Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.<br /><br />Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.<br /><br />Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P<0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P =0.002), lymph node metastasis (P =0.004) and advanced clinical stage (P =0.001). LUAD patients with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for LUAD patients. Moreover, forced expression of RCC2 promoted intra-pulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion and proliferation in vitro. Further study found that RCC2 induced epithelial-mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP -9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT and the expression of MMP-2 and MMP-9.<br /><br />Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK-JNK signaling.

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