抗有丝分裂新靶点 LIV1 的分子调控机制研究及靶向药物筛选

Drugs that interfere with mitotic progression are used extensively as first-line agents for the treatment of cancer. However, current microtubule toxins such as taxanes and vinca alkaloids have severe side effects including myelosuppression and peripheral neuropathies. On the other hand, the new generation anti-mitotic drugs targeting novel mitotic drug targets other than microtubules avoid side effects of neurotoxicity and myelosuppression as hoped, but their efficacy against cancers seems to be much less potent than expected. Thus, to search for more ideal mitotic targets has becoming one of the key issues in developing novel anti-mitotic drugs. Our previous studies have provided significant clues to identify novel anti-mitotic targets. LIV1 is a newly-cloned gene. Until now, only limited studies are available, which proposed LIV1 belongs to a subfamily of ZIP zinc transporters. Previous investigations declare that LIV1 expression is associates with lymph node involvement of metastatic spread in estrogen receptor-positive breast cancer. Nevertheless, we identify that LIV1 as a key regulator of spindle assembly checkpoint activation. More interestingly, LIV1 prevents mitotic slippage from anti-mitotic drug-induced mitotic arrest, and trigger tumor cell death by activating death pathways. Loss of LIV1 expression at the protein level is a common occurrence in many types of tumors. These novel findings highlight a previously unrecognized mechanism to monitor mitotic progression which could be potentially targeted for cancer treatment. In coming study, we will explore the regulatory machine of LIV1 pathway by using comprehensive approaches such as model animals, and screen for the chemical compounds for targeted recovering expression of LIV1 protein in tumors. Further understanding and modulating the LIV1 pathway hold the promise for developing novel anti-mitotic strategy.

抗有丝分裂药物在肿瘤化疗中有举足轻重的地位。然而，经典的微管毒性药存在毒副作用大等缺陷。而新一代抗有丝分裂剂尽管明显降低了毒副作用，但抗肿瘤活性却普遍低于预期。因此，寻找更理想的靶点，已成为研发新的有丝分裂靶向剂亟待解决的关键问题。LIV1 是近年克隆的新基因，既往，为数很少的研究认为 LIV1 是锌离子转运蛋白家族一员，与雌激素阳性乳腺癌的淋巴结转移相关。而申请者则首次发现LIV1不仅调控纺锤体组装检测点的活性，还能阻抑肿瘤细胞"逃逸"有丝分裂阻滞、促进肿瘤细胞死亡。在多种肿瘤中，由于转录后抑制机制，LIV1表达缺失非常普遍。强烈提示LIV1可能是细胞监控有丝分裂的一种新机制、是潜在的治疗新靶点。为此，我们拟采用模式动物学等系统的综合技术手段，深入研究LIV1调控有丝分裂的分子机制，并筛选增强 LIV1蛋白表达的抗肿瘤化合物，为研发新的有丝分裂靶向阻滞剂提供新的、关键的理论基础。

抗有丝分裂药物在肿瘤化疗中有举足轻重的地位。然而，现有的发现均不能很好地解释在有丝分裂阻滞背景下，细胞如何决定和调控“有丝分裂阻滞逃逸信号”和“细胞死亡信号”二个信号的动态调控机制。LIV1是近年克隆的新基因，既往为数很少的研究认为 LIV1 是锌离子转运蛋白家族一员，与雌激素阳性乳腺癌的淋巴结转移相关。在前期工作研究的基础上，我们明确了 LIV1功能失活导致肿瘤细胞逃逸有丝分裂毒性药物诱导的杀伤作用，以二倍体形式继续分裂存活，并出现多种基因组不稳定的典型特征. GRPEL1作为LIV-1 T2下游分子，LIV-1 T2 通过调节GRPLE1泛素化以此改变细胞中GRPEL1表达，从而实现对细胞有丝分裂及细胞凋亡的调控。LIV-1 基因敲除小鼠可以完全重复体外细胞中LIV1-GRPEL1 控制和协调 有丝分裂的功能表型。由于转录后抑制机制，在多种肿瘤中LIV1 –GRPEL1表达缺失，与肿瘤的病理分级和临床化疗耐药直接相关。靶向LIV-1-GRPEL1的小分子肽能再次激活LIV-1-GRPEL1通路从而有效的杀灭肿瘤细胞。综上所述，LIV1-GRPEL1 调控轴在 有丝分裂中承担控制和协调“有丝分裂阻滞逃逸信号”和“细胞死亡信号”二大信号系统的关键作用，为研发新的有丝分裂靶向阻滞剂提供了关键的理论基础。