Activins and activin antagonists in hepatocellular carcinoma

Deli, Alev; Kreidl, Emanuel; Santifaller, Stefan; Trotter, Barbara; Seir, Katja; Berger, Walter; Schulte‐Hermann, Rolf; Rodgarkia-Dara, Chantal; Grusch, Michael

doi:10.3748/wjg.14.1699

Cited by 63 publications

(50 citation statements)

References 154 publications

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“…In general, TGF-b/BMP signaling initially plays the role as a tumor suppressor in epithelial cells, and then as a promoter for invasion and metastasis during the later stages of carcinoma progression. [7][8][9][10][11] Numerous genetic alterations in components associated with the TGF-b/ BMP signaling pathway that correlate with carcinogenesis, tumor progression and prognosis in various types of malignancies have been identified. 8,12,13 In colorectal cancers, for example, where the TGF-b/BMP signaling pathway in general negatively regulates tumor cell proliferation from early carcinogenesis to a later progression stage, loss-of-function mutation in TGF-b/BMP signaling, such as the inactivating mutation of SMAD4, has frequently been identified as an important early carcinogenic event.…”

Section: Uiccmentioning

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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Section: Uiccmentioning

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 connection of follistatin and follistatin-like proteins with activin signaling and their involvement in hepatic functions is discussed below. Additional regulation of activin signal transduction takes place at the receptor level by co-receptors, such as cripto, nodal, betaglycan, or BAMBI and intracellularly, for instance by the inhibitory Smad 6 and 7, and has been reviewed elsewhere [106,107] . …”

Section: Follistatins and Their Role In Ac-tivin Antagonism And Livermentioning

confidence: 99%

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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“…The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8)(9)(10)(11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin.…”

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confidence: 99%

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Zabkiewicz

Resaul

Hargest

et al. 2017

CGP

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Abstract. Background Follistatin (FST) is a secreted extracellular regulatory protein that binds activin and, with less affinity, related TGFβ superfamily members such as bone morphogenetic proteins (BMPs), preventing access to their receptors (1, 2). Originally thought to act on the pituitary to regulate FSH release, FST has subsequently been noted in many other tissues, in particular co-localising with activin resulting in autocrine and paracrine cellular regulation (1, 3). As an antagonist of activin, FST has diverse regulatory roles in embryogenesis, tissue differentiation and repair, gonadal function and inflammatory and immune processes (3, 4).Three major FST isoforms can be produced, namely FST288 (from splice variant mRNA precursor FST317), FST315 (from splice variant mRNA precursor FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus (5). These three main FST isoforms can also be glycosylated to yield six further FST isoforms (6). FST288 and FST315 are differentially expressed in human tissues, but FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (6, 7) .The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8-11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin. Thus, the overall result of activin/FST action in cancer may be both context and cell type specific (3, 6).In the breast, FST is expressed in the normal mammary gland and in different breast proliferative diseases, with additional experimental evidence suggesting that FST can modulate the breast cancer cell cycle (3,(12)(13)(14). However, its role in breast cancer growth and metastasis is far from clear. In this study we demonstrated a clinical correlation between FST expression and survival in breast cancer, and that overexpression of FST in vitro reduces invasion of breast cancer cells. Patients and MethodsCell lines and patient tissue samples. Human breast cell lines MCF-7,MDA MB 231, ZR-751, BT 549 and BT-20 were obtained from and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum and antibiotics (PAA Laboratories Ltd., Somerset, UK). Cells were incubated at 37˚C in 5% CO 2 at 95% humidity.Breast cancer tissue and normal breast tissue samples were collected during surgery at the University Hospital of Wales. In total, 93 tumour samples and 30 normal breast tissue samples were obtained from patients who were enrolled in the study. The tissues obtained during surgery were snap-frozen in liquid nitrogen and stored at −80˚C.

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Activins and activin antagonists in hepatocellular carcinoma

Cited by 63 publications

References 154 publications

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

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

Activins and follistatins: Emerging roles in liver physiology and cancer

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

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