Abstract
To explore the mechanisms underlying clear-cell renal cell carcinoma (ccRCC) metastasis using transcriptional profiling and bioinformatics analysis of ccRCC samples, and to elucidate the role of FOXO3a in ccRCC metastasis. Gene expression profiling was performed using four primary metastatic and five primary nonmetastatic ccRCC samples. The mRNA and protein levels of FOXO3a in ccRCC samples were investigated by real-time reverse transcription PCR and immunohistochemistry, respectively. The association between metastasis-free survival of patients with ccRCC and FOXO3a mRNA levels was analyzed. Biologic functions of FOXO3a in renal cancer cell lines were investigated. The influence of FOXO3a on tumor metastasis was also studied in vivo orthotopic xenograft tumor model. Finally, the mechanism by which FOXO3a attenuation could increase invasion and migration of tumor cells was explored. Bioinformatics analysis of the profiling data identified FOXO3a as a key factor in ccRCC metastasis. FOXO3a expression was decreased in primary metastatic ccRCC samples. Patients with low FOXO3a mRNA levels had poor metastasis-free survival (P = 0.003). Knocking down FOXO3a induced tumor cell invasion and migration in the nonmetastatic ccRCC cells. Induced FOXO3a overexpression in SN12-PM6 cells could inhibit tumor metastasis in vivo. Downregulation of FOXO3a increased SNAIL1 expression, thereby activating the epithelial-mesenchymal transition (EMT) of RCC cell lines. The loss of FOXO3a induced EMT of tumor cells by upregulating SNAIL1, which promoted tumor cells metastasis in vitro and in vivo. Thus, FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases.
Highlights
Renal cell carcinoma (RCC) represents approximately 2% to 3% of all human malignancies, and its most common histologic subtype is the clear-cell RCC, accounting for 80% to 90% of all RCCs [1]
FOXO3a expression was decreased in primary metastatic clear-cell renal cell carcinoma (ccRCC) samples
FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases
Summary
Renal cell carcinoma (RCC) represents approximately 2% to 3% of all human malignancies, and its most common histologic subtype is the clear-cell RCC (ccRCC), accounting for 80% to 90% of all RCCs [1]. Localized and metastatic ccRCC considerably differ in terms of prognosis and therapeutic approach. The 5-year cancer-specific survival is less than 27.1% in metastatic ccRCC, but exceeds 70% in Authors' Affiliations: 1State Key Laboratory of Kidney Diseases, Department of Urology, Military Postgraduate Medical College, Chinese People's Liberation Army General Hospital, Beijing; and 2Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of China. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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