Moinuddin F M, Hirano Hirofumi, Shinsato Yoshinari, Higa Nayuta, Arita Kazunori, Furukawa Tatsuhiko
Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Oncol Lett. 2017 Dec;14(6):7777-7782. doi: 10.3892/ol.2017.7249. Epub 2017 Oct 23.
Glioblastoma multiforme (GBM) is one of the most aggressive types of brain malignancy, with resistance to chemotherapy being a primary treatment obstacle. ATPase copper transporting β (ATP7B) is involved in multidrug resistance; however, its expression in GBM remains to be evaluated. In the present study, GBM specimens from 79 patients who underwent gross total tumor removal followed by concomitant temozolomide (TMZ) chemotherapy and radiotherapy were assessed immunohistochemically. The association between the overall survival times of patients and the expression of ATP7B in neoplastic cells was evaluated. In 12/79 tumors (15.2%) >10% of neoplastic cells were immunohistochemically-positive for ATP7B, and categorized as high-ATP7B GBM. In the remaining 67 tumors (84.8%) the rate of ATP7B-positive cells was <10% and recorded as low-ATP7B GBM. The median overall survival times of patients with high- and low-ATP7B GBM were 14.6, and 24.7 months, respectively. High expression of ATP7B was identified to be associated with shorter overall survival times (hazard ratio, 0.452; 95% confidence interval, 0.206-0.994; P=0.048). Of the 79 patients, 12 underwent a second operation due to recurrence. These tissue samples were also subjected to immunohistochemical study. The ATP7B positivity rate of tumor cells obtained during the second surgery was significantly higher compared with that in the first surgery (9.17±2.56 vs. 2.75±0.55%; P=0.008). In addition, two ATP7B-transfected GBM cell lines were identified to be significantly resistant (3.8- and 1.7-fold, respectively) to TMZ compared with the control cell line. The findings of the present study suggest that ATP7B influences GBM resistance to TMZ.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑恶性肿瘤类型之一，化疗耐药是主要的治疗障碍。ATP酶铜转运β（ATP7B）与多药耐药有关；然而，其在GBM中的表达仍有待评估。在本研究中，对79例行肿瘤全切术，随后接受替莫唑胺（TMZ）同步化疗和放疗的患者的GBM标本进行免疫组织化学评估。评估患者总生存时间与肿瘤细胞中ATP7B表达之间的关联。在79个肿瘤中的12个（15.2%）中，>10%的肿瘤细胞ATP7B免疫组织化学呈阳性，归类为高ATP7B GBM。在其余67个肿瘤（84.8%）中，ATP7B阳性细胞率<10%，记录为低ATP7B GBM。高ATP7B GBM和低ATP7B GBM患者的中位总生存时间分别为14.6个月和24.7个月。ATP7B高表达与较短的总生存时间相关（风险比，0.452；95%置信区间，0.206 - 0.994；P = 0.048）。79例患者中，12例因复发接受二次手术。这些组织样本也进行了免疫组织化学研究。二次手术获取的肿瘤细胞的ATP7B阳性率明显高于首次手术（9.17±2.56对2.75±0.55%；P = 0.008）。此外，与对照细胞系相比，两个ATP7B转染的GBM细胞系对TMZ具有明显抗性（分别为3.8倍和1.7倍）。本研究结果表明，ATP7B影响GBM对TMZ的耐药性。
