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Abstract
Background: Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, with approximately 41,000 new cases and 29,000 deaths annually in the U.S. The management of HCC poses significant challenges due to severe toxicity and inadequate responses to existing chemotherapeutic agents. Aberrant β-catenin signaling is recognized as a crucial factor influencing the differentiation grades of HCC patients. Therefore, there is an urgent need to identify more effective and non-toxic β-catenin inhibitors for cancer treatment. Notably, ormeloxifene (ORM), a clinically approved selective estrogen receptor modulator with a favorable therapeutic index, has demonstrated remarkable anticancer activity, making it a promising candidate for repurposing. This study aims to explore the anticancer potential of ORM against hepatocellular carcinoma.
Methodology: Cell proliferation and colony formation assays were performed to assess the therapeutic activity of ORM in human hepatocellular carcinoma (HepG2, SK-HEP-1, Hep3B, and C3A) cells. Boyden chamber and Matrigel assays were carried out for investigating the effect of ORM on migration and invasion abilities of HCC cells, respectively. The effects of ORM on βcatenin and EMT associated proteins were analyzed through Western blotting and qPCR. Confocal microscopy was used to determine the β-catenin nuclear localization following ORM treatment in HCC cells.
Results: As compared to vehicle-treated group, ORM treatment (2.5-20 µM) suppressed proliferation and colony formation in human hepatocellular carcinoma cells in a dose and timedependent manner. Moreover, ORM treatment suppresses the migration and invasion of human hepatocellular carcinoma cells as shown by wound healing and Matrigel invasion assay, respectively. ORM effectively inhibited the protein levels and mRNA expression of total β-catenin. Additionally, our confocal microscopy results further showed reduced nuclear translocation of βcatenin following the ORM treatment. ORM treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), and induced the expression of pGSK3β. Experiments are also being conducted to see how ORM affects epigenetic markers linked to EMT and β-catenin signaling.
Conclusion: In summary, our findings demonstrate that ORM effectively inhibits β-catenin signaling and exhibits significant anticancer properties in hepatocellular carcinoma. These results suggest that ORM holds promise as a novel therapeutic option for the treatment of HCC, warranting further investigation and development.
Recommended Citation
Sikander, Mohammed; Malik, Shabnam; Zubieta, Daniel; Rodriguez, Anyssa; Vela, Molly; Khan, Sheema; Halaweish, Fathi T.; Yallapu, Murali M.; Jaggi, Meena; and Chauhan, Subhash C., "Ormeloxifene-Mediated Attenuation of β-Catenin Signaling in Hepatocellular Carcinoma Progression" (2025). Research Symposium. 23.
https://scholarworks.utrgv.edu/somrs/2025/talks/23
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Alternative and Complementary Medicine Commons, Biology Commons, Laboratory and Basic Science Research Commons
Ormeloxifene-Mediated Attenuation of β-Catenin Signaling in Hepatocellular Carcinoma Progression
Background: Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, with approximately 41,000 new cases and 29,000 deaths annually in the U.S. The management of HCC poses significant challenges due to severe toxicity and inadequate responses to existing chemotherapeutic agents. Aberrant β-catenin signaling is recognized as a crucial factor influencing the differentiation grades of HCC patients. Therefore, there is an urgent need to identify more effective and non-toxic β-catenin inhibitors for cancer treatment. Notably, ormeloxifene (ORM), a clinically approved selective estrogen receptor modulator with a favorable therapeutic index, has demonstrated remarkable anticancer activity, making it a promising candidate for repurposing. This study aims to explore the anticancer potential of ORM against hepatocellular carcinoma.
Methodology: Cell proliferation and colony formation assays were performed to assess the therapeutic activity of ORM in human hepatocellular carcinoma (HepG2, SK-HEP-1, Hep3B, and C3A) cells. Boyden chamber and Matrigel assays were carried out for investigating the effect of ORM on migration and invasion abilities of HCC cells, respectively. The effects of ORM on βcatenin and EMT associated proteins were analyzed through Western blotting and qPCR. Confocal microscopy was used to determine the β-catenin nuclear localization following ORM treatment in HCC cells.
Results: As compared to vehicle-treated group, ORM treatment (2.5-20 µM) suppressed proliferation and colony formation in human hepatocellular carcinoma cells in a dose and timedependent manner. Moreover, ORM treatment suppresses the migration and invasion of human hepatocellular carcinoma cells as shown by wound healing and Matrigel invasion assay, respectively. ORM effectively inhibited the protein levels and mRNA expression of total β-catenin. Additionally, our confocal microscopy results further showed reduced nuclear translocation of βcatenin following the ORM treatment. ORM treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), and induced the expression of pGSK3β. Experiments are also being conducted to see how ORM affects epigenetic markers linked to EMT and β-catenin signaling.
Conclusion: In summary, our findings demonstrate that ORM effectively inhibits β-catenin signaling and exhibits significant anticancer properties in hepatocellular carcinoma. These results suggest that ORM holds promise as a novel therapeutic option for the treatment of HCC, warranting further investigation and development.
