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01-02-2011 | Thoracic Oncology

FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma

Authors: Naohiro Nishida, MD, Koshi Mimori, MD, Takehiko Yokobori, MD, Tomoya Sudo, MD, Fumiaki Tanaka, MD, Kohei Shibata, MD, Hideshi Ishii, MD, Yuichiro Doki, MD, Masaki Mori, MD, FACS

Published in: Annals of Surgical Oncology | Issue 2/2011

Abstract

Background

FOXC2 has been implicated in cancer progression through its induction of epithelial-to-mesenchymal transition. We analyzed the clinical significance of FOXC2 in esophageal cancer cases, in which early distant metastasis or invasion to nearby organs is an obstacle to treatment.

Methods

Quantitative reverse transcriptase–polymerase chain reaction was used to evaluate FOXC2 mRNA expression in 70 esophageal cancer cases to determine the clinicopathologic significance of FOXC2 expression. Furthermore, we examined associations between FOXC2 expression and matrix metalloproteinases 2 (MMP2) and matrix metalloproteinases 9 (MMP9). We also performed in vitro invasion and migration assays for FOXC2-suppressed esophageal cancer cells.

Results

In clinicopathologic analysis, the high-FOXC2 expression group showed a higher incidence of advanced tumor stage, lymph node metastasis, and lymphatic invasion than the low-FOXC2 expression group (P < 0.05). In particular, tumor stage exhibited the most remarkable difference (P < 0.0001). Expression of MMP2 and MMP9 was far higher in the high-FOXC2 expression group. Furthermore, the high-FOXC2 expression group had a significantly poorer prognosis than did the low expression group (P = 0.006). Multivariate analysis indicated that high FOXC2 expression was an independent prognostic factor for survival. Suppression of FOXC2 expression altered the invasive and the migratory ability of esophageal cancer cells in vitro.

Conclusions

Our findings suggest that FOXC2 could be an important prognostic indicator for esophageal cancer patients. FOXC2 is directly involved in cancer progression and is associated with poor prognosis in esophageal cancer cases.

Argyres MI. Esophageal cancer. N Engl J Med. 2004;350:1363–4.PubMedCrossRef

Thompson SK, Ruszkiewicz AR, Jamieson GG, et al. Improving the accuracy of TNM staging in esophageal cancer: a pathological review of resected specimens. Ann Surg Oncol. 2008;15:3447–58.PubMedCrossRef

Doki Y, Shiozaki H, Tahara H, et al. Correlation between E-cadherin expression and invasiveness in vitro in a human esophageal cancer cell line. Cancer Res. 1993;53:3421–6.PubMed

Hu YC, Lam KY, Law S, et al. Profiling of differentially expressed cancer-related genes in esophageal squamous cell carcinoma (ESCC) using human cancer cDNA arrays: overexpression of oncogene MET correlates with tumor differentiation in ESCC. Clin Cancer Res. 2001;7:3519–25.PubMed

Miller SE, Veale RB. Environmental modulation of alpha(v), alpha(2) and beta(1) integrin subunit expression in human oesophageal squamous cell carcinomas. Cell Biol Int. 2001;25:61–9.PubMedCrossRef

Yu C, Zhou Y, Miao X, et al. Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer. Cancer Res. 2004;64:7622–8.PubMedCrossRef

Mroczko B, Kozlowski M, Groblewska M, et al. The diagnostic value of the measurement of matrix metalloproteinase 9 (MMP-9), squamous cell cancer antigen (SCC) and carcinoembryonic antigen (CEA) in the sera of esophageal cancer patients. Clin Chim Acta. 2008;389:61–6.PubMedCrossRef

Mani SA, Yang J, Brooks M, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA. 2007;104:10069–74.PubMedCrossRef

Hayashi H, Kume T. Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migration. Biochem Biophys Res Commun. 2008;367:584–9.PubMedCrossRef

10.

Thurston G, Noguera-Troise I, Yancopoulos GD. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer. 2007;7:327–31.PubMedCrossRef

11.

Kume T. Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol Histopathol. 2010;25:637–46.PubMed

12.

Sano H, Leboeuf JP, Novitskiy SV, et al. The Foxc2 transcription factor regulates tumor angiogenesis. Biochem Biophys Res Commun. 2010;392:201–6.PubMedCrossRef

13.

Hader C, Marlier A, Cantley L. Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2. Oncogene. 2010;29:1031–40.PubMedCrossRef

14.

Yu S, Shao L, Kilbride H, et al. Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease. Am J Med Genet A. 2010;152A:1257–62.PubMedCrossRef

15.

Utsunomiya T, Hara Y, Kataoka A, et al. Cystatin-like metastasis-associated protein mRNA expression in human colorectal cancer is associated with both liver metastasis and patient survival. Clin Cancer Res. 2002;8:2591–4.PubMed

16.

Utsunomiya T, Okamoto M, Hashimoto M, et al. A gene-expression signature can quantify the degree of hepatic fibrosis in the rat. J Hepatol. 2004;41:399–406.PubMedCrossRef

17.

Ogawa K, Utsunomiya T, Mimori K, et al. Clinical significance of human kallikrein gene 6 messenger RNA expression in colorectal cancer. Clin Cancer Res. 2005;11:2889–93.PubMedCrossRef

18.

Golubkov VS, Strongin AY. Proteolysis-driven oncogenesis. Cell Cycle. 2007;6:147–50.PubMedCrossRef

19.

Basset P, Okada A, Chenard MP, et al. Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol. 1997;15:535–41.PubMedCrossRef

20.

Dagenais SL, Hartsough RL, Erickson RP, et al. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expr Patterns. 2004;4:611–9.PubMedCrossRef

21.

Norrmen C, Ivanov KI, Cheng J, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol. 2009;185:439–57.PubMedCrossRef

22.

Tanpaiboon P, Kantaputra P, Wejathikul K, et al. c. 595–596 insC of FOXC2 underlies lymphedema, distichiasis, ptosis, ankyloglossia, and Robin sequence in a Thai patient. Am J Med Genet A. 2010;152A:737–40.PubMedCrossRef

23.

Ji RC. Lymphatic endothelial cells, lymphedematous lymphangiogenesis, and molecular control of edema formation. Lymphat Res Biol. 2008;6:123–37.PubMedCrossRef

24.

Katoh Y, Katoh M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008;22:271–5.PubMed

Title: FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma
Authors: Naohiro Nishida, MD
Koshi Mimori, MD
Takehiko Yokobori, MD
Tomoya Sudo, MD
Fumiaki Tanaka, MD
Kohei Shibata, MD
Hideshi Ishii, MD
Yuichiro Doki, MD
Masaki Mori, MD, FACS
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 2/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-010-1274-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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