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Published on: March 20, 2018
Tissue Factor Pathway Inhibitor 2 Enhances Hepatocellular Carcinoma Chemosensitivity by Activating
Hongzhong Zhou1, Liwen Zhu1, Yajun Zhang2,3
1Department of Laboratory Medicine, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen University, China.
Abstract:
Chemotherapy resistance presents a major challenge in the treatment of hepatocellular carcinoma (HCC), with the underlying molecular mechanisms largely unknown. This study aimed to investigate the role of tissue factor pathway inhibitor 2 (TFPI2) in modulating HCC chemosensitivity. We explored the impact of TFPI2 on sorafenib sensitivity in patient-derived organoids and mouse models using immunofluorescence analysis, chromatin immunoprecipitation, and RNA immunoprecipitation. We observed the downregulation of TFPI2 in HCC, and its deletion in mice (TFPI2HKO) accelerated DEN-induced liver tumorigenesis. Notably, TFPI2 overexpression increased sorafenib sensitivity in HCC organoids and in vivo models. Mechanistic insights indicated that TFPI2 stabilizes the mRNA of growth arrest and DNA damage-inducible alpha (GADD45A) by engaging the cell cycle and apoptosis regulator 2 (CCAR2), promoting GADD45A-mediated DNA damage and inhibiting homologous recombination repair. Furthermore, TFPI2 protects CCAR2 from ubiquitination-induced degradation by associating with the deubiquitinating enzyme BRCC3. We identified polydatin, a resveratrol glycoside, which upregulates TFPI2 and synergistically enhances the chemosensitizing effect of sorafenib in organoids and in vivo. TFPI2 plays a critical role in CCAR2-GADD45A-induced DNA damage repair, providing a strategy to enhance HCC chemosensitivity. Our findings elucidate the molecular intricacies of chemoresistance in HCC and reveal a potential therapeutic target for alleviating this resistance.
Insights
Tissue factor pathway inhibitor 2 (TFPI2) downregulation promotes liver cancer growth and chemoresistance. Restoring TFPI2 enhances sensitivity to sorafenib by promoting DNA damage and inhibiting repair, offering a new therapeutic strategy.
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.
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