Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway
Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway
复制标题
DOI：
10.1093/carcin/bgs022
复制
发表时间：
2012-04-01
期刊：
影响因子：
4.7
通讯作者：
Klocker, Helmut
中科院分区：
文献类型：
--
作者：
Kong, Lu;Schaefer, Georg;Klocker, Helmut
前列腺癌（PC）仍然是西方国家癌症相关死亡的第二大常见原因。以前的蛋白质组学研究表明，核膜蛋白核纤层蛋白A/C是区分低和高Gleason评分肿瘤和识别高风险癌症的标志物。为了表征其在PC细胞中的功能，我们在PC组织中进行了详细的表达分析，并探讨了PC细胞中核纤层蛋白A/C下调或上调的后果。我们的研究结果证实了核纤层蛋白A/C蛋白在高危癌症中的表达增加，并显示了表达与肿瘤侵袭前沿和侵袭“先锋”肿瘤细胞簇中肿瘤细胞形成的相关性。在前列腺肿瘤细胞系中，LNCaP、DU 145和PC 3小发夹RNA敲低或核纤层蛋白A/C过表达分别导致细胞生长、集落形成、迁移和侵袭的抑制或刺激。进一步的机制研究表明，核纤层蛋白A/C相关的恶性行为是通过调节磷酸肌醇3-激酶（PI 3 K）/AKT/PTEN信号通路来调节的。蛋白质印迹结果表明，敲低或过表达核纤层蛋白A/C分别降低或增加了所有三种细胞系中PI 3 K亚基p110和p85的蛋白水平;在PTEN阴性细胞系LNCaP和PC 3中磷酸化AKT，并且分别增加或降低了PTEN阳性DU 145细胞中的PTEN蛋白水平。总之，我们的数据表明，核纤层蛋白A/C蛋白通过PI 3 K/AKT/PTEN途径积极参与PC细胞的恶性行为。核纤层蛋白A/C可能是一种新的致癌因子，也是治疗PC的新靶点。
Prostate cancer (PC) remains the second most common cause of cancer-related death in Western countries. A previous proteomics study suggested that the nuclear membrane protein lamin A/C to be a maker to discriminate low- and high-Gleason score tumors and to identify high-risk cancers. To characterize its function in PC cells, we performed a detailed expression analysis in PC tissue and explored the consequences of down or upregulation of lamin A/C in PC cells. Our results confirm an increased lamin A/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 small hairpin RNA knockdown or overexpression of lamin A/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the lamin A/C-related malignant behavior is regulated through modulation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway. Western blot results indicated that knockdown or overexpression of lamin A/C decreased or increased, respectively, protein levels of the PI3K subunits p110 and p85 in all three cell lines; phosphor-AKT in the PTEN-negative cell lines LNCaP and PC3, and, increased or decreased, respectively, PTEN protein levels in PTEN-positive DU145 cells. Together, our data suggest that lamin A/C proteins are positively involved in malignant behavior of PC cells through the PI3K/AKT/PTEN pathway. Lamin A/C may represent a new oncogenic factor and a novel therapeutic target for PC.