Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Department of Obstetrics and Gynecology, The Affiliated Cixi Hospital, Wenzhou Medicine University, Cixi, Zhejiang 325000, P.R. China.
Oncol Rep. 2019 Apr;41(4):2351-2360. doi: 10.3892/or.2019.6993. Epub 2019 Feb 1.
The development of cervical cancer (CC) is a multi‑gene, multi‑step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY‑related HMG‑box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation‑specific polymerase chain reaction. The SOX11 expression and promoter methylation in human CC cell lines were also determined. The effect of SOX11 expression restoration after 5‑aza‑2'‑deoxycytidine (5‑Aza‑dC) treatment on the CC cell proliferation ability was evaluated in CC cell lines. SOX11 was highly expressed in normal cervix (NC) and precancerous low‑grade squamous intraepithelial lesions, but weakly expressed or virtually absent in precancerous high‑grade squamous intraepithelial lesions and CC, which is consistent with the result of the western blot analysis. Hypermethylation of the SOX11 promoter was detected in CC, which was significantly higher than that in NC samples at each CpG site. The expression level of SOX11 in the CC cell lines was downregulated compared with the positive control, Tera‑1human teratoma cell line. Upon 5‑Aza‑dC treatment, SOX11 expression was significantly upregulated in the CC cell lines at the mRNA and protein levels, and cell proliferation was inhibited. The results indicated that the downregulation of SOX11 in CC is due to the hypermethylation of the SOX11 promoter region. Thus, SOX11 methylation may have a role in the growth of CC cells and cervical carcinogenesis.
宫颈癌（CC）的发生是一个多基因、多步骤的致癌过程，涉及复杂的遗传和表观遗传机制。SRY 相关高迁移率族框基因 11（SOX11）是转录因子 SOX 家族的成员，在多种肿瘤类型的发展中具有新兴的关键作用。为了阐明 SOX11 在宫颈癌发生中的作用，通过免疫组织化学和 Western blot 分析分析了 SOX11 在人 CC 发展过程中的表达水平。此外，还通过亚硫酸氢盐测序和甲基化特异性聚合酶链反应检查了 SOX11 的甲基化状态。还确定了人 CC 细胞系中 SOX11 的表达和启动子甲基化。在 CC 细胞系中，用 5-氮杂-2'-脱氧胞苷（5-Aza-dC）处理后 SOX11 表达恢复对 CC 细胞增殖能力的影响进行了评估。SOX11 在正常宫颈（NC）和癌前低度鳞状上皮内病变中高表达，但在癌前高度鳞状上皮内病变和 CC 中表达较弱或几乎不存在，这与 Western blot 分析的结果一致。在 CC 中检测到 SOX11 启动子的高甲基化，每个 CpG 位点的甲基化水平均明显高于 NC 样本。与阳性对照，Tera-1 人畸胎瘤细胞系相比，CC 细胞系中 SOX11 的表达水平下调。用 5-Aza-dC 处理后，CC 细胞系中 SOX11 的表达在 mRNA 和蛋白水平均显著上调，细胞增殖受到抑制。结果表明，CC 中 SOX11 的下调是由于 SOX11 启动子区域的高甲基化。因此，SOX11 甲基化可能在 CC 细胞的生长和宫颈癌发生中起作用。
