Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Int J Cancer. 2014 Jul 15;135(2):308-18. doi: 10.1002/ijc.28692. Epub 2014 Jan 10.
Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.
卵巢癌是最致命的妇科恶性肿瘤，而卵巢透明细胞腺癌（OCCA）尤其因其化疗耐药性高，在卵巢癌亚型中预后相对较差。Chromobox (CBX) 7 是多梳抑制复合物 1 的一个组成部分，通过下调 INK4a/ARF 的表达来延长正常人类细胞的寿命，而 INK4a/ARF 的表达会促进细胞周期进程。然而，最近研究 CBX7 表达与患者生存之间关系的报告在肿瘤细胞起源方面存在差异，并且 CBX7 在人类癌中的精确作用仍不清楚。在本研究中，我们通过免疫组织化学分析了 81 例 OCCA 患者的 CBX7 表达，并评估了其与临床结局的关系。CBX7 阳性患者的总生存期和无进展生存期均明显短于 CBX7 阴性患者（p < 0.05）。使用两种 OCCA 细胞系 TOV21G 和 KOC-7C 的 CBX7 敲低实验表明，与对照细胞相比，细胞活力显著降低（p < 0.001）。表达微阵列分析显示，凋亡相关基因，特别是肿瘤坏死因子相关凋亡诱导配体（TRAIL），在 CBX7 敲低细胞中显著上调（p < 0.01）。我们进一步证实，CBX7 敲低导致 OCCA 细胞中 TRAIL 诱导的凋亡。因此，在本研究中，我们首次表明 CBX7 与 OCCA 预后不良有关。我们还成功证明，TRAIL 途径是这些细胞中 CBX7 表达调节的新靶点，并且利用 TRAIL 途径的治疗剂可能对靶向 OCCA 治疗特别有效。
