Prognostic significance of BMP and activin membranebound inhibitor in colorectal cancer

Togo, Nozomi; Ohwada, Susumu; Sakurai, Shunsuke; Toya, Hiroyuki; Sakamoto, Ichiro; Yamada, Tatsuya; Nakano, Tetsuhiro; Muroya, Ken; Takeyoshi, Izumi; Nakajima, Takashi; Sekiya, Takashi; Yamazumi, Yusuke; Nakamura, Tsutomu; Akiyama, Tetsu

doi:10.3748/wjg.14.4880

Cited by 31 publications

(24 citation statements)

References 39 publications

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“…Currently, the role of negative regulator BAMBI in various cancers is controversially discussed. Increased BAMBI expression has been reported for colorectal cancer tissues (11,13) and ovarian cancer cells (12). In contrast, BAMBI was observed to be epigenetically silenced in high-grade bladder cancer (14) and absent in metastasizing melanoma cells (37) and breast cancer tissues (15).…”

Section: Discussionmentioning

confidence: 90%

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Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

et al. 2016

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Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFb elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFb signaling pathway. Alterations of epithelialto-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFb pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFb-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFb signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 90%

“…The expression of BAMBI at high levels has also been detected in colorectal cancer (11) and ovarian cancer (12) and has been linked to metastasis in colorectal cancer (13). By contrast, BAMBI is epigenetically silenced in highgrade bladder cancer (14) and absent from breast cancer (15).…”

Section: Introductionmentioning

confidence: 96%

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

et al. 2016

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“…Continuous BAMBI expression due to activated b-catenin (through the direct binding of TCF/LEF transcription factor to BAMBI promoter region) or TGF-b/BMP signaling itself (through the evolutionary conserved BMP-responsive elements in BAMBI promoter, by the direct binding of SMAD3 and SMAD4 to its promoter region) favors the growth and survival of colorectal cancer cells by acting as a negative feedback system against TGF-b/BMP signaling. 18,19,22,55 It follows, therefore, that colorectal cancer cells expressing the BAMBI gene with hypomethylation of the BAMBI gene promoter have a better chance of surviving in the tumor microenvironment. To the contrary, the effect of the TGF-b/BMP signaling pathway at later progression stages in some aggressive tumors, such as in malignant melanoma, 56 ovarian 57 and bladder cancers, 58,59 often promotes cancer cell invasion and migration by inducing EMT in an autocrine and paracrine manner.…”

Section: 22mentioning

confidence: 99%

BAMBI gene is epigenetically silenced in subset of high‐grade bladder cancer

Khin

Kitazawa

Win³

et al. 2009

Intl Journal of Cancer

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The bone morphogenetic protein (BMP) and activin membranebound inhibitor (BAMBI) is a transmembrane TGFRI/BMPRIrelated pseudoreceptor, antagonizes transforming growth factor (TGF)-b/BMP signaling by inhibiting the formation of functional authentic receptor complexes (TGFRI/BMPRI and TGFRII/ BMPRII). On the assumption that BAMBI gene expression is epigenetically altered during human bladder cancer progression, we screened the expression of BAMBI protein by immunohistochemistry and the methylation status of the BAMBI promoter. In the normal or reactive urothelium, BAMBI expression was mostly overlapped with that of BMPRI, and a similar colocalization pattern was noted in low-grade papillary cancers. In high-grade and invasive cancers, however, mainly two reciprocal immunohistochemical expression patterns were observed: BAMBI-low/BMPRIhigh, and BAMBI-high/BMPRI-low, indicating that BAMBI expression is controlled such that it does not interfere with the responsiveness of high-grade cancer cells to TGF-b/BMP signaling. Moreover, methylation of the BAMBI gene correlated significantly with negative BAMBI expression in bladder tumors. Although BAMBI overexpression significantly increased the number of apoptotic cells in T24 line, knock-down small interfering RNA showed no remarkable change. Cell motility assay revealed that on treatment with either TGF-b1 or BMP2, T24 and HTB9 lines showed a marked increase in the number of migrated cells which, however, decreased significantly through the forced expression of BAMBI. Since certain subsets of aggressive tumors often promote cell motility, invasion and survival by inducing epithelial-to-mesenchymal transition through TGF-b/BMP in an autocrine and paracrine manner, hypermethylation of the BAMBI gene promoter that leads to BAMBI gene suppression may be one of the epigenetic events affecting the invasiveness or aggressiveness of bladder cancers. ' 2009 UICC

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“…18,[22][23][24] Members of the TGFb superfamily play an important role in cardiac development and angiogenesis, which is highlighted by the phenotypes exhibited by knockout mice. Tgfb1 knockout mice all have cardiac defects and have an embryonic lethal phenotype.…”

Section: Introductionmentioning

confidence: 99%

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Salles‐Crawley

Monkman

Ahnström

et al. 2014

Blood

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Key Points• This is the first report to describe the influence of BAMBI on both hemostasis and thrombus stability.• BAMBI present in the blood vessel wall (most likely the endothelium) rather than platelet BAMBI is required for thrombus stability.Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-b superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi 2/2 and Bambi 1/2 mice exhibit mildly prolonged bleeding times compared with Bambi 1/1 littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi 1/1 mice. No defects in thrombin generation in Bambi 2/2 mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi 2/2 mice, Bambitransplanted with Bambi 1/1 bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi 1/1 mice receiving Bambi 2/2 bone marrow transplants.Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability. (Blood. 2014;123(18):2873-2881

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Prognostic significance of BMP and activin membranebound inhibitor in colorectal cancer

Cited by 31 publications

References 39 publications

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

BAMBI gene is epigenetically silenced in subset of high‐grade bladder cancer

Vessel wall BAMBI contributes to hemostasis and thrombus stability

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