Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells

Gotō, Tomoko; Takano, Masashi; Albergaria, André; Briese, Juliane; Pomeranz, Karen M.; Cloke, Brianna; Fusi, Luca; Feroze-Zaidi, Fakhera; Maywald, N; Sajin, Maria; Dina, Roberto; Ishihara, O; Takeda, Satoru; Lam, Eric W.‐F.; Bamberger, Ana‐Maria; Ghaem‐Maghami, Sadaf; Brosens, Jan J.

doi:10.1038/sj.onc.1210626

Cited by 96 publications

(88 citation statements)

References 37 publications

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“…37 The elevated expression of FOXO1 in HEC1B cells has been reported previously. 38 Wang et al 39 demonstrated that SIRT1 deacetylated FOXO3, which, in turn, triggered apoptosis by upregulating the genes necessary for cell death, and facilitated its degradation via poly-ubiquitination by the ubiquitinligase, Skp2 (S-phase kinase associated protein 2). The expression of FOXO3A protein was not changed by knockdown or overexpression of SIRT1 in our study.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Asaka

Miyamoto

Yumura

et al. 2015

Laboratory Investigation

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Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (Po0.05), and its overexpression was associated with a shorter survival (Po0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Asaka

Miyamoto

Yumura

et al. 2015

Laboratory Investigation

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“…23 Family members including FOXA1, FOXC1, FOXO1 and FOXP1 were found to be aberrantly expressed in EEC. 13,24,25 miRBase and TargetScan databases predict these FOX genes to be potentially targeted by 11/16 dysregulated miRNAs (miR-7, miR-9, miR135b, miR-183, miR-199b, miR-204, miR-205, miR-223, miR-449, miR-449b and miR-494) retrieved from our profiling data. Among 4 cancer progression-and metastasis-related miRNAs we identified, miR-7, miR-449b and miR-204 target FOX genes concurrently.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

“…Among 4 cancer progression-and metastasis-related miRNAs we identified, miR-7, miR-449b and miR-204 target FOX genes concurrently. As FOX genes are involved in progression and metastasis of various cancers 23 including EEC, 10,13,24 this provided the basis for focusing further investigation on FOX genes. Our study confirmed miR-204 directly targets FOXC1 3 0 UTR, and overexpression of miR-204 diminishes FOXC1 mRNA and protein expressions in endometrioid-type endometrial cancer cell line, HEC1A.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

“…MicroRNAs (miRNAs) are small noncoding RNA molecules of [19][20][21][22][23][24] nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes.…”

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confidence: 99%

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Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

152

128

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TXMicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3 0 -untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression-and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.Endometrial cancer is a common cause of gynecological cancer death. The most dominant subtype, endometrioid endometrial cancer (EEC), accounts for >80% of this cancer. Menopause and unopposed estrogenic stimulation are typical risk factors. Patients are generally treated with surgery, radiation, chemotherapy or hormone therapy. Patients with early stage disease have 5-year survival rates over 80%, however, about 15-20% develop metastasis. 1 These patients and those with advanced stage disease or recurrence have poor prognosis due to limitation of effective treatment. 2 Understanding the pathogenesis of this disease may provide insights for the development of novel therapeutic strategies.MicroRNAs (miRNAs) are small noncoding RNA molecules of 19-24 nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes. 4 In human cancers, >50% of the miRNA genes are located in chromosomal fragile sites, minimal regions containing loss of heterozygosity, minimal amplicons or common breakpoint regions. 5 DNA ...

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“…Deregulation of FOXO1 has been shown to promote cell proliferation and tumorgenesis in prostate, breast, and endometrial cancer cells (Jackson et al, 2000;Huang et al, 2004;Goto et al, 2008a). FOXO1 has become a major target in preventing tumorigenesis (Arden, 2006;Yang and Hung, 2009).…”

Section: Introductionmentioning

confidence: 99%

FOXO1 is a tumor suppressor in cervical cancer

Zhang¹,

Gui²,

Zhao³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Forkhead box protein O1 (FOXO1) is an important transcriptional regulator of cell proliferation, and is considered essential for tumor growth and progression. However, the function of FOXO1 in human cervical cancer remains unclear. In this study, we investigated the role of FOXO1 in cervical cancer. Our results showed that FOXO1 expression was lower in cervical cancer than in cervical intraepithelial neoplasia and normal cervix by immunohistochemical analysis (P < 0.05). The level of FOXO1 in high-grade lesions was significantly lower than in low-grade lesion (P < 0.05), indicating that deficient expression of FOXO1 is involved in tumor progression and significantly associated with late-stage tumors (P < 0.05), which was further supported by clinicopathological, real-time polymerase chain reaction, and Western blotting analysis. Moreover, we confirmed that the overexpression of FOXO1 remarkably repressed cell growth and blocked cell proliferation, accompanied by cell-cycle arrest in the G 2 /M phase and upregulation of caspases-3 and -9 gene expression. Collectively, our data suggest that FOXO1 plays a vital role in inhibiting cervical cancer development by inducing cell-cycle arrest 6605-6616 (2015) and apoptosis. FOXO1 expression is a favorable prognostic factor for human cervical cancer.

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Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells

Cited by 96 publications

References 37 publications

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

FOXO1 is a tumor suppressor in cervical cancer

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