Chishiki Mayuko, Takagi Kiyoshi, Sato Ai, Miki Yasuhiro, Yamamoto Yuta, Ebata Akiko, Shibahara Yukiko, Watanabe Mika, Ishida Takanori, Sasano Hironobu, Suzuki Takashi
Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Cancer Sci. 2017 Jul;108(7):1510-1519. doi: 10.1111/cas.13251. Epub 2017 May 19.
It is well known that comedo necrosis is closely associated with an aggressive phenotype of ductal carcinoma in situ (DCIS) of human breast, but its molecular mechanisms remain largely unclear. Therefore, in this study, we first examined the gene expression profile of comedo DCIS based on microarray data and identified CYC1 as a gene associated with comedo necrosis. Cytochrome c1 (CYC1) is a subunit of complex III in the mitochondrial oxidative phosphorylation that is involved in energy production. However, the significance of CYC1 has not yet been examined in DCIS. We therefore immunolocalized CYC1 in 47 DCIS cases. CYC1 immunoreactivity was detected in 40% of DCIS cases, and the immunohistochemical CYC1 status was significantly associated with tumor size, nuclear grade, comedo necrosis, van Nuys classification, and Ki-67 labeling index. Subsequent in vitro studies indicated that CYC1 was significantly associated with mitochondrial membrane potential in MCF10DCIS.com DCIS cells. Moreover, CYC1 significantly promoted proliferation activity of MCF10DCIS.com cells and the cells transfected with CYC1 siRNA decreased pro-apoptotic caspase 3 activity under hypoxic or anoxic conditions. Considering that the center of DCIS is poorly oxygenated, these results indicate that CYC1 plays important roles in cell proliferation and comedo necrosis through the elevated oxidative phosphorylation activity in human DCIS.
众所周知，粉刺样坏死与人类乳腺导管原位癌（DCIS）的侵袭性表型密切相关，但其分子机制仍不清楚。因此，在本研究中，我们首先基于微阵列数据检查了粉刺样DCIS的基因表达谱，并确定CYC1为与粉刺样坏死相关的基因。细胞色素c1（CYC1）是线粒体氧化磷酸化复合体III的一个亚基，参与能量产生。然而，CYC1在DCIS中的意义尚未得到研究。因此，我们对47例DCIS病例进行了CYC1免疫定位。在40%的DCIS病例中检测到CYC1免疫反应性，免疫组化CYC1状态与肿瘤大小、核分级、粉刺样坏死、van Nuys分类和Ki-67标记指数显著相关。随后的体外研究表明，CYC1与MCF10DCIS.com DCIS细胞中的线粒体膜电位显著相关。此外，CYC1显著促进MCF10DCIS.com细胞的增殖活性，并且在缺氧或无氧条件下，转染CYC1 siRNA的细胞降低了促凋亡半胱天冬酶-3的活性。考虑到DCIS的中心氧合不足，这些结果表明CYC1通过提高人DCIS中的氧化磷酸化活性在细胞增殖和粉刺样坏死中发挥重要作用。
