IGF-1 mediates 38-54% of BMI-liver cancer risk, with lower IGF-1 levels linked to higher risk.
Background
The global incidence of liver cancer is rising, with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) being major risk factors. While the link between high Body Mass Index (BMI) and liver cancer is established, the precise biological mechanisms remain incompletely understood. Insulin-like Growth Factor 1 (IGF-1) is a crucial hormone involved in cell growth, metabolism, and inflammation, and its dysregulation has been implicated in various cancers. Clarifying IGF-1's role as a mediator in adiposity-related liver carcinogenesis could identify new targets for prevention or intervention.
Study Design
Researchers conducted a prospective analysis using data from 432,203 UK Biobank participants. They assessed the relationship between BMI, IGF-1, and liver cancer risk using four definitions for liver cancer (ICD-10 C22 and C220), excluding diagnoses within 24 or 60 months post-baseline to reduce reverse causality. Linear regression models were used to evaluate the BMI-IGF-1 relationship. Cox proportional hazards models, adjusted for various covariates, examined associations with liver cancer risk. Finally, mediation analysis with 5000 bootstrap iterations quantified IGF-1's mediating effect.
Results
Elevated BMI was significantly associated with an increased risk of liver cancer, showing a multivariable HR = 1.071 (p < 0.0001). This association was notably attenuated after adjusting for IGF-1 levels, with the HR decreasing to 1.037 (p < 0.0001), indicating IGF-1's mediating role. A negative correlation was observed between BMI and IGF-1, where higher BMI was associated with lower IGF-1 levels (multivariable β = -0.150; p < 0.0001). IGF-1 exhibited a non-linear relationship with liver cancer risk, with particularly lower levels (approximately less than 18 nmol/L) being linked to a higher risk. This suggests a threshold effect where insufficient IGF-1 contributes to risk. > IGF-1 was found to mediate a substantial 37.76%-53.64% of the association between BMI and liver cancer risk, highlighting its critical mechanistic involvement. These findings underscore that BMI-related reductions in IGF-1 are a significant pathway in liver carcinogenesis.
Key Findings
- Elevated BMI correlated with increased liver cancer risk (HR = 1.071; p < 0.0001).
- BMI negatively correlated with IGF-1 levels (β = -0.150; p < 0.0001).
- Lower IGF-1 levels (< 18 nmol/L) were associated with higher liver cancer risk.
- IGF-1 mediated 37.76%-53.64% of the BMI-liver cancer association.
Why It Matters
This study provides compelling evidence that IGF-1 is a key mediator in the link between obesity and liver cancer, suggesting that maintaining healthy IGF-1 levels could be a strategy to mitigate risk. For individuals with high BMI, monitoring IGF-1 levels might become a relevant biomarker, potentially guiding lifestyle interventions or future pharmacological approaches. While this is an observational study, the large cohort size strengthens the mechanistic hypothesis that BMI-induced IGF-1 reduction contributes to liver carcinogenesis. Future research could explore interventions targeting IGF-1 pathways or maintaining optimal IGF-1 levels in individuals with high BMI to reduce liver cancer risk. This opens avenues for personalized risk assessment and preventative strategies, moving beyond just BMI reduction to include metabolic pathway modulation.
igf-1
liver-cancer
bmi
obesity
cancer-risk
epidemiology