Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

Abstract

Purpose: 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.Experimental Design: 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.Results: 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 ¼ 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.Conclusions: 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. Clin Cancer Res; 20(7); 1779-90. Ó2014 AACR.

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

“…For OS-RC-2, inhibitory effect of KLF6 on microvessel forming could be reversed by E2F1 (P < 0.001). Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001. the orthotopic and metastatic model, due to its pulmonary metastatic property (22). ShE2F1 group mice exhibited a strong reversed effect (Fig.…”

Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a

“…FoxO3 acts as a transcription factor and triggers apoptosis through induction of death genes such as FasL and Bim1 [34]. Ni et al showed that FOXO3a silencing promoted invasiveness of renal cancer cells and metastasis of renal cancer cells in vivo [35]. Furthermore, Gopinath et al demonstrated a functional requirement for FOXO3a as a regulator of the Notch signaling pathway, a pathway critical for the self-renewal and maintenance of CSCs [36].…”

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“…Further, they showed that statin therapy regulates protein FOXO3a activation, suggesting a potential mechanism for simvastatin's anti-metastatic effects (Wolfe et al 2015). Downregulation of FOXO3a increases metastasis formation and predicts worse metastasis-free survival in patients with renal cell carcinoma (Ni et al 2014). These results suggest that statins can inhibit metastasis development and progression based on their ability to affect signal molecules involved in regulation of cell migration and cell proliferation.…”