The Association of Transforming Growth Factor‐β1 with Myometrial Invasion of Endometrial Carcinomas through Effects on Matrix Metalloproteinase

Yabushita, Hiromitsu; Narumiya, Hisao; Hiratake, K.; Yamada, Hidefumi; Shimazu, Mitsuma; Sawaguchi, K; Noguchi, Masayoshi; Nakanishi, Masami

doi:10.1111/j.1447-0756.2000.tb01305.x

Cited by 22 publications

(16 citation statements)

References 21 publications

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“…TGF-␤1 and TGF-␤2, which were unable to trigger MMP-9 expression by these cells, did not stimulate the invasiveness of KLE cells. Others had reported that TGF-␤1 increased invasiveness in KLE cells (20), but in the latter study TGF-␤1 increased MMP-9 expression by KLE cells, which nonetheless supports our findings that increased MMP-9 expression confers invasive properties to endometrial carcinoma cells. The fact that TGF-␤3 induces the expression of MMP-9 by KLE cells suggests the presence of a positive loop for regulation of autocrine TGF-␤3 tumor promoting effect, because MMP-9 can activate latent TGF-␤ isoforms into their active forms (26).…”

Section: Discussionsupporting

confidence: 92%

“…lines. High levels of TGF-␤1 transcripts are presents in KLE cells, in agreement with previous reports of TGF-␤1 production by endometrial carcinoma cells in vitro and in vivo (19,20). In addition, the KLE cell line is tumorigenic when injected subcutaneously in nude mice and invasive (21), which indicates a late stage phenotype and legitimates the evaluation of the invasion promoting effects of TGF-␤s.…”

Section: Discussionsupporting

confidence: 90%

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Transforming Growth Factor-β3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9

Themsche

Mathieu

Parent

et al. 2007

Journal of Biological Chemistry

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Tumor cells often acquire intrinsic resistance to the growth inhibitory and pro-apoptotic effects of transforming growth factor-␤ (TGF-␤); moreover, TGF-␤ can confer invasive properties to established tumor cells. In the present study, we show that TGF-␤ isoforms (TGF-␤1, TGF-␤2, and TGF-␤3) trigger proper Smad signaling in human endometrial carcinoma cell lines and efficiently inhibit cellular proliferation. These cells, however, exhibit a high degree of resistance to TGF-␤ pro-apoptotic effects; we found that this resistant phenotype would be acquired through up-regulation of X-linked inhibitor of apoptosis protein (XIAP) levels. In addition, using RNA interference and pharmacological inhibitors, we show that TGF-␤ increases cellular invasiveness via two distinct signaling pathways in endometrial carcinoma cells: phosphatidylinositol 3-kinase/ AKT-dependent up-regulation of XIAP and protein kinase Cdependent induction of matrix-metalloproteinase-9 (MMP-9) expression. Additionally, these findings were correlated with clinical observations showing abundant TGF-␤ immunoreactivity in human endometrial carcinoma tumors in vivo, extending from the epithelial compartment to the stroma upon acquisition of an invasive phenotype (gradually from grades I to III). Collectively our results describe for the first time a role for TGF-␤3 in tumor invasiveness.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Transforming Growth Factor-β3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9

Themsche

Mathieu

Parent

et al. 2007

Journal of Biological Chemistry

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“…To fill this data gap, we explored the antitumor effect of progesterone on TGFb signaling at three levels: ligands, receptors, and SMADs. High levels of TGFbs are present in endometrial carcinoma cells in vitro and in vivo (38)(39). TGFb isoforms have been shown to act on endometrial cell growth by autocrine or paracrine mechanisms and are implicated in several processes of tumorigenesis and metastasis (8).…”

Section: Discussionmentioning

confidence: 99%

Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

Bokhari

Lee

Raboteau

et al. 2014

Cancer Prevention Research

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Increased expression of TGFb isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFb. The goal of this study was to characterize the effect of progesterone on TGFb signaling pathway components and on TGFb-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFb isoforms at 72 hours after treatment except for TGFb2 in HEC-1B and TGFb3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFb receptors in HEC-1B cells and all but TGFbR1 in Ishikawa cells. Progesterone reduced TGFbR3 expression in RL-95 cells at 72 hours, but TGFbR1 and bR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFb1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFbRI blocked TGFb1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFb signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth. Cancer Prev Res; 7(10); 1045-55. Ó2014 AACR.

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“…Many researchers have shown that TGF-ß induces the expression of MMPs (like MMP-2, MMP-9, MMP-10) in several human cancer cell lines, such as prostate (31), bladder (13), breast (32), endometrial (33), oral (29) and ovarian cancer (12). However, no previous study has investigated a possible correlation between serum levels of MMP-2 and TGF-ß in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

Malaponte¹

2010

Oncol Rep

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Abstract. Previous studies have found that matrix metalloproteinase-2 (MMP-2) and transforming growth factor-ß (TGF-ß) can be considered as biomarkers and indices of disease progression in several human cancers. In this study, we investigated the plasma levels of MMP-2 and TGF-ß and their correlation in 49 primary cutaneous melanoma and 10 metastatic melanoma. Plasma MMP-2 and TGF-ß levels in patients with primary melanoma were significantly higher than those of healthy controls. These protein levels were significantly higher in patients with metastatic melanoma. A positive correlation between plasma levels of MMP-2 and TGF-ß in melanoma patients supports the hypothesis that TGF-ß triggers the release of MMP-2. The immunohistochemistry analysis shows that MMP-2 and TGF-ß were highly expressed in tumor tissues as well as in matched plasma samples. This finding suggests that these proteins are released from tumor cells. Overall, our data indicate that MMP-2 and TGF-ß may represent novel diagnostic markers and therapeutic targets in melanoma and the determination of their concentration could be a useful diagnostic and prognostic indicator. TGF-ß, leading the tissue invasion mediated by MMP-2, is a strong promoter of tumor progression. Therefore, reducing or blocking the activity of TGF-ß may represent a promising target in therapeutic strategies for limiting the growth of melanoma.

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The Association of Transforming Growth Factor‐β1 with Myometrial Invasion of Endometrial Carcinomas through Effects on Matrix Metalloproteinase

Abstract: Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF-beta 1 in an autocrine or paracrine fashion.

Cited by 22 publications

References 21 publications

Transforming Growth Factor-β3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9

Transforming Growth Factor-β3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9

Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

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