Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 11331–11337 | Cite as

Low level of FOXL1 indicates a worse prognosis for gastric cancer patients

Original Article

Abstract

The aim of this study was to detect forkhead box L1 (FOXL1) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse transcriptase polymerase chain reaction were performed to detect FOXL1 tissue expression in 109 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of FOXL1 expression. The chi-square test was used to analyze the relationship between FOXL1 expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan–Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of FOXL1 messenger RNA (mRNA) was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.043). Clinicopathological analysis showed that FOXL1 expression was significantly correlated with depth of invasion (P = 0.017), lymph node metastasis (P = 0.019), and distant metastasis (P = 0.047). FOXL1-negative as opposed to the FOXL1-positive patients had lower 5-year overall survival (14.06 vs. 37.78 %, P < 0.001). Multivariate analysis suggested that FOXL1 expression might be an independent prognostic indicator (hazard ratio = 0.307, 95 % confidence interval, 0.187–0.505; P < 0.001) for GC patients. In conclusion, our findings provide evidence that FOXL1 might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.

Keywords

FOXL1 Gastric cancer Overall survival Prognosis 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81372341 and 30972883).

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflicts of interest

None

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Jung H, Lee HH, Song KY, Jeon HM, Park CH. Validation of the seventh edition of the American Joint Committee on Cancer TNM staging system for gastric cancer. Cancer-Am Cancer Soc. 2011;117:2371–8.Google Scholar
  5. 5.
    Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol. 2002;250:1–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS. Fox’s in development and disease. Trends Genet. 2003;19:339–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 2009;10:233–40.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.CrossRefPubMedGoogle Scholar
  9. 9.
    Lam EW, Brosens JJ, Gomes AR, Koo CY. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013;13:482–95.CrossRefPubMedGoogle Scholar
  10. 10.
    Yu M, Tang Z, Meng F, Tai M, Zhang J, Wang R, Liu C, Wu Q. Elevated expression of FoxM1 promotes the tumor cell proliferation in hepatocellular carcinoma. Tumour Biol. 2015. [Epub ahead of print].Google Scholar
  11. 11.
    Zhang HG, Xu XW, Shi XP, Han BW, Li ZH, Ren WH, Chen PJ, Lou YF, Li B, Luo XY. Overexpression of forkhead box protein M1 (FOXM1) plays a critical role in colorectal cancer. Clin Transl Oncol 2015. [Epub ahead of print].Google Scholar
  12. 12.
    Raychaudhuri P, Park HJ. FoxM1: a master regulator of tumor metastasis. Cancer Res. 2011;71:4329–33.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liu D, Zhang Z, Kong CZ. High FOXM1 expression was associated with bladder carcinogenesis. Tumour Biol. 2013;34(2):1131–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH. Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res. 2007;67:8293–300.CrossRefPubMedGoogle Scholar
  15. 15.
    Wei P, Zhang N, Wang Y, Li D, Wang L, Sun X, et al. FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL. Int J Biol Sci. 2015;11:186–98.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pei Y, Wang P, Liu H, He F, Ming L. FOXQ1 promotes esophageal cancer proliferation and metastasis by negatively modulating CDH1. Biomed Pharmacother. 2015;74:89–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen J, Huang Q, Wang F. Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma. Tumour Biol. 2014;35:7195–200.CrossRefPubMedGoogle Scholar
  18. 18.
    Yan JH, Zhao CL, Ding LB, Zhou X. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer. Biochem Biophys Res Commun. 2015;466:111–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Yan X, Zhou H, Zhang T, Xu P, Zhang S, Huang W, et al. Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumour Biol. 2015;36(12):9611–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Takano-Maruyama M, Hase K, Fukamachi H, Kato Y, Koseki H, Ohno H. Foxl1-deficient mice exhibit aberrant epithelial cell positioning resulting from dysregulated EphB/EphrinB expression in the small intestine. Am J Physiol Gastrointest Liver Physiol. 2006;291:G163–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Kaestner KH, Silberg DG, Traber PG, Schutz G. The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev. 1997;11:1583–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Perreault N, Sackett SD, Katz JP, Furth EE, Kaestner KH. Foxl1 is a mesenchymal modifier of Min in carcinogenesis of stomach and colon. Genes Dev. 2005;19:311–5.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fukuda K, Yoshida H, Sato T, Furumoto TA, Mizutani-Koseki Y, Suzuki Y, et al. Mesenchymal expression of Foxl1, a winged helix transcriptional factor, regulates generation and maintenance of gut-associated lymphoid organs. Dev Biol. 2003;255:278–89.CrossRefPubMedGoogle Scholar
  24. 24.
    Kaestner KH, Bleckmann SC, Monaghan AP, Schlondorff J, Mincheva A, Lichter P, et al. Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development. Development. 1996;122:1751–8.PubMedGoogle Scholar
  25. 25.
    Nakada C, Satoh S, Tabata Y, Arai K, Watanabe S. Transcriptional repressor foxl1 regulates central nervous system development by suppressing shh expression in zebra fish. Mol Cell Biol. 2006;26:7246–57.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang G, He P, Gaedcke J, Ghadimi BM, Ried T, Yfantis HG, et al. FOXL1, a novel candidate tumor suppressor, inhibits tumor aggressiveness and predicts outcome in human pancreatic cancer. Cancer Res. 2013;73:5416–25.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Qin Y, Gong W, Zhang M, Wang J, Tang Z, Quan Z. Forkhead box L1 is frequently downregulated in gallbladder cancer and inhibits cell growth through apoptosis induction by mitochondrial dysfunction. Plos One. 2014;9:e102084.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yang FQ, Yang FP, Li W, Liu M, Wang GC, Che JP, et al. Foxl1 inhibits tumor invasion and predicts outcome in human renal cancer. Int J Clin Exp Pathol. 2014;7:110–22.PubMedGoogle Scholar
  29. 29.
    Chen X, Deng M, Ma L, Zhou J, Xiao Y, Zhou X, et al. Inhibitory effects of forkhead box L1 gene on osteosarcoma growth through the induction of cell cycle arrest and apoptosis. Oncol Rep. 2015;34:265–71.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Zhai Ertao
    • 1
  • Chen Jianhui
    • 1
  • Chen Chuangqi
    • 1
  • Qin Changjiang
    • 1
  • Chen Sile
    • 1
  • He Yulong
    • 1
  • Cai Shirong
    • 1
  • Wu Hui
    • 1
  1. 1.Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

Personalised recommendations