Targeting stroma and tumor, silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma
Tahereh Setayesh1, Ying Hu1, Farzam Vaziri1
1Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Abstract:
This study examines inhibiting galectin 1 (Gal1) as a treatment option for hepatocellular carcinoma (HCC). Gal1 has immunosuppressive and cancer-promoting roles. Our data showed that Gal1 was highly expressed in human and mouse HCC. The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival. The roles of Gal1 in HCC were studied using overexpression (OE) or silencing using Igals1 siRNA delivered by AAV9. Prior to HCC initiation induced by RAS and AKT mutations, lgals1-OE and silencing had opposite impacts on tumor load. The treatment effect of lgals1 siRNA was further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9% or even 42% of the body weight. Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC, inhibiting matrix formation and recognition of foreign antigen in CD45+ cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing. Within the tumors, silencing Gal1 inhibited translational initiation, elongation, and termination. Furthermore, Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor, and the anti-HCC effect of lgals1 siRNA was CD8-dependent. Overall, Gal1 silencing has a promising potential for HCC treatment.
Insights
Inhibiting galectin 1 (Gal1) shows promise for treating hepatocellular carcinoma (HCC). Gal1 silencing reduced tumor growth and enhanced anti-tumor immunity, suggesting a new therapeutic strategy for HCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Galectin 1 (Gal1) plays a significant role in cancer progression and immune suppression.
- High Gal1 expression in hepatocellular carcinoma (HCC) correlates with advanced stages and poor survival.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting Gal1 in hepatocellular carcinoma (HCC).
- To elucidate the mechanisms underlying Gal1's role in HCC development and progression.
Main Methods:
- Gal1 levels were assessed in human and mouse HCC tissues.
- Gal1 function was studied using overexpression and lgals1 siRNA delivered via AAV9 in a mouse model.
- Spatial transcriptomics and immune cell profiling were employed to analyze treatment effects.
Main Results:
- Gal1 was highly expressed in HCC, correlating with disease stage and reduced survival.
- Silencing Gal1 (lgals1 siRNA) significantly reduced tumor load, even in advanced HCC.
- Gal1 inhibition suppressed matrix formation, enhanced foreign antigen recognition, and boosted cytotoxic T cell infiltration.
Conclusions:
- Gal1 silencing demonstrates significant anti-HCC effects, mediated by immune cell modulation and T cell expansion.
- Targeting Gal1 presents a promising therapeutic strategy for hepatocellular carcinoma.
- The anti-tumor efficacy of Gal1 silencing is CD8-dependent.
