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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

Authors: Bassem Refaat, Adel Galal El-Shemi, Amr Mohamed Mohamed, Osama Adnan Kensara, Jawwad Ahmad, Shakir Idris

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Activin-A may exert pro- or anti-tumorigenic activities depending on cellular context. However, little is known about its role, or the other mature activin proteins, in colorectal carcinoma (CRC). This study measured the expression of activin βA- & βB-subunits, activin type IIA & IIB receptors, smads 2/3/4/6/7 and follistatin in CRC induced by azoxymethane (AOM) in rats. The results were compared with controls and disseminated according to the characteristics of histopathological lesions.

Methods

Eighty male Wistar rats were allocated into 20 controls and the remaining were equally divided between short ‘S-AOM’ (15 weeks) and long ‘L-AOM’ (35 weeks) groups following injecting AOM for 2 weeks. Subsequent to gross and histopathological examinations and digital image analysis, the expression of all molecules was measured by immunohistochemistry and quantitative RT-PCR. Activin-A, activin-B, activin-AB and follistatin were measured by ELISA in serum and colon tissue homogenates.

Results

Colonic pre-neoplastic and cancerous lesions were identified in both AOM groups and their numbers and sizes were significantly (P < 0.05) greater in the L-AOM group. All the molecules were expressed in normal colonic epithelial cells. There was a significantly (P < 0.05) greater expression of βA-subunit, IIB receptor and follistatin in both pre-neoplastic and cancerous tissues. Oppositely, a significant (P < 0.05) decrease in the remaining molecules was detected in both AOM groups. Metastatic lesions were only observed within the L-AOM group and were associated with the most significant alterations of all molecules. Significantly higher concentrations of activin-A and follistatin and lower activin-AB were also detected in both groups of AOM. Tissue and serum concentrations of activin-A and follistatin correlated positively, while tissue activin-AB inversely, and significantly with the numbers and sizes of colonic lesions.

Conclusions

Normal rat colon epithelial cells are capable of synthesising, controlling as well as responding to activins in a paracrine/autocrine manner. Colonic activin systems are pathologically altered during tumorigenesis and appear to be time and lesion-dependent. Activins could also be potential sensitive markers and/or molecular targets for the diagnosis and/or treatment of CRC. Further studies are required to illustrate the clinical value of activins and their related proteins in colon cancer.
Appendix
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Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
2.
3.
Yaffee P, Osipov A, Tan C, Tuli R, Hendifar A. Review of systemic therapies for locally advanced and metastatic rectal cancer. J Gastrointes Oncol. 2015;6:185–200.
4.
Al-Hajeili M, Marshall JL, Smaglo BG. Neoadjuvant Treatment for Surgically Resectable Metastatic Colorectal Cancer. Oncology (Williston Park). 2016;30:10–6.
5.
Patel K, Sun W. Neoadjuvant Treatment for Surgically Resectable Metastatic Colorectal Cancer: Is There an Optimal Succession? Oncology (Williston Park). 2016;30:23.
6.
7.
Pai SG, Fuloria J. Novel therapeutic agents in the treatment of metastatic colorectal cancer. World J Gastrointes Oncol. 2016;8:99–104.CrossRef
8.
Chen J, Huang XF. The signal pathways in azoxymethane-induced colon cancer and preventive implications. Cancer Biol Ther. 2009;8:1313–7.CrossRefPubMed
9.
Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. Prognostic significance of transforming growth factor beta (TGF-beta) signaling axis molecules and E-cadherin in colorectal cancer. Tumour Biol. 2012;33:1005–14.CrossRefPubMed
10.
Refaat B, Ashshi AM, El-Shemi AG, Azhar E. Activins and Follistatin in Chronic Hepatitis C and Its Treatment with Pegylated-Interferon-alpha Based Therapy. Mediators Inflamm. 2015;2015:287640.PubMedPubMedCentral
11.
12.
Thompson TB, Lerch TF, Cook RW, Woodruff TK, Jardetzky TS. The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev Cell. 2005;9:535–43.CrossRefPubMed
13.
Zhang Y, Bao YL, Yang MT, Wu Y, Yu CL, Huang YX, et al. Activin A induces SLC5A8 expression through the Smad3 signaling pathway in human colon cancer RKO cells. Int J Biochem Cell Biol. 2010;42:1964–72.CrossRefPubMed
14.
15.
Pholnukulkit P, Sonoyama K, Kawabata J. Activin A induces phosphorylation of Smad2 but not complex formation of Smad2 with Smad4 in human colon cancer cell line HT-29. Biosci Biotechnol Biochem. 2003;67:2042–4.CrossRefPubMed
16.
Jung B, Gomez J, Chau E, Cabral J, Lee JK, Anselm A, et al. Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms. PLoS One. 2009;4:e8308.CrossRefPubMedPubMedCentral
17.
Jung BH, Beck SE, Cabral J, Chau E, Cabrera BL, Fiorino A, et al. Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin. Gastroenterology. 2007;132:633–44.CrossRefPubMed
18.
Deacu E, Mori Y, Sato F, Yin J, Olaru A, Sterian A, et al. Activin type II receptor restoration in ACVR2-deficient colon cancer cells induces transforming growth factor-beta response pathway genes. Cancer Res. 2004;64:7690–6.CrossRefPubMed
19.
20.
Okano M, Yamamoto H, Ohkuma H, Kano Y, Kim H, Nishikawa S, et al. Significance of INHBA expression in human colorectal cancer. Oncol Rep. 2013;30:2903–8.PubMed
21.
Wu S, Qi Y, Niu LM, Xie DX, Cui XL, Liu ZH. Activin A as a novel biomarker for colorectal adenocarcinoma in humans. Eur Rev Med Pharmacol Sci. 2015;19:4371–8.PubMed
22.
Washington MK, Powell AE, Sullivan R, Sundberg JP, Wright N, Coffey RJ, et al. Pathology of rodent models of intestinal cancer: progress report and recommendations. Gastroenterology. 2013;144:705–17.CrossRefPubMedPubMedCentral
23.
Refaat B, El-Shemi AG, Kensara OA, Mohamed AM, Idris S, Ahmad J, et al. Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer. J Exp Clin Cancer Res. 2015;34:71.CrossRefPubMedPubMedCentral
24.
25.
Papadopulos F, Spinelli M, Valente S, Foroni L, Orrico C, Alviano F, et al. Common tasks in microscopic and ultrastructural image analysis using ImageJ. Ultrastruct Pathol. 2007;31:401–7.CrossRefPubMed
26.
Schindelin J, Rueden CT, Hiner MC, Eliceiri KW. The ImageJ ecosystem: An open platform for biomedical image analysis. Mol Reprod Dev. 2015;82:518–29.CrossRefPubMed
27.
Yoshimi N, Morioka T, Kinjo T, Inamine M, Kaneshiro T, Shimizu T, et al. Histological and immunohistochemical observations of mucin-depleted foci (MDF) stained with Alcian blue, in rat colon carcinogenesis induced with 1,2-dimethylhydrazine dihydrochloride. Cancer Sci. 2004;95:792–7.CrossRefPubMed
28.
Ochiai M, Hippo Y, Izumiya M, Watanabe M, Nakagama H. Newly defined aberrant crypt foci as a marker for dysplasia in the rat colon. Cancer Sci. 2014;105:943–50.CrossRefPubMedPubMedCentral
29.
Refaat B, El-Shemi AG, Ashshi AM, Mahamid EW, Al-Qadi NM. Pegylated Interferon-alpha Modulates Liver Concentrations of Activin-A and Its Related Proteins in Normal Wistar Rat. Mediators Inflamm. 2015;2015:414207.PubMedPubMedCentral
30.
Pretlow TP, O’Riordan MA, Somich GA, Amini SB, Pretlow TG. Aberrant crypts correlate with tumor incidence in F344 rats treated with azoxymethane and phytate. Carcinogenesis. 1992;13:1509–12.CrossRefPubMed
31.
Paulsen JE, Loberg EM, Olstorn HB, Knutsen H, Steffensen IL, Alexander J. Flat dysplastic aberrant crypt foci are related to tumorigenesis in the colon of azoxymethane-treated rat. Cancer Res. 2005;65:121–9.PubMed
32.
Femia AP, Dolara P, Caderni G. Mucin-depleted foci (MDF) in the colon of rats treated with azoxymethane (AOM) are useful biomarkers for colon carcinogenesis. Carcinogenesis. 2004;25:277–81.CrossRefPubMed
33.
Sakai E, Morioka T, Yamada E, Ohkubo H, Higurashi T, Hosono K, et al. Identification of preneoplastic lesions as mucin-depleted foci in patients with sporadic colorectal cancer. Cancer Sci. 2012;103:144–9.CrossRefPubMed
34.
Femia AP, Bendinelli B, Giannini A, Salvadori M, Pinzani P, Dolara P, et al. Mucin-depleted foci have beta-catenin gene mutations, altered expression of its protein, and are dose- and time-dependent in the colon of 1,2-dimethylhydrazine-treated rats. Int J Cancer. 2005;116:9–15.CrossRefPubMed
35.
Boman BM, Fields JZ, Cavanaugh KL, Guetter A, Runquist OA. How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer. Cancer Res. 2008;68:3304–13.CrossRefPubMed
36.
Jain P, Mondal SK, Sinha SK, Mukhopadhyay M, Chakraborty I. Diagnostic and prognostic significance of different mucin expression, preoperative CEA, and CA-125 in colorectal carcinoma: A clinicopathological study. J Nat Sci Biol Med. 2014;5:404–8.CrossRefPubMedPubMedCentral
37.
Sonoyama K, Rutatip S, Kasai T. Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2000;278:G89–97.PubMed
38.
Kawamura N, Nobusawa R, Mashima H, Kanzaki M, Shibata H, Kojima I. Production of activin A in human intestinal epithelial cell line. Dig Dis Sci. 1995;40:2280–5.CrossRefPubMed
39.
Zhang YQ, Resta S, Jung B, Barrett KE, Sarvetnick N. Upregulation of activin signaling in experimental colitis. Am J Physiol Gastrointest Liver Physiol. 2009;297:G768–80.CrossRefPubMedPubMedCentral
40.
Fukamachi H, Kato S, Asashima M, Ichinose M, Yuasa Y. Activin A regulates growth of gastro-intestinal epithelial cells by mediating epithelial-mesenchymal interaction. Dev Growth Differ. 2013;55:786–91.CrossRefPubMed
41.
Dignass AU, Jung S, Harder-d’Heureuse J, Wiedenmann B. Functional relevance of activin A in the intestinal epithelium. Scand J Gastroenterol. 2002;37:936–43.CrossRefPubMed
42.
Dohi T, Ejima C, Kato R, Kawamura YI, Kawashima R, Mizutani N, et al. Therapeutic potential of follistatin for colonic inflammation in mice. Gastroenterology. 2005;128:411–23.CrossRefPubMed
43.
44.
Brown CW, Houston-Hawkins DE, Woodruff TK, Matzuk MM. Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nat Genet. 2000;25:453–7.CrossRefPubMed
45.
Brown CW, Li L, Houston-Hawkins DE, Matzuk MM. Activins are critical modulators of growth and survival. Mol Endocrinol. 2003;17:2404–17.CrossRefPubMed
46.
47.
Dame MK, Jiang Y, Appelman HD, Copley KD, McClintock SD, Aslam MN, et al. Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived. Lab Invest. 2014;94:222–34.CrossRefPubMed
48.
Freeman TJ, Smith JJ, Chen X, Washington MK, Roland JT, Means AL, et al. Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of beta-catenin. Gastroenterology. 2012;142:562–71. e2.CrossRefPubMed
49.
Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M, et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 2013;73:725–35.CrossRefPubMed
50.
Fukushima T, Mashiko M, Takita K, Otake T, Endo Y, Sekikawa K, et al. Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer. J Exp Clin Cancer Res. 2003;22:315–20.PubMed
51.
Jueckstock J, Burkhardt N, Kuhn C, Blankenstein T, Mahner S, Schindlbeck C, et al. Expression of Activin During and After Chemotherapy in Peripheral Blood of Patients with Primary Breast Cancer. Anticancer Res. 2016;36:2153–9.PubMed
52.
Matzuk MM, Kumar TR, Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature. 1995;374:356–60.CrossRefPubMed
53.
Oh SP, Li E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 1997;11:1812–26.CrossRefPubMed
54.
Trudeau VL, Matzuk MM, Hache RJ, Renaud LP. Overexpression of activin-beta A subunit mRNA is associated with decreased activin type II receptor mRNA levels in the testes of alpha-inhibin deficient mice. Biochem Biophys Res Commun. 1994;203:105–12.CrossRefPubMed
55.
Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;142:531–43.CrossRefPubMed
56.
Le Bras GF, Loomans HA, Taylor CJ, Revetta FL, Andl CD. Activin A balance regulates epithelial invasiveness and tumorigenesis. Lab Invest. 2014;94:1134–46.CrossRefPubMedPubMedCentral
57.
Zhang B, Zhang B, Chen X, Bae S, Singh K, Washington MK, et al. Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway. Br J Cancer. 2014;110:946–57.CrossRefPubMedPubMedCentral
58.
Grossi V, Peserico A, Tezil T, Simone C. p38alpha MAPK pathway: a key factor in colorectal cancer therapy and chemoresistance. World J Gastroenterol. 2014;20:9744–58.CrossRefPubMedPubMedCentral
59.
Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert AW, Abdolmaleky HM, et al. Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011;71:998–1008.CrossRefPubMedPubMedCentral
60.
Ottley E, Gold E. Insensitivity to the growth inhibitory effects of activin A: an acquired capability in prostate cancer progression. Cytokine Growth Factor Rev. 2012;23:119–25.CrossRefPubMed
61.
Antsiferova M, Werner S. The bright and the dark sides of activin in wound healing and cancer. J Cell Sci. 2012;125:3929–37.CrossRefPubMed
62.
Gold E, Risbridger G. Activins and activin antagonists in the prostate and prostate cancer. Mol Cell Endocrinol. 2012;359:107–12.CrossRefPubMed
63.
Sepporta MV, Tumminello FM, Flandina C, Crescimanno M, Giammanco M, La Guardia M, et al. Follistatin as potential therapeutic target in prostate cancer. Target Oncol. 2013;8:215–23.CrossRefPubMed
64.
Togashi Y, Kogita A, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, et al. Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. Cancer Lett. 2015;356:819–27.CrossRefPubMed
Metadata
Title
Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer
Authors
Bassem Refaat
Adel Galal El-Shemi
Amr Mohamed Mohamed
Osama Adnan Kensara
Jawwad Ahmad
Shakir Idris
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2914-9

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