Paired box 5 increases the chemosensitivity of esophageal squamous cell cancer cells by promoting p53 signaling activity.
Paired box 5 increases the chemosensitivity of esophageal squamous cell cancer cells by promoting p53 signaling activity.
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DOI：
10.1097/cm9.0000000000002018
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发表时间：
2022-02-21
影响因子：
6.1
通讯作者：
Dai G
中科院分区：
文献类型：
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作者：
Zhang W;Yan W;Qian N;Han Q;Zhang W;Dai G
基因启动子甲基化是肿瘤发生的一个重要表观遗传学改变，在肿瘤的发生发展中起着重要作用。PAX 5基因是B细胞分化和胚胎神经发育早期的重要调控因子，在多种肿瘤中由于甲基化而下调，其在食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）发病机制中的作用尚不清楚。为了阐明PAX 5在ESCC中的作用，研究了8个ESCC细胞系、51个原发性ESCC组织样本和8个正常食管粘膜样本，并查询了癌症基因组图谱（TCGA）。逆转录-聚合酶链反应和蛋白质印迹法检测PAX 5的表达。通过流式细胞术、集落形成试验和3-（4，5-二甲基-2-噻唑基）-2，5-二苯基-2-H-溴化四氮唑试验检测PAX 5过表达或沉默的ESCC细胞系的细胞凋亡、增殖和化疗敏感性。建立肿瘤异种移植模型用于体内验证。PAX 5基因甲基化在原发性食管鳞癌中的阳性率为37.3%（19/51），与年龄（P = 0.007）和肿瘤淋巴结转移分期（P = 0.014）显著相关。 TCGA数据分析表明PAX 5表达与启动子区域甲基化呈负相关（cg 00464519的r =-0.189，P=0.011; cg 02538199的r=-0.228，P =0.002）。 PAX 5表达的恢复抑制了ESCC细胞系的细胞增殖、促进了细胞凋亡并抑制了肿瘤生长，这一点在异种移植小鼠中得到了验证。异位PAX 5表达显著增加p53报告荧光素酶活性，并增加p53信使RNA和蛋白水平。PAX 5与p53启动子区域的直接相互作用通过染色质免疫沉淀测定证实。PAX 5致敏ESCC细胞系KYSE 150和KYSE 30对氟尿嘧啶和多西他赛的再表达。PAX 5的沉默诱导KYSE 450细胞对这些药物的抗性。PAX 5作为一种受启动子区甲基化调控的抑癌基因，在人ESCC中抑制增殖，促进凋亡，并诱导p53信号转导的激活。PAX 5可作为食管鳞癌的化疗敏感标志物。
Gene promoter methylation is a major epigenetic change in cancers, which plays critical roles in carcinogenesis. As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment, the paired box 5 (PAX5) gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma (ESCC) pathogenesis remains unclear. To elucidate the role of PAX5 in ESCC, eight ESCC cell lines, 51 primary ESCC tissue samples, and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas (TCGA) was queried. PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting. Cell apoptosis, proliferation, and chemosensitivity were detected by flow cytometry, colony formation assays, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing. Tumor xenograft models were established for in vivo verification. PAX5 methylation was found in 37.3% (19/51) of primary ESCC samples, which was significantly associated with age (P = 0.007) and tumor-node-metastasis stage (P = 0.014). TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation (r = −0.189, P = 0.011 for cg00464519 and r = −0.228, P = 0.002 for cg02538199). Restoration of PAX5 expression suppressed cell proliferation, promoted apoptosis, and inhibited tumor growth of ESCC cell lines, which was verified in xenografted mice. Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels. A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays. Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel. Silencing of PAX5 induced resistance of KYSE450 cells to these drugs. As a tumor suppressor gene regulated by promoter region methylation in human ESCC, PAX5 inhibits proliferation, promotes apoptosis, and induces activation of p53 signaling. PAX5 may serve as a chemosensitive marker of ESCC.
DOI：
10.1186/bcr3326
发表时间：
2012-11-06
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Lønning PE;Knappskog S
通讯作者：
Knappskog S
食管鳞状细胞癌中抑癌基因的启动子甲基化。
影响因子：
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作者：
Li JS;Ying JM;Wang XW;Wang ZH;Tao Q;Li LL
通讯作者：
Li LL