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FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway.

ABSTRACT: The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/FOXO3a axis.

SUBMITTER: Kelley K

PROVIDER: S-EPMC3130617 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway.

Kelley Kevin K Berberich Steven J SJ

American journal of cancer research 20110101 1

The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to i ...[more]

PMID: 21743838

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Project description:The early diagnosis and treatment of liver hepatocellular carcinoma (LIHC) remains a major challenge. Therefore, it is of great significance to strengthen basic research on LIHC in order to improve the prevention and treatment of the disease. Numerous studies have indicated that the PI3K/Akt and FoxO signaling pathways mediate proliferation, survival and migration during the development of LIHC. Therefore, they have become a target for LIHC treatment. Furthermore, let-7c has been demonstrated to repress cell proliferation, migration and invasion, and to induce G1 phase arrest and apoptosis of LIHC cells. However, the mechanism of its action is not clear. In the present study, the association between let-7c and the PI3K/Akt/FoxO signaling pathway, as well as their roles in the development of LIHC were investigated using The Cancer Genome Atlas and various public databases (Tumor-miRNA-Pathway, OncomiR, DIANA-TarBase v8, KOBAS 3.0, ONCOMINE, Kaplan-Meier plotter, LinkedOmics, UALCAN and cBioPortal). The effects of let-7c-5p on PI3K/Akt/FoxO signaling pathway-related target genes were analyzed following overexpression of let-7c-5p in the MHCC-97H cell line via reverse transcription-quantitative PCR, and the let-7c-5p target genes belonging to the PI3K/Akt/FOXO signaling pathway in LIHC were screened out. GO and KEGG enrichment analyses of these target genes was performed using g:Profiler, gOST. In addition, GeneMANIA and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to determine the gene-gene and protein-protein interaction networks, respectively. The data demonstrated that cyclin B2 (CCNB2), cyclin E2 (CCNE2), cyclin dependent kinase 4 (CDK4), homer scaffold protein 1 (HOMER1), heat shock protein 90 α family class A member 1 (HSP90AA1), neuroblastoma RAS viral oncogene homolog (NRAS), protein phosphatase 2 catalytic subunit α (PPP2CA), protein kinase AMP-activated catalytic subunit α2 (PRKAA2) and Rac family small GTPase 1 (RAC1) may be target genes of let-7c-5p. These genes, particularly CCNE2, were associated with poor overall survival and could be promising candidate biomarkers for disease and poor prognosis in LIHC. Among them, seven genes (CCNE2, CDK4, HSP90AA1, NRAS, PPP2CA, PRKAA2 and RAC1) belonged to the PI3K-Akt signaling pathway and four genes (CCNB2, HOMER1, NRAS and PRKAA2) belonged to the FoxO signaling pathway. The majority of these genes were closely associated with the cell cycle and their elevated expression may aggravate cell cycle disorders. Therefore, let-7c may be considered to be an anti-oncogene of LIHC. The present study may provide novel targets and strategies for the diagnosis and treatment of LIHC.

Project description:To explore the influence of hyperhomocysteinemia (hHcys) on the tibial fracture healing in rats and its effect on the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT) signaling pathway. A total of 36 Sprague-Dawley rats were randomly divided into sham group (n=12), tibial fracture group (n=12) and hHcys + fracture group (n=12). The rats in tibial fracture group underwent the tibial fracture surgery, while the model of tibial fracture and hHcys was established in hHcys + fracture group. The level of plasma homocysteine (Hcy) in each group was analyzed using the full-automatic biochemical analyzer, the fracture stress biomechanical measurement was performed, and the ultimate bending strength and torque were calculated. Moreover, the protein expressions of PI3K and phosphorylated (p)-AKT in tibial tissues were detected using western blotting, the messenger ribonucleic acid (mRNA) levels of Bcl-2 associated X protein (Bax) and caspase-3 were detected using quantitative polymerase chain reaction (qPCR), the apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and the expressions of inflammatory factors were detected via immunohistochemistry. Compared with sham group, tibial fracture group and hHcys + fracture group had a significantly increased level of plasma Hcy, significantly decreased ultimate bending strength and torque, obviously decreased relative protein expressions of PI3K and p-AKT, increased mRNA levels of Bax and caspase-3 and an increased expression of pro-inflammatory factor tumor necrosis factor-? (TNF-?). Compared with tibial fracture group, hHcys + fracture group had a higher level of plasma Hcy, lower ultimate bending strength and torque, lower relative protein expressions of PI3K and p-AKT, higher mRNA levels of Bax and caspase-3, a higher apoptosis rate and a higher expression of TNF-?. hHcys blocks the downstream apoptotic signal transduction, promotes apoptosis and inflammatory response, and affects fracture healing through affecting the PI3K/AKT signaling pathway.

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FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway.

Publications

FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway.

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