Molecular Therapy Research Center, Sungkyunkwan University, Samsung Medical Center, 50 Ilwon-dong, Kangnamgu, Seoul 135-710, Korea.
Carcinogenesis. 2012 Jan;33(1):77-83. doi: 10.1093/carcin/bgr257. Epub 2011 Nov 16.
Ovarian cancer is a gynecological cancer with a high death rate. We utilized global gene expression profiles of ovarian carcinomas obtained by complementary DNA (cDNA) microarray to identify ovarian cancer-specific proteins. CD9 was upregulated in ovarian carcinomas, and overexpression of the CD9 protein was detected in ovarian carcinomas by immunohistochemistry. CD9 was also overexpressed in several cancer cell lines, including ovarian cancer cells. In order to elucidate the biological significance of highly expressed CD9 in cancer cells, functional studies of CD9 were performed by ectopic expression, knockdown of CD9 using small interfering RNA (siRNA) and blockage of CD9 activity using the CD9-specific monoclonal antibody ALB6. Ectopic CD9 induced cell survival. In order to identify signaling pathways related to CD9, the gene expressions of CD9/SKOV3 cells were analyzed by cDNA microarray. Among the many upregulated genes, tumor necrosis factor (TNF)-α was induced in CD9/SKOV3 cells. The effect of overexpressed CD9 on the downstream signaling events of TNF-α was further investigated. In CD9/SKOV3 cells, the nuclear factor-kappaB (NF-κB)-signaling pathway was constitutively activated. Knockdown of CD9 by siRNA and blockage of CD9 activity by ALB6 in ovarian cancer cells demonstrated that constitutive activation of NF-κB is CD9 dependent and that CD9 is involved in anti-apoptosis. A CD9 functional study was performed in an ovarian cancer-xenograft mouse by injecting ALB6 into the peritoneum. ALB6 resulted in reduced tumor weight compared with that of control IgG(1). Collectively, these results demonstrate that CD9 functions as an oncogene and represents a target for the development of cancer-specific therapeutics.
卵巢癌是一种死亡率很高的妇科癌症。我们利用 cDNA 微阵列获得的卵巢癌的全球基因表达谱来鉴定卵巢癌特异性蛋白。CD9 在卵巢癌中上调，免疫组织化学检测到 CD9 蛋白在卵巢癌中过表达。CD9 也在几种癌细胞系中过表达，包括卵巢癌细胞。为了阐明高度表达的 CD9 在癌细胞中的生物学意义，通过异位表达、使用小干扰 RNA (siRNA) 敲低 CD9 以及使用 CD9 特异性单克隆抗体 ALB6 阻断 CD9 活性来进行 CD9 的功能研究。异位表达 CD9 诱导细胞存活。为了鉴定与 CD9 相关的信号通路，通过 cDNA 微阵列分析 CD9/SKOV3 细胞的基因表达。在许多上调的基因中，CD9/SKOV3 细胞中诱导产生了肿瘤坏死因子 (TNF)-α。进一步研究了过表达 CD9 对 TNF-α下游信号事件的影响。在 CD9/SKOV3 细胞中，核因子-κB (NF-κB)-信号通路被持续激活。siRNA 敲低 CD9 和 ALB6 阻断 CD9 活性在卵巢癌细胞中的作用表明，NF-κB 的持续激活依赖于 CD9，并且 CD9 参与抗细胞凋亡。通过向卵巢癌异种移植小鼠的腹腔内注射 ALB6 进行 CD9 功能研究。与对照 IgG(1) 相比，ALB6 导致肿瘤重量减轻。总之，这些结果表明 CD9 作为一种癌基因发挥作用，是开发癌症特异性治疗方法的靶标。
