YY1 是三氧化二砷治疗 HPV 感染引起的宫颈癌的一个新的潜在治疗靶点。
YY1 is a novel potential therapeutic target for the treatment of HPV infection-induced cervical cancer by arsenic trioxide.
机构信息
Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
出版信息
Int J Gynecol Cancer. 2011 Aug;21(6):1097-104. doi: 10.1097/IGC.0b013e31821d2525.
OBJECTIVE
YY1 is a zinc finger transcription factor involved in the regulation of cell growth, development, and differentiation. Although YY1 can regulate human papillomavirus-type (HPV) viral oncogenes E6 and E7, it remains unknown if YY1 plays a key role in carcinoma progression of HPV-infected cells. Here we sought to determine whether YY1 is upregulated in the cervical cancer tissues and YY1 inhibition contributes to apoptosis of cervical cancer cells, which is at least partly p53 dependent. Therefore, YY1 can be a potential therapeutic target for cervical cancer treatment by arsenic trioxide (As2O3).
MATERIALS AND METHODS
The expression level of YY1 was examined and analyzed by Western blot in pathologically confirmed primary cervical cancer samples, in the adjacent normal samples, as well as in normal cervix samples. The effects of YY1 inhibition by specific small interfering RNA in HeLa cells were determined by Western blot analysis of p53 level, cell growth curve, colony formation assay, and apoptosis. The contribution of YY1 to As2O3-induced p53 activation and apoptosis was also examined by Western blot and cell cycle analysis.
RESULTS
Here we report that the expression level of YY1 is significantly elevated in the primary cancer tissues. In HPV-positive HeLa cells, small interfering RNA-mediated YY1 inhibition induced apoptosis and increased the expression of p53. Treatment of HeLa cells with As2O3, a known anti-cervical cancer agent, reduced both protein and mRNA levels of YY1 in HeLa cells. YY1 knockdown significantly further enhanced As2O3-induced apoptosis.
CONCLUSIONS
These results demonstrated that the expression of YY1 is upregulated in cervical carcinomas and that YY1 plays a critical role in the progression of HPV-positive cervical cancer. In addition, YY1 inhibition induces p53 activation and apoptosis in HPV-infected HeLa cells. Thus, YY1 is an As2O3 target and could serve as a potential drug sensitizer for anti-cervical cancer therapy.
目的
YY1 是一种锌指转录因子，参与细胞生长、发育和分化的调节。尽管 YY1 可以调节人乳头瘤病毒（HPV）病毒癌基因 E6 和 E7，但尚不清楚 YY1 是否在 HPV 感染细胞的癌前病变中发挥关键作用。在这里，我们试图确定 YY1 是否在上皮性宫颈癌组织中上调，以及 YY1 抑制是否有助于宫颈癌细胞凋亡，这至少部分依赖于 p53。因此，YY1 可以成为三氧化二砷（As2O3）治疗宫颈癌的潜在治疗靶点。
材料和方法
通过 Western blot 检测和分析病理证实的原发性宫颈癌标本、相邻正常标本和正常宫颈标本中 YY1 的表达水平。通过 Western blot 分析 p53 水平、细胞生长曲线、集落形成试验和细胞凋亡来确定特异性小干扰 RNA 对 HeLa 细胞中 YY1 抑制的影响。还通过 Western blot 和细胞周期分析来研究 YY1 对 As2O3 诱导的 p53 激活和细胞凋亡的贡献。
结果
我们报告称，YY1 的表达水平在上皮性宫颈癌组织中显著升高。在 HPV 阳性的 HeLa 细胞中，小干扰 RNA 介导的 YY1 抑制诱导细胞凋亡并增加 p53 的表达。用三氧化二砷（一种已知的抗宫颈癌药物）处理 HeLa 细胞，可降低 HeLa 细胞中 YY1 的蛋白和 mRNA 水平。YY1 敲低显著增强了 As2O3 诱导的细胞凋亡。
结论
这些结果表明，YY1 在宫颈癌中表达上调，YY1 在 HPV 阳性宫颈癌的进展中起关键作用。此外，YY1 抑制诱导 HPV 感染的 HeLa 细胞中 p53 激活和凋亡。因此，YY1 是 As2O3 的靶标，可作为宫颈癌治疗的潜在药物增敏剂。
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