Tissue Factor Pathway Inhibitor 2 Enhances Hepatocellular Carcinoma Chemosensitivity by Activating...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Chemotherapy resistance is a significant hurdle in hepatocellular carcinoma (HCC) treatment.
• The molecular mechanisms driving chemoresistance in HCC remain largely undefined.

Purpose of the Study:

• To investigate the role of tissue factor pathway inhibitor 2 (TFPI2) in modulating HCC chemosensitivity.
• To explore TFPI2's impact on sorafenib sensitivity in HCC models.

Main Methods:

• Immunofluorescence analysis, chromatin immunoprecipitation, and RNA immunoprecipitation were employed.
• Experiments utilized patient-derived HCC organoids and mouse models.
• Investigated the interaction between TFPI2, CCAR2, and GADD45A.

Main Results:

• TFPI2 was found to be downregulated in HCC, and its absence accelerated liver tumorigenesis in mice.
• Overexpression of TFPI2 significantly enhanced sorafenib sensitivity in both organoid and in vivo models.
• TFPI2 stabilizes GADD45A mRNA via CCAR2, promoting DNA damage and inhibiting repair, while also protecting CCAR2 from degradation.

Conclusions:

• TFPI2 plays a crucial role in DNA damage repair pathways, influencing HCC chemosensitivity.
• TFPI2 upregulation, potentially via polydatin, offers a promising strategy to overcome sorafenib resistance in HCC.
• TFPI2 represents a potential therapeutic target for enhancing chemotherapy efficacy in hepatocellular carcinoma.