Molecular Regulation Mechanism Of The Antimitotic Target LIV1

Aim:Drugs that perturb the process of cell division have proved to be effective in anticancer therapies.Traditional microtubule toxic drugs are poor selectivity, and have side effects, and new generation anti-mitotic agents can not kill the mitotic slippage cells effectively. Therefore, how to effectively kill the mitotic escape cells is the main issues to enhance the effective of anti-mitotic drugs. In our previous study, we screening out the effective gene LIV1by SMART technology, and in the follow up study, we gradually prove LIV1is a key regulator of mitotic checkpoint.Method:The cell viability in different treatments was determined by MTT; When the siRNA depleted the LIV1expression, the mitosis and apoptosis induced by anti-mitotic drugs were detected by flow cytometry; Immunofluorescence assayed the LIV1cellular localization; Flow cytometry and confocal laser scanning analyzed cell cycle and apoptosis in cells expressed exogenous LIV1. Immunohistochemical detected the clinical correlation between LIV1expression and tumors.Results:AS-LIV1stable cells with depletion of LIV1expression were against TSA-induced apoptosis, while resistant to anti-mitotic drug-induced apoptosis, but not resistant to cisplatin-induced apoptosis; Depletion of LIV1expression by siRNA can resist to the reduction of cell viability induced by Paclitaxel; The lose of LIV1cause the mitotic checkpoint inactivation, tumor cells mitotic slipage, avoid apoptosis and carried out normal mitosis; Shake-off experiments showed depletion of LIV1can speed up the process of mitosis and cause abnormal mitotic chromosome alignment and immature chromosome segregation; Depletion of LIV1in Long-term can arise chromosome instability including micronucleus, multinucleus, and>2N or<2N X chromosomes; LIV1localized in the endoplasmic reticulum; Even importantly, the overexpression of LIV1can trigger tumor cells death; And it is important that LIV1is frequently decreased expression in lots of human cancer.Conclution:We purpose LIV1and it’s pathway can be the important anti-mitotic molecular target. Through establishment of reseach model to study the LIV1and its pathway, which regulate the mitosis in physiological and pathological conditions. Finally by finding LIV1expression enhancer we can get a more effective tumor-antagonistic drugs, which can open up a new targets and direction for the treatment of tumors.