2309

FOXO3

Emerging evidence has revealed a negative correlation between Forkhead box-O (FOXO) expression and prostate cancer grade and spread, indicating its role as a suppressor of prostate cancer metastasis. However, there is still incomplete understanding about the role of FOXO transcription factors in prostate cancer progression. In this investigation, we demonstrate that FOXO3a significantly inhibits the expression beta-catenin in prostate cancer cells. The mechanism of inhibiting beta-catenin expression involves the FOXO3a-mediated transactivated microRNA-34b/c, which consequently suppressed beta-catenin mRNA expression by targeting the untranslated regions (UTRs) of beta-catenin. Additionally, FOXO3a can directly bind to beta-catenin, and competes with TCF for interaction with beta-catenin, thereby inhibiting beta-catenin/TCF transcriptional activity and reducing the expression of beta-catenin target genes. Furthermore, prostate cancer cells expressing FOXO3a shRNAs display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers, whereas knockdown of beta-catenin results in reversal of shFOXO3a-mediated EMT phenotypic changes. Collectively, these observations demonstrated that FOXO3a inhibits malignant phenotypes that are dependent on beta-catenin-dependent modulation of EMT-related genes, and provided fresh insight into the mechanisms by which a FOXO3a-miR-34b/c axis restrains canonical beta-catenin signaling cascades in prostate cancer cell.CI - Copyright (c) 2015 Elsevier Inc. All rights reserved.

Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis.

SIRT3, a mitochondrial NAD(+)-dependent deacetylase, has been reported to restrain prostate cancer growth both in vitro and in vivo, however, its role in metastatic prostate cancer has not been revealed. In this study, we reported that SIRT3 inhibited the epithelial-mesenchymal transition (EMT) and migration of prostatic cancer cells in vitro and their metastasis in vivo. Consistently, based on analyses of tissue microarray and microarray datasets, lower SIRT3 expression level was correlated with higher prostate cancer Gleason scores, and SIRT3 expression were significantly decreased in metastatic tissues compared with prostate tumor tissues. Mechanistically, SIRT3 promoted FOXO3A expression by attenuating Wnt/beta-catenin pathway, thereby inhibiting EMT and migration of prostate cancer cells. Indeed, SIRT3's inhibitory effect on EMT and migration of prostate cancer cells can be rescued after applying Wnt/beta-catenin pathway activator LiCl, or boosted by wnt inhibitor XAV939. Together, this study revealed a novel mechanism for prostate cancer metastasis that involves SIRT3/ Wnt/beta-catenin/ FOXO3A signaling to modulate EMT and cell migration.CI - Copyright (c) 2018 Elsevier Inc. All rights reserved.

BACKGROUND: Early invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. The transcription factor FOXO3a is inactivated in various types of solid cancers and the loss of FOXO3a is associated with EMT and tumor metastasis. In this study, we sought to explore whether SPRY2, a regulator of receptor tyrosine kinase (RTK) signaling, is involved in FOXO3a-mediated EMT and metastasis in PDAC. METHODS: Immunohistochemistry was performed in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues. Cell proliferation and apoptosis were assessed by cell counting kit and flow cytometry, while cell migration and invasion were evaluated with wound healing and transwell assays. The changes in mRNA and protein levels were estimated by qRT-PCR and western blot. BALB/c nude mice xenograft model was established to evaluate tumorigenesis and metastasis in vivo. RESULTS: FOXO3a expression was remarkably reduced in PDAC tissues, and correlated with metastasis-associated clinicopathologic characteristics and poor prognosis in patients with PDAC. In addition to the promotion of proliferation and suppression of apoptosis, knockdown of FOXO3a or SPRY2 induced EMT and promoted the migration and invasion of PDAC cells via activation of the beta-catenin/TCF4 pathway. Moreover, silencing of SPRY2 reversed the suppressor effects induced by FOXO3a overexpression on EMT-associated migration and invasion of PDAC cells, while blockade of beta-catenin reversed the effects of SPRY2 loss. FOXO3a knockdown decreased SPRY2 protein stability, whereas SPRY2 knockdown enhanced beta-catenin protein stability. In vivo, FOXO3a knockdown promoted the tumorigenic ability and metastasis of PDAC cells. CONCLUSIONS: Our study suggests that knockdown of FOXO3a induces EMT and promotes metastasis of PDAC by activation of the beta-catenin/TCF4 pathway through SPRY2. Thus, FOXO3a may represent a candidate therapeutic target in PDAC.