High interstitial fluid pressure enhances USP1-dependent KIF11 protein stability to promote hepatocellular carcinoma progression.

BACKGROUND

HCC is characterized by a high interstitial fluid pressure (HIFP) environment, which appears to support cancer cell survival. However, the mechanisms behind this phenomenon are not fully understood.

METHODS

This study investigates the role of kinesin family member 11 (KIF11) in HCC under HIFP conditions, using both in vivo and in vitro models. In vitro experiments replicated the HIFP environment to observe changes in HCC cell behavior and protein expression, while in vivo studies involved mice portal hypertension to create an orthotopic liver cancer model, allowing for the evaluation of tumor progression. Additionally, clinical samples from HCC patients were analyzed for consistency with the experimental findings.

RESULTS

Results demonstrated that the HIFP environment significantly increased the proliferation, invasion, and metastasis in HCC cells. Omics analysis and subsequent molecular validation revealed that KIF11 protein levels were markedly upregulated under HIFP, despite no significant change in mRNA levels. Further investigation showed that this upregulation was linked to a reduction in KIF11's ubiquitin-mediated degradation, suggesting that the HIFP environment stabilizes KIF11 expression by inhibiting its degradation pathway. Co-immunoprecipitation and proteomic analysis identified ubiquitin-specific peptidase 1 (USP1) as a crucial factor in this process, deubiquitinating KIF11 at the K77 site, thus stabilizing its protein levels. Clinical analysis confirmed that both USP1 and KIF11 were significantly overexpressed in HCC patients with portal hypertension, with a strong correlation between the two. Inhibition of USP1 using ML323 significantly reduced KIF11 protein levels and suppressed tumor progression in the mouse model.

CONCLUSION

These findings suggest that the HIFP environment fosters HCC progression through USP1-mediated stabilization of KIF11, highlighting USP1 as a potential therapeutic target, especially in patients with portal hypertension.