TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition

Shirakihara, Takuya; Horiguchi, Kotaro; Miyazawa, Keiji; Ehata, Shogo; Shibata, Tatsuhiro; Morita, Ikuo; Miyazono, Kohei; Saitoh, Masao

doi:10.1038/emboj.2010.351

Cited by 214 publications

(257 citation statements)

References 40 publications

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“…It is worth mentioning that TGFb acts as a tumor suppressor in normal tissue, but plays an oncogenic role in tumors, 32 by promoting cell growth and development of epithelial-to-mesenchymal transition. 33,34 Interestingly, in our study, we identified two different patterns of FGFR2 immunostaining: cytoplasmic and nuclear. Although cytoplasmic expression was higher in endometrial carcinoma in comparison with the adjacent atrophic endometrium from the same patients, nuclear FGFR2 FGFR2 EXON 11 These results suggest that a shift of FGFR2 from the cytoplasm to the nucleus may be associated with decreased oncogenic activity.…”

Section: Fgfr2 Mutationsmentioning

confidence: 52%

FGFR2 alterations in endometrial carcinoma

et al. 2011

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Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P ¼ 0.001), with an inverse correlation with Ki67 (P ¼ 0.00032), suggesting a tumor-suppressor role for FGFR2 in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P ¼ 0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P ¼ 0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P ¼ 0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P ¼ 0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

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Section: Fgfr2 Mutationsmentioning

confidence: 52%

FGFR2 alterations in endometrial carcinoma

et al. 2011

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“…In some reported studies (38,39), δEF1 was found to be required for the TGF-β-mediated induction of α-SMA. Therefore, we speculated that FGF-2 could activate ctBP1 through the MEK-ERK pathway and bind to δEF1, thereby playing a role in the α-SMA induction by TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of α-SMA by the Ectodomain of FGFR2c Attenuates Lung Fibrosis

Wang

Zhiyou

et al. 2012

Mol Med

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The soluble ectodomain of fibroblast growth factor receptor-IIIc (sFGFR2c) is able to bind to fibroblast growth factor (FGF) ligands and block the activation of the FGF-signaling pathway. In this study, sFGFR2c inhibited lung fibrosis dramatically in vitro and in vivo. The upregulation of α-smooth muscle actin (α-SMA) in fibroblasts by transforming growth factor-β1 (TGF-β1) is an important step in the process of lung fibrosis, in which FGF-2, released by TGF-β1, is involved. sFGFR2c inhibited α-SMA induction by TGF-β1 via both the extracellular signal-regulated kinase 1/2 (ERK1/2) and Smad3 pathways in primary mouse lung fibroblasts and the proliferation of mouse lung fibroblasts. In a mouse model of bleomycin (BLM)-induced lung fibrosis, mice were treated with sFGFR2c from d 3 or d 10 to 31 after BLM administration. Then we used hematoxylin and eosin staining, Masson staining and immunohistochemical staining to evaluate the inhibitory effects of sFGFR2c on lung fibrosis. The treatment with sFGFR2c resulted in significant attenuation of the lung fibrosis score and collagen deposition. The expression levels of α-SMA, p-FGFRs, p-ERK1/2 and p-Smad3 in the lungs of sFGFR2c-treated mice were markedly lower. sFGFR2c may have potential for the treatment of lung fibrosis as an FGF-2 antagonist.

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“…Further work is now required to investigate the contribution of alternative splicing, as a way to alter the Net1 versus Net1A transcript ratio. Recent findings on other genes whose alternative mRNA splicing is modulated directly by TGF-b (Shirakihara et al, 2011) suggest that regulation of RNA splicing by TGF-b may be a more general phenomenon with wider implications for cancer biology.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition

et al. 2011

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In the present study we analyzed the regulation of the two isoforms of the RhoA-specific guanine nucleotide exchange factor Net1 by transforming growth factor-b (TGF-b) in keratinocytes. We report that short-term TGF-b treatment selectively induced Net1 isoform2 (Net1A) but not Net1 isoform1. This led to upregulation of cytoplasmic Net1A protein levels that were necessary for TGF-b-mediated RhoA activation. Smad signaling and the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway were involved in Net1A upregulation by TGF-b. Interestingly, long-term TGF-b treatment resulted in Net1 mRNA downregulation and Net1A protein degradation by the proteasome. Furthermore, we identified the microRNA miR-24 as a novel post-transcriptional regulator of Net1A expression. Silencing of Net1A resulted in disruption of E-cadherin-and zonula occludens-1 (ZO-1)-mediated junctions, as well as expression of the transcriptional repressor of E-cadherin, Slug and the mesenchymal markers N-cadherin, plasminogen activator inhibitor-1 (PAI-1) and fibronectin, indicating that late TGFb-induced downregulation of Net1A is involved in epithelial-to-mesenchymal transition (EMT). Finally, miR-24 was found to be implicated in the regulation of the EMT program in response to TGF-b and was shown to be directly involved in the TGF-b-induced breast cancer cell invasiveness through Net1A regulation. Our results emphasize the importance of Net1 isoform2 in the short-and long-term TGF-b-mediated regulation of EMT.

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TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition

Cited by 214 publications

References 40 publications

FGFR2 alterations in endometrial carcinoma

FGFR2 alterations in endometrial carcinoma

Inhibition of α-SMA by the Ectodomain of FGFR2c Attenuates Lung Fibrosis

Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition

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