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Tumor Biology

, Volume 35, Issue 7, pp 7047–7056 | Cite as

Expression of BAMBI and its combination with Smad7 correlates with tumor invasion and poor prognosis in gastric cancer

  • Yining Zhang
  • Zhaojin Yu
  • Qinghuan Xiao
  • Xuren Sun
  • Zhi Zhu
  • Junyan Zhang
  • Huimian Xu
  • Minjie Wei
  • Mingjun Sun
Research Article

Abstract

Bone morphogenetic proteins and activin membrane-bound inhibitor (BAMBI) and drosophila mothers against decapentaplegic protein 7 (Smad7) are known to negatively regulate the transforming growth factor-β (TGF-β) signaling and play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of BAMBI alone or in combination with Smad7 is associated with the progression of gastric cancer. In the present study, we investigated the expression of BAMBI and Smad7 in 276 cancer tissues and 263 tumor-adjacent tissues from gastric cancer patients, using tissue-microarray-based immunohistochemistry. The expression of BAMBI and Smad7 was significantly higher in cancer tissues than in tumor-adjacent tissues. The expression of BAMBI was significantly correlated with increased depth of invasion (P = 0.010), lymphatic invasion (P < 0.001), lymph node metastasis (P = 0.001), TNM stage (P = 0.008), and decreased differentiation (P = 0.046). The expression of BAMBI was associated with a significantly shorter overall survival (OS) (P = 0.006) and disease-free survival (DFS) (P = 0.011). The combined expression of BAMBI and Smad7 was associated with more invasion and metastasis as well as less survival time in gastric cancer patients. The univariate analysis showed that the expression of BAMBI alone or in combination with Smad7 was significantly associated with the OS and DFS. These findings suggest that BAMBI and Smad7 may cooperatively inhibit the TGF-β signaling, and thus promote the progression of gastric cancer.

Keywords

BAMBI Smad7 Gastric cancer Immunohistochemistry Prognosis 

Abbreviations

BAMBI

Bone morphogenetic proteins and activin membrane-bound inhibitor

CI

Confidence interval

DAB

3,3-Diaminobenzidine

DFS

Disease-free survival

OS

Overall survival

RR

Relative risk

Smad7

Drosophila mothers against decapentaplegic protein 7

TGF-β

Transforming growth factor-β

Wnt

Wingless and INT-1

Notes

Acknowledgments

We would like to thank Dr. Lin Zhao from the Department of Pharmacology, School of Pharmaceutical Sciences, China Medical University for the help to statistical analysis. This study was supported, in part, by grants from Research Fund for the Doctoral Program in College of Chinese Education Department (No. 20102104110004) and scientific and technological projects of Liaoning Province Science and Technology Department (Nos. 2009225011-2 and 2013225049).

Conflicts of interest

None

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Wittekind C, Neid M. Cancer invasion and metastasis. Oncology. 2005;69 Suppl 1:14–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–30.CrossRefPubMedGoogle Scholar
  4. 4.
    de Caestecker MP, Piek E, Roberts AB. Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst. 2000;92:1388–402.CrossRefPubMedGoogle Scholar
  5. 5.
    Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.CrossRefPubMedGoogle Scholar
  6. 6.
    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular jekyll and hyde of cancer. Nat Rev Cancer. 2006;6:506–20.CrossRefPubMedGoogle Scholar
  7. 7.
    Maehara Y, Kakeji Y, Kabashima A, Emi Y, Watanabe A, Akazawa K, et al. Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol. 1999;17:607–14.PubMedGoogle Scholar
  8. 8.
    Saito H, Tsujitani S, Oka S, Kondo A, Ikeguchi M, Maeta M, et al. An elevated serum level of transforming growth factor-beta 1 (TGF-beta 1) significantly correlated with lymph node metastasis and poor prognosis in patients with gastric carcinoma. Anticancer Res. 2000;20:4489–93.PubMedGoogle Scholar
  9. 9.
    Vagenas K, Spyropoulos C, Gavala V, Tsamandas AC. TGFbeta1, TGFbeta2, and TGFbeta3 protein expression in gastric carcinomas: correlation with prognostics factors and patient survival. J Surg Res. 2007;139:182–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Markowitz SD, Roberts AB. Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev. 1996;7:93–102.CrossRefPubMedGoogle Scholar
  11. 11.
    Katz LH, Li Y, Chen JS, Munoz NM, Majumdar A, Chen J, et al. Targeting TGF-beta signaling in cancer. Expert Opin Ther Targets. 2013;17:743–60.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, et al. Silencing of TGF-beta signalling by the pseudoreceptor bambi. Nature. 1999;401:480–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Degen WG, Weterman MA, van Groningen JJ, Cornelissen IM, Lemmers JP, Agterbos MA, et al. Expression of nma, a novel gene, inversely correlates with the metastatic potential of human melanoma cell lines and xenografts. Int J Cancer. 1996;65:460–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Harrison CA, Gray PC, Vale WW, Robertson DM. Antagonists of activin signaling: mechanisms and potential biological applications. Trends Endocrinol Metab. 2005;16:73–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Sekiya T, Adachi S, Kohu K, Yamada T, Higuchi O, Furukawa Y, et al. Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells. J Biol Chem. 2004;279:6840–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen Y, Guo Y, Ge X, Itoh H, Watanabe A, Fujiwara T, et al. Elevated expression and potential roles of human Sp5, a member of Sp transcription factor family, in human cancers. Biochem Biophys Res Commun. 2006;340:758–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Miao S, Zhao L, Gao J, Wang H, Cui Z. Distribution and mrna expression of bambi in non-small-cell lung cancer. Zhongguo Fei Ai Za Zhi. 2009;12:203–7.PubMedGoogle Scholar
  18. 18.
    Khin SS, Kitazawa R, Win N, Aye TT, Mori K, Kondo T, et al. BAMBI gene is epigenetically silenced in subset of high-grade bladder cancer. Int J Cancer. 2009;125:328–38.CrossRefPubMedGoogle Scholar
  19. 19.
    Togo N. Prognostic significance of bmp and activin membrane-bound inhibitor in colorectal cancer. World J Gastroenterol. 2008;14:4880.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Fritzmann J, Morkel M, Besser D, Budczies J, Kosel F, Brembeck FH, et al. A colorectal cancer expression profile that includes transforming growth factor β inhibitor bambi predicts metastatic potential. Gastroenterology. 2009;137:165–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Sasaki T, Sasahira T, Shimura H, Ikeda S, Kuniyasu H. Effect of nma on growth inhibition by tgf-betaa in human gastric carcinoma cell lines. Oncol Rep. 2004;11:1219–23.PubMedGoogle Scholar
  22. 22.
    Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, et al. Human BAMBI cooperates with smad7 to inhibit transforming growth factor-signaling. J Biol Chem. 2009;284:30097–104.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Paulsen M, Legewie S, Eils R, Karaulanov E, Niehrs C. Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development. Proc Natl Acad Sci U S A. 2011;108:10202–7.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Park YN, Chae KJ, Oh BK, Choi J, Choi KS, Park C. Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta. Hepatogastroenterology. 2004;51:396–400.PubMedGoogle Scholar
  25. 25.
    Huang Q, Liu L, Liu CH, Shao F, Xie F, Zhang CH, et al. Expression of Smad7 in cholangiocarcinoma: prognostic significance and implications for tumor metastasis. Asian Pac J Cancer Prev. 2012;13:5161–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Osawa H, Nakajima M, Kato H, Fukuchi M, Kuwano H. Prognostic value of the expression of Smad6 and Smad7, as inhibitory smads of the TGF-beta superfamily, in esophageal squamous cell carcinoma. Anticancer Res. 2004;24:3703–9.PubMedGoogle Scholar
  27. 27.
    Theohari I, Giannopoulou I, Magkou C, Nomikos A, Melissaris S, Nakopoulou L. Differential effect of the expression of TGF-beta pathway inhibitors, Smad-7 and ski, on invasive breast carcinomas: relation to biologic behavior. APMIS. 2012;120:92–100.CrossRefPubMedGoogle Scholar
  28. 28.
    Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005;23:2078–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Lin Z, Gao C, Ning Y, He X, Wu W, Chen YG. The pseudoreceptor bmp and activin membrane-bound inhibitor positively modulates wnt/beta-catenin signaling. J Biol Chem. 2008;283:33053–8.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Kiesslich T, Alinger B, Wolkersdorfer GW, Ocker M, Neureiter D, Berr F. Active Wnt signalling is associated with low differentiation and high proliferation in human biliary tract cancer in vitro and in vivo and is sensitive to pharmacological inhibition. Int J Oncol. 2010;36:49–58.PubMedGoogle Scholar
  31. 31.
    van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002;111:241–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G. Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am J Pathol. 2001;158:987–96.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, et al. Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem. 2002;277:39919–25.CrossRefPubMedGoogle Scholar
  34. 34.
    Wu Y, Li Q, Zhou X, Yu J, Mu Y, Munker S, et al. Decreased levels of active Smad2 correlate with poor prognosis in gastric cancer. PLoS One. 2012;7:e35684.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Yining Zhang
    • 1
  • Zhaojin Yu
    • 2
  • Qinghuan Xiao
    • 2
  • Xuren Sun
    • 3
  • Zhi Zhu
    • 3
  • Junyan Zhang
    • 3
  • Huimian Xu
    • 3
  • Minjie Wei
    • 2
    • 4
  • Mingjun Sun
    • 1
  1. 1.Department of Gastrointestinal EndoscopyThe First Affiliated Hospital of China Medical UniversityShenyang CityChina
  2. 2.Department of Pharmacology, School of Pharmaceutical SciencesChina Medical UniversityShenyangChina
  3. 3.Department of Surgical OncologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
  4. 4.Institute of Pathology and PathophysiologyChina Medical UniversityShenyangChina

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