FoxO3a and disease progression

Nho, Richard Seonghun; Hergert, Polla

doi:10.4331/wjbc.v5.i3.346

Cited by 143 publications

(117 citation statements)

References 86 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…More importantly, FOXO3a has been found to increase several target genes, such as TRAIL, PUMA, FasL, and BIM, which is essential for the gefitinib-induced killing of NSCLC cells (14,27), and the suppression of FOXO3a in breast cancer cells result in a reduction of gefitinib-induced cell cycle arrest and cell death (18). These results are consistent with our observations, which showed that 24% of lung cancer patients with high FOXO3a have a better response to EGFR-TKIs and progression-free survival outcomes, suggesting that FOXO3a expression is involved in the regulation of the EGFR-TKI-induced apoptotic response and is a good marker for predicting the therapeutic effects of EGFR-TKIs in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, FOXO3a is a transcription factor that acts as a tumor suppressor by inducing cell cycle arrest, and the down-regulation of FOXO3a is involved in the tumorigenesis of various cancer types (14). Studies indicate that FOXO3a activity is negatively regulated by oncogenic kinases, such as AKT, IKK, and ERK (15)(16)(17), and the activation of these oncogenic kinases is associated with FOXO3a suppression, which triggers cancer progression.…”

Section: Nf-κb-driven Suppression Of Foxo3a Contributes To Egfr Mutatmentioning

confidence: 99%

See 1 more Smart Citation

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Nf-κb-driven Suppression Of Foxo3a Contributes To Egfr Mutatmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In this study, we identified several miRNAs that are highly relevant to IRI and found that miR-155 expression was remarkably increased both in HK2 cells (a human renal tubular cell line) subjected to HRI and in renal tissues from IRI rats. FoxO3a is involved in the inhibition of cell death and the promotion of cellular growth in ischemic renal diseases [53]. Several miRNA databases, including TargetScan, miRDB and miRanda, show that FoxO3a is a potential target gene for miR-155.…”

Section: Mir-155 Directly Targets Foxo3a In Hk2 Cells During Hrimentioning

confidence: 99%

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

Huang²,

梁英³

et al. 2016

Cell Physiol Biochem

101

View full text Add to dashboard Cite

Background/Aims: Ischemia/reperfusion injury (IRI) plays a crucial role in renal transplantation and can cause renal failure associated with pyroptosis, a pro-inflammatory-induced programmed cell death. Small endogenous non-coding RNAs have been shown to be involved in renal ischemia/reperfusion injury. This study was performed to investigate which miRNAs regulate pyroptosis in response to renal ischemia/reperfusion injury and determine the mechanism underlying this regulation. Methods: An in vivo rat model of renal IRI was established, and the serum and kidneys were harvested 24 h after reperfusion to assess renal function and histological changes. For the in vitro study, the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia (5% CO₂, 1% O₂, and 94% N2) followed by 12 h of reoxygenation (5% CO₂, 21% O₂, and 74% N₂). The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Bioinformatics analyses were applied to predict miR-155 targets, which were then confirmed by a luciferase reporter assay. Results: We found that the levels of pyroptosis-related proteins, including caspase-1, caspase-11, IL-1β and IL-18, were significantly increased after renal ischemia/reperfusion injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in HK2 cells. Furthermore, our study revealed that miR-155 expression was substantially increased in the renal tissues of IRI rats and in HRI HK2 cells. Up-regulation of miR-155 promoted HK2 cell pyroptosis in HRI; conversely, knockdown of miR-155 attenuated this process. To understand the signaling mechanisms underlying the pro-pyroptotic activity of miR-155, we found that exogenous expression of miR-155 up-regulated the expression of caspase-1 as well as the pro-inflammatory cytokines IL-1β and IL-18. Moreover, miR-155 directly repressed FoxO3a expression and its downstream protein apoptosis repressor with caspase recruitment domain (ARC). Conclusions: Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.

show abstract

“…Autophagy is involved in tissue remodelling during embryonic development [7]. Involvement of autophagy in the liver fibrosis and other liver diseases is a well-established fact [4,8,9]. However, there is no direct link for miRNA-21 involvement in development of liver fibrosis [10,11].…”

Section: Mini Reviewmentioning

confidence: 99%