Nuclear forkhead box O3a accumulation contributing to the proliferative suppression in liver cancer cells by PI3K/Akt signaling pathway

Hou, Yu; Sun, Ge; Xu, Jiang; Zhu, Zhenfang; Yang, Jijin

doi:10.4103/0973-1482.204891

Cited by 6 publications

(2 citation statements)

References 5 publications

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“…Studies show that by inhibiting the PI3K/Akt pathway, petroleum ether (PE) may induce the apoptosis of hepatocellular carcinoma cells, thus producing an anti-tumor effect 32. Hou et al indicated that inhibition of the PI3K/Akt pathway could significantly reduce the phosphorylation level of FOXO3a, accompanied by an increase in the total level of FOXO3a, and significantly inhibited the proliferation of tumor cells 33. Stearoyl-CoA desaturase 1 (SCD1) regulates autophagy through the AMPK pathway and has a great influence on HCC 34.…”

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confidence: 99%

Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma

Chen¹,

Yan²,

Feng³

et al. 2021

IJGM

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Objective For the identification of abnormally methylated differentially expressed genes (MDEGs) in hepatocellular carcinoma (HCC), this study integrated four microarray datasets to investigate the fundamental mechanisms of tumorigenesis. Methods We obtained the expression (GSE76427, GSE57957) and methylation (GSE89852, GSE54503) profiles from Gene Expression Omnibus (GEO). The abnormally MDEGs were identified by using R software. We used the clusterProfiler package for the functional and pathway enrichment analysis. The String database was used to build the protein–protein interaction (PPI) network and visualize it in Cytoscape. MCODE was employed in the module analysis. Additionally, Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) were employed to validate results. Lastly, we used cBioPortal software to examine the hub genetic alterations. Results We identified 162 hypermethylated, down-regulated genes and 190 hypomethylated, up-regulated genes. Up-regulated genes with low methylation were enriched in biological processes, such as keratinocyte proliferation, and calcium homeostasis. Pathway analysis was enriched in the AMPK and PI3K-Akt signaling pathways. The PPI network identified PTK2, VWF, and ITGA2 as hypomethylated, high-expressing hub genes. Down-regulated genes with high methylation were related to responses to peptide hormones and estradiol, multi-multicellular organism process. Pathway analysis indicated enrichment in camp, oxytocin signaling pathways. The PPI network identified CFTR, ESR1, and CXCL12 as hypermethylated, low-expressing hub genes. Upon verification in TCGA databases, we found that the expression and methylation statuses of the hub genes changed significantly, and it was consistent with our results. Conclusion The novel abnormally MDEGs and pathways in HCC were identified. These results helped us further understand the molecular mechanisms underlying HCC invasion, metastasis, and development. Hub genes can serve as biomarkers for an accurate diagnosis and treatment of HCC, and PTK2, VWF, ITGA2, CFTR, ESR1, and CXCL12 are included.

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confidence: 99%

Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma

Chen¹,

Yan²,

Feng³

et al. 2021

IJGM

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“…42 Aberrantly activated Akt and suppressed FoxO3a have been reported in a number of cancers. 43 There is also increasing evidence that many cytotoxic drugs induce apoptosis in cancer cells by altering the Akt-FoxO3a pathway. For example, docetaxel induces cancer cell apoptosis by enhancing FoxO3a activity and stimulating its nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

<p>Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a</p>

Rajamanickam

Yan

et al. 2020

CMAR

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Background: Gastric cancer is one of the leading causes of cancer-related deaths. Allylated monocarbonyl analogs of curcumin (MACs) have been reported to selectively inhibit a broad range of human cancers including gastric cancer. However, the precise molecular mechanisms underlying the inhibitory activities of MACs are not fully known. Methods: In this study, we examined the anti-tumor activities of an allylated MAC, CA6, on gastric cancer cells and gastric cancer xenograft mouse model. The potential molecular antitumor mechanisms of CA6 were also elucidated. Results: Our data show that CA6 exhibited significant cytotoxicity in gastric cancer cells, which was seen as an induction of G2/M cell cycle arrest and apoptosis. These activities were mediated through an elaboration of ROS levels in gastric cancer cells and induction of endoplasmic reticulum stress. CA6 increased ROS levels through directly binding to and inhibiting thioredoxin reductase R1 (TrxR1). Also, CA6-generated ROS inhibited Akt and activated forkhead O3A (FoxO3a), causing cytotoxicity in gastric cancer cells. Finally, CA6 treatment dose-dependently reduced the growth of gastric cancer xenografts in tumor-bearing mice, which was associated with reduced TrxR1 activity and increased ROS in the tumor. Conclusion: In summary, our studies demonstrate that CA6 inhibited gastric cancer growth by inhibiting TrxR1 and increasing ROS, which in turn activated FoxO3a through suppressing Akt. CA6 is a potential candidate for the treatment of gastric cancer.

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FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes

et al. 2022

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Upon injury, the liver is capable of substantial regeneration from the original tissue until an appropriate functional size. The underlying mechanisms controlling the liver regeneration processes are not well elucidated. Previous studies have proposed that the transcription factor FoxO3 is involved in various liver diseases, but its exact role in the regulation of liver regeneration remains largely unclear. To directly test the detailed role of FoxO3 in liver regeneration, both a constitutive Albumin-Cre driver line and adeno-associated virus serotype 8 (AAV8)-Tbg-Cre (AAV-Cre)-injected adult FoxO3fl/fl mice were subjected to 70% partial hepatectomy (PH). Our data demonstrate that FoxO3 deletion accelerates liver regeneration primarily by limiting polyploidization and promoting the proliferation of hepatocytes during liver regeneration. RNA-seq analysis indicates that FoxO3 deficiency greatly alters the expression of gene sets associated with cell proliferation and apoptosis during liver regeneration. Chromatin immunoprecipitation-PCR (ChIP-PCR) and luciferase reporter assays reveal that FoxO3 promotes the expression of Nox4 but suppresses the expression of Nr4a1 in hepatocytes. AAV8 virus-mediated overexpression of Nox4 and knockdown of Nr4a1 significantly suppressed hepatocyte proliferation and liver regeneration in FoxO3-deficient mice. We demonstrate that FoxO3 negatively controls hepatocyte proliferation through Nox4 upregulation and Nr4a1 downregulation, thereby ensuring appropriate functional regeneration of the liver. Our findings provide novel mechanistic insight into the therapeutic mechanisms of FoxO3 in liver damage and repair.

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Nuclear forkhead box O3a accumulation contributing to the proliferative suppression in liver cancer cells by PI3K/Akt signaling pathway

Cited by 6 publications

References 5 publications

Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma

Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma

<p>Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a</p>

FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes

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