gal1 was commonly overexpressed in PIK3CA-driven preneoplastic and neoplastic liver lesions. The induced HCCs displayed a strong lipogenic phenotype, and concordantly, expression of the master regulator of lipogenesis Stearoyl-CoA desaturase-1 was found to depend on Gal1. Moreover, combinatory drug screenings revealed synergy between the Gal1 inhibitor OTX008 and PIK3CA- or JAK/STAT-inhibitors. To complement these findings, both STAT1 and 2 were recognized as Gal1 effectors by proteomics.

Conclusions Overall, our research indicates that PIK3CA-induced hepatocarcinogenesis is characterized by elevated Gal1, which functionally regulates both lipogenesis and STAT proteins. Furthermore, these findings uncover a specific vulnerability, which can be targeted by Gal1- and receptor tyrosine kinase-inhibitor combinatory treatment regimens offering potential therapeutic venues for human HCC.

Publication History

Article published online:
26 January 2022