S100A4 mediates endometrial cancer invasion and is a target of TGF-β1 signaling

Xie, Ran; Schlumbrecht, Matthew; Shipley, Gregory L.; Xie, Shuai; Bassett, Roland L.; Broaddus, Russell R.

doi:10.1038/labinvest.2009.52

Cited by 45 publications

(42 citation statements)

References 51 publications

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“…In a previous report, we identified S100A2 as a downstream target of TGF-β signalling [14]. Other S100 members like S100A4 and S100A11 are reported to be regulated by TGF-β [13,38]. However, the mechanism of regulation for any S100 family proteins by TGF-β has not been studied so far.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast S100A2 overexpression was detected specifically in basal-like breast tissues and regarded as potential target for the treatment of such breast cancers [8]. Overexpression of S100A2 has also been reported in ovarian carcinomas [9], early stage NSCLCs (nonsmall cell lung carcinomas) [10], mixed tumours of the skin containing neoplastic myoepithelial cells [11], well-differentiated oesophageal squamous cell carcinomas [12] and all grades of endometrioid tumours [13]. These observations suggest an important role for S100A2 in the progression of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion

Naz

Ranganathan

Bodapati

et al. 2012

Biochemical Journal

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S100A2, an EF hand calcium-binding protein, is a potential biomarker in several cancers and is also a TGF-β (transforming growth factor-β)-regulated gene in melanoma and lung cancer cells. However, the mechanism of S100A2 regulation by TGF-β and its significance in cancer progression remains largely unknown. In the present study we report the mechanism of S100A2 regulation by TGF-β and its possible role in TGF-β-mediated tumour promotion. Characterization of the S100A2 promoter revealed an AP-1 (activator protein-1) element at positions -1161 to -1151 as being the most critical factor for the TGF-β1 response. Chromatin immunoprecipitation and electrophoretic mobility-shift assays confirmed the functional binding of the AP-1 complex, predominantly JunB, to the S100A2 promoter in response to TGF-β1 in HaCaT keratinocytes. JunB overexpression markedly stimulated the S100A2 promoter which was blocked by the dominant-negative JunB and MEK1 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1] inhibitor, PD98059. Intriguingly, despite the presence of a putative SMAD-binding element, S100A2 regulation by TGF-β1 was found to be SMAD3 independent. Interestingly, p53 protein and TGF-β1 show synergistic regulation of the S100A2 promoter. Finally, knockdown of S100A2 expression compromised TGF-β1-induced cell migration and invasion of Hep3B cells. Together our findings highlight an important link between the TGF-β1-induced MAPK and p53 signalling pathways in the regulation of S100A2 expression and pro-tumorigenic actions.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion

Naz

Ranganathan

Bodapati

et al. 2012

Biochemical Journal

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“…In endometrioma and deep endometriosis lesions, chronic inflammation and fibrosis represents a common finding and TGF-b signaling is critically involved in the fibrotic reaction (29,30), enhancing the expression of a fibrosis marker (31). TGF-b family members and AMH act through serine/threonine kinase receptors and Smad effectors, and the regulate Smad expression and phosphorylation in endometrial epithelial and stromal cells (13,14,32,33).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of antimüllerian hormone and its receptor in endometriosis

Carrarelli

Rocha

Belmonte

et al. 2014

Fertility and Sterility

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Objective: To evaluate antim€ ullerian hormone (AMH) and AMH receptor II (AMHRII) mRNA and protein expression in endometrium and in ovarian or deep lesions of women with endometriosis. Design: Prospective study. Setting: University hospitals in Italy and Brazil. Patients: Patients with endometriosis (n ¼ 55) and healthy women (n ¼ 45). Interventions: Specimens of endometrium obtained by hysteroscopy from patients with endometriosis and from healthy control subjects; specimens of ovarian endometriosis (n ¼ 29) or of deep endometriosis (n ¼ 26) were collected by laparoscopy. Serum samples were collected in some endometriotic patients (n ¼ 23) and healthy control subjects (n ¼ 20). Main Outcome Measure(s): AMH and AMHRII mRNA levels were evaluated by quantitative reverse-transcription polymerase chain reaction and protein localization by immunohistochemistry. AMH levels in tissue homogenates and in serum were assessed by ELISA. Result(s): Endometrium from women with endometriosis showed higher AMH and AMHRII mRNA levels than control women, with no significant differences between proliferative and secretory phases. Specimens collected from ovarian or deep endometriosis showed the highest AMH and AMHRII mRNA expression. Immunolocalization study confirmed the high AMH and AMHRII protein expression in endometriotic lesions. No difference of serum AMH levels between the groups was found. Conclusion(s):The increased AMH and AMHRII mRNA and protein expression in endometrium and in endometriotic lesions suggests a possible involvement of AMH in endometriosis.

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“…ID1 and S100A4, well-known as metastasis promoters in EEC, are overexpressed in high-grade EEC. 32,33 Furthermore, TGF-beta signaling is recognized as an important pathway that controls the S100A4-mediated cell invasion in endometrial cancers. 33 Nonetheless, neither miRBase nor TargetScan database predicts direct targeting of these mRNAs in the 3 0 UTR of miR-204.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

“…32,33 Furthermore, TGF-beta signaling is recognized as an important pathway that controls the S100A4-mediated cell invasion in endometrial cancers. 33 Nonetheless, neither miRBase nor TargetScan database predicts direct targeting of these mRNAs in the 3 0 UTR of miR-204. Therefore, we proposed that miR-204 regulates these cancer progression-and metastasis-related genes indirectly.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

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

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

155

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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S100A4 mediates endometrial cancer invasion and is a target of TGF-β1 signaling

Cited by 45 publications

References 51 publications

Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion

Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion

Increased expression of antimüllerian hormone and its receptor in endometriosis

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

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