核纤层蛋白 laminA/C 促进前列腺癌侵袭转移的分子机制及作为潜在治疗靶点的研究

前列腺癌死亡率居男性癌症死亡率的第二位，高度异质性是其区别于其它肿瘤的重要特点。最近研究提出lamin A 可能是识别肿瘤分化和判断预后的新的肿瘤标志物。前期研究发现laminA/C 可增加前列腺癌细胞迁移及侵袭力；下调时可增加前列腺癌细胞的凋亡率；在前列腺癌组织中表达显著差异。目前，尚不知道lamin A/C表达差异性的意义及介导凋亡的机制。我们推测它可能是一种侵袭性前列腺癌的标志物及治疗靶标，可通过上皮间质转换机制调控癌细胞的迁移及侵袭。本项目拟采用免疫组织化学技术研究组织芯片中laminA/C与上皮及间质细胞标志物的关联性；建立laminA/C表达差异的细胞模型，研究上皮间质转换中信号通路及miRNA调控的差异；建立侵袭性动物模型，研究靶向前列腺癌中laminA/C 的疗效及机制。进而阐明laminA/C表达差异性的意义，揭示其可作为新的肿瘤标志物及治疗靶标提供可靠的实验依据。

Prostate cancer remains the second most common cause of cancer-related death in Western countries. A previous proteomics study suggested the nuclear membrane protein laminA/C to be a maker to discriminate low and high Gleason score tumors and to identify high risk cancers. To characterize its function in prostate cancer cells, we performed a detailed expression analysis in prostate cancer tissue and explored the consequences of down or up-regulation of laminA/C in prostate cancer cells. Our results confirm an increased laminA/C protein expression in high risk cancers and show association of expression with tumor cell formations at the invasion fronts of tumors and in invasion "spearheading" tumor cell clusters. In the prostate tumor cell lines LNCaP, DU145, and PC3 shRNA knockdown or overexpression of laminA/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the laminA/C-related malignant behavior is regulated through modulation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway. In this study, we found two interesting problems, first, the expression of laminA/C was heterogeneous with low immunostaining of central tumor areas and higher intensity staining at tumor boundary areas especially in subcapsular extensions and in a region of tumor growth into the adjacent lipoid tissue, second, survival of prostate cancer cell lines with stable knockdown laminA/C was dramatically reduced than that of benign prostatic hyperplasia epithial cell lines with stable knockdown laminA/C, on the other hand, apoptosis rate of them was increased compared with that of benign prostatic hyperplasia epithial cell lines. The mechanism of the heterogeneous expression pattern of lamninA/C is unknown till now. So we hypothesize that laminA/C is a characteristic biomarker to distinguish aggressive prostate cancer cell differentiation and a molecular target for treatment of invasive prostate cancer. We plan to establish and analyze benign basal epithelium, low-invasive or high-invasive prostate cancer cell lines and invasive prostate cancer animal models to unravel the undelaying mechanism. A candidate pathway that might be involved is epithelial to stromal transition (EMT). From this point of view, we will further explore laminA/C genomic differences or miroRNA regulation difference in the different benign and tumor models using DNA　sequence and molecular biology technology; At the same time, we will explore if laminA/C is related to biomarkers and pathway of EMT on the cell model by gene overexpression or knockdown techniques; At last, we will explore the laminA/C siRNA treatment effect in an invasive prostate cancer animal model. In summary, we will supply enough experimental datas to support our views for laminA/C as a new molecular biomaker in the progression of prostate cancer and potentially novel target for invasive prostate cancer therapeutics.