Tumor Biology

, Volume 36, Issue 11, pp 8781–8787 | Cite as

Overexpression of Wnt7α protein predicts poor survival in patients with colorectal carcinoma

  • Yichong Wang
  • Jiufeng Wei
  • Shujun Zhang
  • Guodong Li
  • Tao Zhang
  • Xin Yu
  • Hongsheng Chen
  • Ming Liu
Research Article
  • 121 Downloads

Abstract

Wnt7α (wingless-type MMTV integration site family, member 7A) is a secreted glycoprotein that plays a critical role in tumorigenesis and development by controlling cell proliferation and differentiation. Whether Wnt7α has the properties of an oncogene or not is an interesting issue because of its diverse expression in different tumors. In the present study, Wnt7α protein expression was evaluated through immunohistochemistry and Western blot analysis. Univariate and multivariate analyses were applied to explore the associations between Wnt7α staining score and various clinical parameters, including overall survival (OS) and disease-free survival (DFS), and a total of 212 patients with colorectal cancer (CRC) were surveyed. Wnt7α was strongly expressed in most CRC tissues but weakly expressed in adjacent normal mucosa, colorectal adenomas, and colonic polyps. High levels of Wnt7α expression were strongly associated with tumor size (P = 0.006), lymph node involvement (P < 0.001), and the international tumor–node–metastasis (TNM) stage (P = 0.005). Patients with strong Wnt7α expression showed significantly poorer OS and DFS than patients with weak Wnt7α expression (P < 0.0001, both). Multivariate Cox analysis confirmed that Wnt7α protein expression and TNM stage are independent factors of adverse OS and DFS in CRC patients. Taken together, our results present evidence that Wnt7α overexpression is associated with an unfavorable prognosis and that positive Wnt7α, in addition to TNM stage, may be an independent prognosis factor influencing OS and DFS prediction in CRC patients.

Keywords

Colorectal cancer Wnt7α Prognosis Immunohistochemistry 

Notes

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81372612), the Heilongjiang Province Outstanding Youth Science Fund, and the Study Abroad Returnees Science Foundation of Heilongjiang (Nos. LC201109, JC201203).

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.
    Li S, Wang J, Lu Y, Fan D. Screening and early diagnosis of colorectal cancer in China: a 12 year retrospect (1994–2006). J Cancer Res Clin Oncol. 2007;133:679–86.CrossRefPubMedGoogle Scholar
  3. 3.
    Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal cancer. CA Cancer J Clin. 2007;57:168–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59:366–78.CrossRefPubMedGoogle Scholar
  5. 5.
    Wilson PM, Labonte MJ, Lenz HJ. Molecular markers in the treatment of metastatic colorectal cancer. Cancer J. 2010;16:262–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Akkoca AN, Yanık S, Ozdemir ZT, Cihan FG, Sayar S, Cincin TG, et al. TNM and Modified Dukes staging along with the demographic characteristics of patients with colorectal carcinoma. Int J Clin Exp Med. 2014;7:2828–35.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010;375:1030–47.CrossRefPubMedGoogle Scholar
  8. 8.
    Wan XB, Zhao Y, Fan XJ, Cai HM, Zhang Y, Chen MY, et al. Molecular prognostic prediction for locally advanced nasopharyngeal carcinoma by support vector machine integrated approach. PLoS One. 2012;7, e31989.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Xu J, Wan XB, Huang XF, Chan KC, Hong MH, Wang LH, et al. Serologic antienzyme rate of Epstein-Barr virus DNase-specific neutralizing antibody segregates TNM classification in nasopharyngeal carcinoma. J Clin Oncol. 2010;28:5202–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Fan XJ, Wan XB, Fu XH, Wu PH, Chen DK, Wang PN, et al. Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer. Tumour Biol. 2014;35:10487–95.CrossRefPubMedGoogle Scholar
  11. 11.
    Fang Y, Jiang Y, Wang X, Yang X, Gao Y, Wang J. Somatic mutations of the HER2 in metastatic breast cancer. Tumour Biol. 2014;35:11851–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Pinto D, Gregorieff A, Begthel H, Clevers H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17:1709–13.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    De A. Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin (Shanghai). 2011;43:745–56.CrossRefGoogle Scholar
  14. 14.
    Asad M, Wong MK, Tan TZ, Choolani M, Low J, Mori S, et al. FZD7 drives in vitro aggressiveness in stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. Cell Death Dis. 2014;5, e1346.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW, MacBeath G. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell. 2014;159:844–56.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cleary AS, Leonard TL, Gestl SA, Gunther EJ. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature. 2014;508:113–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tian J, He H, Lei G. Wnt/β-catenin pathway in bone cancers. Tumour Biol. 2014;35:9439–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Xu Y, Li H, Huang C, Zhao T, Zhang H, Zheng C, et al. Wnt2 protein plays a role in the progression of pancreatic cancer promoted by pancreatic stellate cells. Med Oncol. 2015;32:97.CrossRefPubMedGoogle Scholar
  19. 19.
    Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Bikkavilli RK, Avasarala S, Van Scoyk M, Arcaroli J, Brzezinski C, Zhang W, et al. Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene. 2015. doi: 10.1038/onc.2015.2.PubMedCentralGoogle Scholar
  21. 21.
    Hirata T, Zheng Q, Chen Z, Kinoshita H, Okamoto J, Kratz J, et al. Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma. Oncol Rep. 2015;33:2052–60.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kirikoshi H, Katoh M. Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. Int J Oncol. 2002;21:895–900.PubMedGoogle Scholar
  23. 23.
    Ikegawa S, Kumano Y, Okui K, Fujiwara T, Takahashi E, Nakamura Y. Isolation, characterization and chromosomal assignment of the human WNT7A gene. Cytogenet Cell Genet. 1996;74:149–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Hayashi K, Burghardt RC, Bazer FW, Spencer TE. WNTs in the ovine uterus: potential regulation of periimplantation ovine conceptus development. Endocrinology. 2007;148:3496–506.CrossRefPubMedGoogle Scholar
  25. 25.
    Yoshioka S, King ML, Ran S, Okuda H, MacLean 2nd JA, McAsey ME, et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol Cancer Res. 2012;10:469–82.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang XL, Peng CJ, Peng J, Jiang LY, Ning XM, Zheng JH. Prognostic role of Wnt7a expression in ovarian carcinoma patients. Neoplasma. 2010;57:545–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Liu T, Gao H, Yang M, Zhao T, Liu Y, Lou G. Correlation of TNFAIP8 overexpression with the proliferation, metastasis, and disease-free survival in endometrial cancer. Tumor Biol. 2014;35:5805–14.CrossRefGoogle Scholar
  28. 28.
    Sancho E, Batlle E, Clevers H. Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol. 2004;20:695–723.CrossRefPubMedGoogle Scholar
  29. 29.
    Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99–109.CrossRefPubMedGoogle Scholar
  30. 30.
    Winn RA, Marek L, Han SY, Rodriguez K, Rodriguez N, Hammond M, et al. Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation. J Biol Chem. 2005;280:19625–34.CrossRefPubMedGoogle Scholar
  31. 31.
    Winn RA, Van Scoyk M, Hammond M, Rodriguez K, Crossno Jr JT, Heasley LE, et al. Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2005;281:26943–50.CrossRefGoogle Scholar
  32. 32.
    Ohira T, Gemmill RM, Ferguson K, Kusy S, Roche J, Brambilla E, et al. WNT7a induces E-cadherin in lung cancer cells. Proc Natl Acad Sci U S A. 2003;100:10429–34.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kondratov AG, Kvasha SM, Stoliar LA, Romanenko AM, Zgonnyk YM, Gordiyuk VV, et al. Alterations of the WNT7A gene in clear cell renal cell carcinomas. PLoS One. 2012;7, e47012.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ochoa-Hernández AB, Ramos-Solano M, Meza-Canales ID, García-Castro B, Rosales-Reynoso MA, Rosales-Aviña JA, et al. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation. BMC Cancer. 2012;12:60.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yichong Wang
    • 1
  • Jiufeng Wei
    • 1
  • Shujun Zhang
    • 2
  • Guodong Li
    • 1
  • Tao Zhang
    • 3
  • Xin Yu
    • 4
  • Hongsheng Chen
    • 1
  • Ming Liu
    • 1
  1. 1.Department of General Surgery, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina
  2. 2.Department of Pathology, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina
  3. 3.Department of Orthopedics, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina
  4. 4.Department of Gastroenterology, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina

Personalised recommendations