Study On The Inhibition Of Melanoma Metastasis By Targeting The Oncogenic Protein ?-catenin

Metastatic melanoma accounts for 60%of death among the skin cancer.The main reason of the cancer patient death is the metastasis of melanoma cells to the important organs,such as lung,brain,and liver,resulting in the dysfunction of these organs.Although great efforts have been made to treat the metastatic melanoma,effective drugs against the disease are still lacking in the clinical setting.Early melanoma can be removed by surgical resection,combined with chemotherapy and radiotherapy.But the 5-year survival rate of the metastatic melanoma patients is only 14%.So far,effective drugs against metastatic melanoma are absent in the clinical setting.Therefore,how to inhibit tumor metastasis is a key scientific question for treatment of melanoma.?-catenin is the most critical effector protein in the Wnt signaling pathway.It enters into cell nucleus and binds to TCF/LEF transcription factors to activate transcription of various cancer metastasis-related genes,such as MMP9 and Axin2,thereby enhancing the Wnt-?-catenin signaling pathway,activating EMT and promoting cancer metastasis.Current inhibitors against the Wnt-?-catenin signaling pathway have been tried in clinical trials,but the anti-cancer efficacy is very low.Therefore,how to target ?-catenin is a scientific question to be solved in the study of cancer metastasis.We explored effective components that enable to inhibit the metastasis of melanoma from 120 types of the traditional Chinese medicinal herbs,and selected a monomer named lycorine hydrochloride(LH)that is sensitive to melanoma after screening.It has been reported by us and other researchers that LH exerts anti-cancer effect,but the role of LH against melanoma metastasis has not yet been reported so far.Therefore,we raised the scientific question:Can LH target the expression of ?-catenin to inhibit melanoma metastasis?To this end,we proposed the scientific hypothesis that LH can inhibit the metastasis of melanoma by targeting oncogenes such as ?-catenin.In this investigation,we mainly carried out experimental research at the molecular biology,cell biology,and animal three levels.At the molecular level,we found that the LH effectively increased ?-catenin protein degradation in melanoma cells in the dose and time dependent manners.And mechanistic study showed that LH increased the ?-catenin protein degradation mainly through the ubiquitination-proteasome pathway.In vivo,studies displayed that LH reduced pulmonary metastases of melanoma in nude mice,and prolonged the survival time of the tumor-bearing mice with very low toxicity.At the cell level,we found that LH can effectively inhibit the adhesion,migration,and invasion of melanoma cells.The mechanistic studies revealed that LH mainly reduced the protein level of ?-catenin and inhibited the expression of P-catenin downstream metastatic genes matrix metallopeptidase 9(MMP9)and Axin2.In summary,we found that LH can effectively inhibit the migration,invasion and metastasis of melanoma cells by targeting oncogenes such as ?-catenin.Our findings provide new strategy and drug candidate for the treatment of metastatic melanoma.