Zhu Yalong, Zhou Jianhua, Ji Ying, Yu Baoqing
Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China.
Mol Med Rep. 2014 Aug;10(2):737-42. doi: 10.3892/mmr.2014.2314. Epub 2014 Jun 10.
Members of AKT kinase family are central modulators in numerous signaling cascades, which regulate metabolism, cell proliferation, survival and growth. Previously, the knockdown of AKT2 expression has been demonstrated to enhance the efficacy of chemotherapy in patients with osteosarcoma. However, it is currently unknown whether the aberrant expression of AKT2 has relevance to the progression of osteosarcoma. The aim of the present study was to investigate the clinicopathological and prognostic value of AKT2 in osteosarcoma. Formalin-fixed paraffin embedded osteosarcoma and self-paired non-cancerous bone tissue samples were obtained from 126 patients with osteosarcomas. AKT2 expression was detected by an immunohistochemistry assay. Patient survival rates were determined by the Kaplan-Meier method and log-rank test. Cox regression was adopted for multivariate analysis of the prognostic factors to examine the effect of AKT on event-free survival and overall survival in patients with osteosarcomas. AKT2 expression in osteosarcoma tissues was significantly higher than that in non-cancerous bone tissues (immunostaining score, 6.39±1.62 vs. 3.46±1.03; P<0.001). In addition, the elevated expression of AKT2 protein was significantly associated with positive recurrence (P=0.023), the presence of metastasis (P=0.006) and poor response to chemotherapy (P=0.015). Furthermore, patients with high AKT2 expression had significantly shorter event-free survival (P<0.001) and overall survival times (P<0.001) than those with lower expression levels. Multivariate analysis further demonstrated that AKT2 expression (P=0.029 and 0.016, respectively), the status of recurrence (P=0.018 and 0.012, respectively) and metastasis (P=0.020 and 0.015, respectively), and the response to chemotherapy (P=0.011 and 0.008, respectively) were all independent prognostic factors for event-free survival and overall survival time. To the best of our knowledge, these data have supported the findings for the first time, that the elevated expression of AKT2 may be associated with aggressive clinical behavior and poor outcome in patients with osteosarcomas. Therefore, AKT2 may be a candidate marker of unfavorable prognosis in osteosarcoma.
AKT激酶家族成员是众多信号级联反应中的核心调节因子，这些信号级联反应调节代谢、细胞增殖、存活和生长。此前，已证明敲低AKT2表达可提高骨肉瘤患者化疗的疗效。然而，目前尚不清楚AKT2的异常表达是否与骨肉瘤的进展相关。本研究的目的是探讨AKT2在骨肉瘤中的临床病理及预后价值。从126例骨肉瘤患者中获取福尔马林固定石蜡包埋的骨肉瘤组织及自身配对的非癌性骨组织样本。采用免疫组织化学法检测AKT2表达。采用Kaplan-Meier法和对数秩检验确定患者生存率。采用Cox回归对预后因素进行多因素分析，以检验AKT对骨肉瘤患者无事件生存期和总生存期的影响。骨肉瘤组织中AKT2表达明显高于非癌性骨组织（免疫染色评分：6.39±1.62 vs. 3.46±1.03；P<0.001）。此外，AKT2蛋白表达升高与阳性复发（P=0.023）、转移的存在（P=0.006）及化疗反应差（P=0.015）显著相关。此外，AKT2高表达患者的无事件生存期（P<0.001）和总生存期（P<0.001）明显短于低表达水平患者。多因素分析进一步表明，AKT2表达（分别为P=0.029和0.016）、复发状态（分别为P=0.018和0.012）和转移（分别为P=0.020和0.015）以及化疗反应（分别为P=0.011和0.008）均是无事件生存期和总生存期的独立预后因素。据我们所知，这些数据首次支持了以下发现，即AKT2表达升高可能与骨肉瘤患者的侵袭性临床行为和不良预后相关。因此，AKT2可能是骨肉瘤预后不良的候选标志物。
