Background: The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods: In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in a patient-derived xenograft nude mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination, and immunofluorescence were utilized to evaluate the regulatory signaling pathway. Results: Our research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, the therapeutic effects of genipin in a patient-derived HCC xenograft nude mice model were also demonstrated. Conclusions: In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with the SH2-STAT-3 domain and suppressing the activity of STAT-3. In the future, further research is planned to explore the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.
Background Signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signalling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in patient-derived xenograft mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination and immunofluorescence were utilized to evaluate the regulatory signalling pathway. Results Our research have demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may attribute to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, we also demonstrated the therapeutic effects of genipin in patient-derived HCC xenograft mice model.Conclusion In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with SH2-STAT-3 domain and suppressing the activity of STAT-3. In future study, further research are expected for exploring the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.
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