Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1α in erk-responsive lung cancer

Abstract

Metastatic spread of cancer cells portends a poor prognosis and mortality for lung cancer patients. Hypoxia-inducible factor-1α (HIF-1α) enhances tumor cell motility by activating the epithelial-to-mesenchymal transition (EMT), which is considered a prerequisite for metastasis. Recent studies of microRNA involvement in cancer invasion and metastasis have highlighted the role of such RNAs in tumor development. However, little work has been done to identify tumor suppressor microRNAs that target HIF-1α to down-modulate the EMT and thereby counteract the aggressiveness and metastasis of lung cancer cells. Here, we identified the 3′-untranslated region of HIF-1α mRNA as a target of miR-622 and established that miR-622-mediated down-modulation of HIF-1α correlates with decreased levels of mesenchymal proteins, including Snail, β-catenin, and vimentin. Functional analyses revealed that increased miR-622 expression inhibited lung cancer cell migration and invasion in vitro. miR-622 also inhibited the genesis of metastatic lung nodules as demonstrated in a lung cancer xenograft model in which nude mice were transplanted with A549 cells expressing miR-622. Mechanistic analyses showed that overexpression of EGF decreased the miR-622 level in A549 cells, and this reduction could be rescued by administrating U0126, an inhibitor of ERK. Moreover, miR-622 overexpression mediated by the transcription factor FOXO3a decreased the invasiveness of lung tumor cells by inhibiting HIF-1α via inactivation of ERK signaling in U0126-treated A549 cells. These findings highlight the pivotal role of the FOXO3a/miR-622 axis in inhibiting HIF-1α to interfere with tumor metastasis, and this information may contribute to development of novel therapeutic strategies for treating aggressive lung cancer.

Nucleosome Assembly Protein 1-Like 1 (Nap1l1) Regulates the Proliferation of Murine Induced Pluripotent Stem Cells

“…Huang et al reported that activation of p53 and p21 was related to the inactivation of PI3K/AKT and ERK signaling pathways during virus replication [39]. PI3K/ AKT or MEK/ERK pathways, has been reported to control proliferation and differentiation of stem cells [26][27][28]. The present study suggests that Nap1l1 activates ERK or AKT pathway to promote the proliferation by downregulation of p21 and p27 and upregulation of cyclin B1 in iPSC.…”

“…Here, we used the U0126, a specific inhibitor of MEK, which can efficiently inhibit the MEK-mediated phosphorylation of ERK [27], to inhibit ERK activation as previous study [28], while MK2206 was used as the AKT inhibitor in the present study. The results showed that U0126 or MK2206 greatly reversed the proliferous effect induced by Nap1l1 overexpression in iPSC.…”

Downregulation of N-Acetylglucosaminyltransferase GCNT3 by miR-302b-3p Decreases Non-Small Cell Lung Cancer (NSCLC) Cell Proliferation, Migration and Invasion

“…In addition, the Erk signaling pathway has been shown to be frequently activated in numerous kinds of human cancers [43][44][45]. Aberrant activation of phosphorylated Erk1/2 induced by miRNAs has been observed in lung cancer [45][46][47]. Recent reports point out that miR-379 acts as a tumor [45], miR-7 inhibits the activation of ERK/MAPK signaling pathway by down-regulating FAK expression [46], and miR-622 overexpression decreases invasion in lung tumor cells by inhibiting HIF-1alpha via inactivation of ERK signaling in A549 cell [47].…”

“…Aberrant activation of phosphorylated Erk1/2 induced by miRNAs has been observed in lung cancer [45][46][47]. Recent reports point out that miR-379 acts as a tumor [45], miR-7 inhibits the activation of ERK/MAPK signaling pathway by down-regulating FAK expression [46], and miR-622 overexpression decreases invasion in lung tumor cells by inhibiting HIF-1alpha via inactivation of ERK signaling in A549 cell [47]. Consistent with these findings, we found that the p-Erk level was significantly decreased in response to GCNT3 silencing or miR-302b-3p overexpression in XWLC and NCI-H292 cells, suggesting that the effect of the miR-302b-3p/GCNT3 signaling pathway in NSCLC may depend on the activation of p-Erk.…”

MicroRNA-93 Promotes Epithelial–Mesenchymal Transition of Endometrial Carcinoma Cells

“…Recurrence and metastasis are important causes of death in patients with endometrial cancer, and some studies have found that tumor invasion and metastasis are closely related to epithelial–mesenchymal transition (EMT) [2–6]. EMT is an intricate process where cancer cells demonstrate the loss of polarity and cell phenotype alteration from epithelial to mesenchymal morphology and it is considered a prerequisite for the typical tumor phenotypes of upregulated angiogenesis, enhanced cell motility, and extracellular matrix invasion [7–8]. In addition, it has been indicated that, in endometrial carcinoma, metastasis and recurrence are closely related with EMT [9–10].…”