High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer
High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer
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DOI：
10.1007/s12282-010-0228-3
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发表时间：
2012-04-01
期刊：
影响因子：
4
通讯作者：
Mokbel, Kefah
中科院分区：
文献类型：
--
作者：
Salhab, Mohamed;Patani, Neill;Mokbel, Kefah
线粒体功能障碍可能与基因组不稳定有关，并且与包括乳腺癌 (BC) 在内的多种人类恶性肿瘤的发病机制有关。线粒体蛋白、线粒体内膜转位酶 17 同源物 A (TIMM17A) 有助于形成对于线粒体功能至关重要的前蛋白输入复合物。在这项研究中，评估了良性和恶性乳腺组织中的TIMM17A mRNA表达，并与病理和临床结果相关。对乳腺癌组织（n = 127）和正常组织（n = 33）进行RNA提取和反转录，使用实时定量PCR测定转录物水平并针对CK19进行归一化。比较转录水平，然后根据肿瘤大小、肿瘤分级、雌激素受体 (ER) 状态、淋巴结受累、TNM 分期、诺丁汉预后指数 (NPI) 和 10 年随访期的临床结果进行分析。与正常组织相比（平均转录水平 = 12.7），TIMM17A mRNA 表达在 BC (62, p = 0.006)、TNM-1 中更高(37.9，p = 0.05)、TNM-2 (114，p = 0.034)、NPI-2 (81，p = 0.041)、疾病进展患者 (169，p = 0.017) 和死于 BC 的患者 (179，p = 0.026)。表达随肿瘤分级而增加； 1 级与 2 级（12.1 vs.70，p = 0.007）、1 级与 3 级（12.1 vs.73，p = 0.065，[不显着] NS）以及 1 级与 2 级和 3 级（12.1 vs. 72，p = 0.0048）。较高的转录水平与 ER-α 阳性（94 vs. 31.6，p = 0.073，NS）和 ER-β 阴性（82 vs. 16，p = 0.015）相关。淋巴结阳性与较高的转录水平显着相关（101 vs. 28.1，p = 0.046）。与无病患者（平均转录水平 = 24.6）相比，疾病进展患者和死于 BC 的患者中 TIMM17A 表达显着较高（179，p = 0.037）。中位随访 10 年后，较高的转录水平与较差的总体生存率显着相关 (p = 0.010)。在多变量分析中，TIMM17A 表达成为总体生存的强有力的独立预测因子 (p = 0.033)。TIMM17A mRNA 表达与不利的病理参数显着相关，包括肿瘤分级、淋巴结阳性、TNM 分期和 NPI；除了不良的临床结果，例如疾病进展、无病生存和总体生存。 TIMM17A 可作为预后标记物和潜在治疗策略的新型线粒体靶点。
Mitochondrial dysfunction can be associated with genomic instability and has been implicated in the pathogenesis of several human malignancies, including breast cancer (BC). The mitochondrial protein, translocase of inner mitochondrial membrane 17 homolog A (TIMM17A) contributes to a pre-protein import complex, essential for mitochondrial function. In this study, TIMM17A mRNA expression was evaluated in benign and malignant breast tissues and correlated with pathological and clinical outcomes.Breast cancer tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, transcript levels were determined by using real-time quantitative PCR and normalized against CK19. Transcript levels were compared and then analysed against tumour size, tumour grade, oestrogen receptor (ER) status, nodal involvement, TNM stage, Nottingham prognostic index (NPI) and clinical outcome over a 10-year follow-up period.Compared to normal tissue (mean transcript level = 12.7), TIMM17A mRNA expression was higher in BC (62, p = 0.006), TNM-1 (37.9, p = 0.05), TNM-2 (114, p = 0.034), NPI-2 (81, p = 0.041), patients with progressive disease (169, p = 0.017) and those who died from BC (179, p = 0.026). Expression increased with tumour grade; grade 1 versus 2 (12.1 vs.70, p = 0.007), grade 1 versus 3 (12.1 vs.73, p = 0.065, [not significant] NS) and grade 1 versus 2 and 3 (12.1 vs. 72, p = 0.0048). Higher transcript levels were associated with ER-alpha positivity (94 vs. 31.6, p = 0.073, NS) and ER-beta negativity (82 vs. 16, p = 0.015). Nodal positivity was significantly associated with higher transcript levels (101 vs. 28.1, p = 0.046). Compared to disease-free patients (mean transcript level = 24.6), TIMM17A expression was significantly higher in those with progressive disease and patients who died of BC (179, p = 0.037). Higher transcript levels were significantly associated with poorer overall survival after a median follow-up of 10 years (p = 0.010). TIMM17A expression emerged as a strong independent predictor of overall survival in multivariate analysis (p = 0.033).TIMM17A mRNA expression is significantly associated with unfavourable pathological parameters including tumour grade, nodal positivity, TNM stage and NPI; in addition to adverse clinical outcomes such as progressive disease, disease-free and overall survival. TIMM17A offers utility as a prognostic marker and a novel mitochondrial target for potential therapeutic strategies.