The radiation-induced cell-death signaling pathway is activated by concurrent use of cisplatin in sequential biopsy specimens from patients with cervical cancer
The radiation-induced cell-death signaling pathway is activated by concurrent use of cisplatin in sequential biopsy specimens from patients with cervical cancer
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DOI：
10.4161/cbt.6.6.4098
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发表时间：
2007-06-01
影响因子：
3.6
通讯作者：
Imai, Takashi
中科院分区：
文献类型：
--
作者：
Iwakawa, Mayumi;Ohno, Tatsuya;Imai, Takashi
目的：探讨铂类化合物联合放疗治疗宫颈癌相关基因表达的变化。患者和方法：39例宫颈鳞癌患者在分次放疗前和分次放疗中采集活检标本。20例患者接受单纯放疗(RT)，19例患者接受同样的放疗加顺铂(CRT)化疗。使用由44K人类序列组成的单色寡核苷酸芯片研究了治疗诱导的基因表达的变化。石蜡包埋标本用于检测细胞凋亡和治疗反应基因的蛋白表达。通过实时逆转录聚合酶链式反应评估这些基因的mRNA表达的变化。结果：CDKN1A、Bax、TNFSF8和RRM2B的表达在CRT(9Gy单用顺铂)后持续上调。虽然不同肿瘤之间的差异更大，但单纯的RT(9Gy射线)也引起了类似的表达变化。两组细胞凋亡率均显著增加。CRT可显著增加CDKN1A阳性细胞弥漫性分布的病例数。在高频率的标本中检测到2q33-ter基因缺失和3q26-ter获得，60%的人乳头瘤病毒DNA阳性，3个肿瘤有p53基因的缺失/突变。CDKN1A、Bax、TNFSF8、RRM2B的表达变化与组间差异无统计学意义。结论：利用宫颈肿瘤治疗前后的活检标本，我们发现了与细胞死亡信号通路相关的治疗诱导基因。CRT产生了已知辐射反应基因表达变化的同质模式。
Objective: To identify changes in gene expression related to the concurrent use of platinum compounds with radiotherapy, in the treatment of cervical cancer.Patients and Methods: Biopsy specimens were obtained from 39 patients with squamous cell carcinoma of the uterine cervix, before and during fractionated radiotherapy. Twenty patients were treated with radiotherapy (RT) alone, while 19 received the same radiotherapy plus concomitant chemotherapy with cisplatin (CRT). Changes in gene expression induced by treatment were investigated using single-color oligo-microarrays consisting of 44K human sequences. Paraffin-embedded samples were used to examine apoptosis and the expression of protein by treatment-responsive genes. Changes in mRNA expression were assessed for these genes by real-time reverse transcriptase-polymerase chain reaction. Aberrant genomic change (detected using microarray-based comparative genomic hybridization), human papillomavirus infection, and p53 status were also evaluated.Results: The expression of CDKN1A, BAX, TNFSF8 and RRM2B was consistently upregulated by CRT (9 Gy with a single administration of cisplatin). Similar expression changes were induced by RT (9 Gy) alone, although the variability between tumors was greater. Apoptotic cells were significantly increased in both groups. CRT significantly increased the numbers of cases with diffusely distributed CDKN1A-positive cells. Genetic losses at 2q33-ter and gains of 3q26-ter were detected in the samples with high frequency; 60% were positive for human papillomavirus DNA; and three tumors had deletions/mutations of the p53 gene. There was no difference in the incidence of these genomic changes between the groups, and no association was found with the changes in expression of CDKN1A, BAX, TNFSF8 or RRM2B.Conclusions: Using biopsy samples from pretreatment and midtreatment cervical tumors, we identified therapy-induced genes related to the cell death signaling pathway. CRT produced a homogenous pattern of changes in expression of known radiation-responsive genes.