Lloret Marta, Lara Pedro Carlos, Bordón Elisa, Fontes Fausto, Rey Agustin, Pinar Beatriz, Falcón Orlando
Radiation Oncology Department, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):976-9. doi: 10.1016/j.ijrobp.2008.11.013.
We investigated the relationship between major vault protein (MVP) expression, the nonhomologous end-joining (NHEJ) repair gene Ku70/80, and related genes involved in the regulation of apoptosis and proliferation to shed light on the possible causes of genetic instability, tumor progression, and resistance to oncologic treatment in patients with clinical cervical cancer.
One hundred sixteen consecutive patients with localized cervix carcinoma were prospectively included in this study from July 1997 to Dec 2003. Patients were staged according to the tumor, node, metastasis (TNM) classification. Forty patients had Stage I disease, 45 had Stage II, and 31 had Stage III/IVA. Most patients had squamous tumors (98 cases) and Grades II (52 cases) and III (45 cases) carcinomas. Expression of MVP, Ku70/80, Insulin-Like Growth Factor-1 receptor (IGF-1R), BCL2-associated X protein (BAX), B-cell CLL/lymphoma 2 (BCL-2), p53, and Ki67 was studied by using immunohistochemistry in paraffin-embedded tumor tissue.
Tumors overexpressing MVP (65 of 116 cases) showed low levels of Ku70/80 (p = 0.013) and BAX expression (p < 0.0001). Furthermore, low Ku70/80 expression was strongly related to suppressed BAX (p < 0.001) and, to a lesser extent, upregulated BCL-2 (p = 0.042), altered p53 (p = 0.038), and increased proliferation (p = 0.002).
We hypothesize that an early regulatory mechanism favors homologous or NHEJ repair at first, mediated by vaults along with other factors yet to be elucidated. If vaults are overexpressed, NHEJ repair may be suppressed by means of several mechanisms, with resultant genomic instability. These mechanisms may be associated with the decision of damaged cells to survive and proliferate, favoring tumor progression and reducing tumor response to oncologic treatment through the development of resistant cell phenotypes. Additional clinical studies are necessary to test this hypothesis.
我们研究了主要穹窿蛋白（MVP）表达、非同源末端连接（NHEJ）修复基因Ku70/80以及参与细胞凋亡和增殖调控的相关基因之间的关系，以阐明临床宫颈癌患者遗传不稳定、肿瘤进展及对肿瘤治疗耐药的可能原因。
1997年7月至2003年12月，前瞻性纳入116例连续的局限性宫颈癌患者。根据肿瘤、淋巴结、转移（TNM）分类对患者进行分期。40例患者为I期疾病，45例为II期，31例为III/IVA期。大多数患者为鳞状肿瘤（98例），II级（52例）和III级（45例）癌。采用免疫组织化学方法研究石蜡包埋肿瘤组织中MVP、Ku70/80、胰岛素样生长因子-1受体（IGF-1R）、BCL2相关X蛋白（BAX）、B细胞淋巴瘤/白血病-2（BCL-2）、p53和Ki67的表达。
过表达MVP的肿瘤（116例中的65例）显示Ku70/80水平较低（p = 0.013）和BAX表达较低（p < 0.0001）。此外，低Ku70/80表达与BAX受抑制密切相关（p < 0.001），在较小程度上与BCL-2上调（p = 0.042）、p53改变（p = 0.038）及增殖增加（p = 0.002）有关。
我们推测一种早期调控机制首先有利于同源或NHEJ修复，由穹窿体以及其他有待阐明的因素介导。如果穹窿体过表达，NHEJ修复可能通过多种机制受到抑制，导致基因组不稳定。这些机制可能与受损细胞存活和增殖的决定有关，通过耐药细胞表型的发展促进肿瘤进展并降低肿瘤对肿瘤治疗的反应。需要更多的临床研究来验证这一假设。
