Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer.
Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer.
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PP2A抑制剂SET癌蛋白的过度表达与人类非小细胞肺癌的肿瘤进展和不良预后相关
DOI：
10.18632/oncotarget.3818
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Liu H;Gu Y;Wang H;Yin J;Zheng G;Zhang Z;Lu M;Wang C;He Z
SET癌蛋白是蛋白磷酸酶2A（PP 2A）的内源性抑制剂，SET介导的PP 2A抑制是促进多种人类白血病发生和发展的重要调节机制。然而，其在实体瘤（如非小细胞肺癌（NSCLC））中的潜在相关性仍然未知。在本研究中，我们发现SET在人NSCLC细胞系和NSCLC组织中明显过表达。临床病理分析显示SET的表达与临床分期（p < 0.001）、淋巴结转移（p < 0.05）密切相关。Kaplan-Meier分析显示SET高表达患者的总生存率低于SET低表达患者。此外，SET在NSCLC细胞中的敲低导致增殖和侵袭能力减弱。SET对细胞增殖和侵袭的生物学效应是通过抑制PP 2A，激活AKT和ERK，增加cyclinD 1和MMP 9的表达，降低p27的表达来实现的。此外，我们观察到使用SET拮抗剂FTY 720恢复PP 2A在体外损害增殖和侵袭潜力，以及在体内抑制NSCLC细胞的肿瘤生长。SET蛋白在NSCLC的发生、发展过程中起重要作用，有望成为NSCLC患者的一个潜在的预后指标和新的治疗靶点。
SET oncoprotein is an endogenous inhibitor of protein phosphatase 2A (PP2A), and SET-mediated PP2A inhibition is an important regulatory mechanism for promoting cancer initiation and progression of several types of human leukemia disease. However, its potential relevance in solid tumors as non-small cell lung cancer (NSCLC) remains mostly unknown. In this study, we showed that SET was evidently overexpressed in human NSCLC cell lines and NSCLC tissues. Clinicopathologic analysis showed that SET expression was significantly correlated with clinical stage (p < 0.001), and lymph node metastasis (p < 0.05). Kaplan-Meier analysis revealed that patients with high SET expression had poorer overall survival rates than those with low SET expression. Moreover, knockdown of SET in NSCLC cells resulted in attenuated proliferative and invasive abilities. The biological effect of SET on proliferation and invasion was mediated by the inhibition of the PP2A, which in turn, activation of AKT and ERK, increased the expression of cyclin D1 and MMP9, and decreased the expression of p27. Furthermore, we observed that restoration of PP2A using SET antagonist FTY720 impaired proliferative and invasive potential in vitro, as well as inhibited tumor growth in vivo of NSCLC cells. Taken together, SET oncoprotein plays an important role in NSCLC progression, which could serve as a potential prognosis marker and a novel therapeutic target for NSCLC patients.