Song Lei, Duan Ping, Gan Yibo, Li Pei, Zhao Chen, Xu Jianzhong, Zhang Zehua, Zhou Qiang
Department of Orthopaedics, First Affliated Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
Southwest Eye Hospital, First Affliated Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
Int J Oncol. 2017 Feb;50(2):535-544. doi: 10.3892/ijo.2016.3820. Epub 2016 Dec 28.
Cisplatin-resistance has become a major impediment in the medical treatment of cancers such as osteosarcoma, the most common primary malignancy of bone. Since lysophosphatidic acid acyltransferase β (LPAATβ) was reported to be critically involved in osteosarcoma, our study investigated the role of LPAATβ in human osteosarcoma with cisplatin-resistance. Expression of LPAATβ or other relevant proteins were analyzed in 40 osteosarcoma patients by immunohistochemistry analysis (IHC), and in cisplatin‑resistant sublines by real-time PCR and western blotting. Next, the synthesized siRNA was inserted into the lentivirus vector and silencing of LPAATβ expression was employed to determine the effect of LPAATβ on cisplatin-resistant osteosarcoma cell viability in vitro and osteosarcoma tumor growth in vivo with cisplatin treatment. Exogenous LPAATβ mediated by heritable RNAi decreased cisplatin‑resistant sensitivity through activating the PI3K/Akt/mTOR signaling pathway. We further demonstrate that silencing LPAATβ effectively inhibited tumor growth in nude mice with xenografts of cisplatin‑resistant osteosarcoma cells. IHC assay results showed that PI3K/Akt/mTOR signaling pathway was also involved in this process. Our results suggested that LPAATβ may play an important role in osteosarcoma and silencing LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of cisplatin-resistance.
顺铂耐药已成为骨肉瘤等癌症医学治疗中的主要障碍，骨肉瘤是最常见的原发性骨恶性肿瘤。由于据报道溶血磷脂酸酰基转移酶β（LPAATβ）在骨肉瘤中起关键作用，我们的研究调查了LPAATβ在耐顺铂的人类骨肉瘤中的作用。通过免疫组织化学分析（IHC）对40例骨肉瘤患者的LPAATβ或其他相关蛋白表达进行分析，并通过实时PCR和蛋白质印迹法对耐顺铂亚系进行分析。接下来，将合成的小干扰RNA（siRNA）插入慢病毒载体中，采用LPAATβ表达沉默来确定LPAATβ对体外耐顺铂骨肉瘤细胞活力以及体内顺铂治疗的骨肉瘤肿瘤生长的影响。遗传性RNA干扰介导的外源性LPAATβ通过激活PI3K/Akt/mTOR信号通路降低了顺铂耐药敏感性。我们进一步证明，沉默LPAATβ可有效抑制携带耐顺铂骨肉瘤细胞异种移植的裸鼠肿瘤生长。免疫组织化学分析结果表明，PI3K/Akt/mTOR信号通路也参与了这一过程。我们的结果表明，LPAATβ可能在骨肉瘤中起重要作用，沉默LPAATβ可能被用作耐顺铂临床管理的一种新的治疗策略。
