Skip to main content
Top
Published in: Annals of Surgical Oncology 1/2011

01-01-2011 | Translational Research and Biomarkers

STC2: A Predictive Marker for Lymph Node Metastasis in Esophageal Squamous-Cell Carcinoma

Authors: Yoshiaki Kita, MD, PhD, Koshi Mimori, MD, PhD, Masaaki Iwatsuki, MD, PhD, Takehiko Yokobori, MD, PhD, Keisuke Ieta, MD, PhD, Fumiaki Tanaka, MD, PhD, Hideshi Ishii, MD, PhD, Hiroshi Okumura, MD, PhD, Shoji Natsugoe, MD, PhD, Masaki Mori, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Issue 1/2011

Login to get access

Abstract

Background

We sought to identify genes associated with the progression and metastasis of esophageal squamous-cell cancer by comparing the expression profiles of normal, primary cancer, and metastatic cancer cells isolated with laser microdissection.

Methods

Oligo microarray analysis identified several lymph node-specific, metastasis-related genes. STC2 (stanniocalcin 2), which was overexpressed in esophageal cancer cases, was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were used to explore the clinicopathologic significance of STC2 expression status in 70 cases. Additionally, the functional role of STC2 in esophageal cancer was studied by the attenuation of STC2 in an esophageal cancer cell line.

Results

Laser microdissection and oligo microarray analysis identified 63 candidate genes. Among them, STC2 showed higher expression in cancer tissue than in corresponding normal tissue (P < 0.001). STC2 expression was significantly correlated with lymph node metastasis, lymphatic invasion, and distant metastasis (P = 0.005, 0.007, and 0.038, respectively). Patients whose tumors had high STC2 expression had a worse 5-year survival rate than patients whose tumors had a low STC2 expression level (P = 0.016). STC2 transfected cells had a significantly higher proliferation rate than control cells (P < 0.001). Additionally, STC2 transfected cells were more invasive in vitro (P < 0.001) than control cells. These findings were validated by means of RNA interference assays.

Conclusions

We identified lymph node-specific, metastasis-related genes in esophageal cancer cells. One of these, STC2, may be associated with lymph node metastasis, making it a potential prognostic marker for esophageal cancer patients.
Literature
1.
go back to reference Sugimachi K, Matsuura H, Kai H, et al. Prognostic factors of esophageal carcinoma: univariate and multivariate analyses. J Surg Oncol. 1986;31:108–12.CrossRefPubMed Sugimachi K, Matsuura H, Kai H, et al. Prognostic factors of esophageal carcinoma: univariate and multivariate analyses. J Surg Oncol. 1986;31:108–12.CrossRefPubMed
2.
go back to reference Natsugoe S, Matsumoto M, Okumura H, et al. Prognostic factors in patients with submucosal esophageal cancer. J Gastrointest Surg. 2004;8:631–5.CrossRefPubMed Natsugoe S, Matsumoto M, Okumura H, et al. Prognostic factors in patients with submucosal esophageal cancer. J Gastrointest Surg. 2004;8:631–5.CrossRefPubMed
3.
go back to reference Inoue H, Matsuyama A, Mimori K, Ueo H, Mori M. Prognostic score of gastric cancer determined by cDNA microarray. Clin Cancer Res. 2002;8:3475–9.PubMed Inoue H, Matsuyama A, Mimori K, Ueo H, Mori M. Prognostic score of gastric cancer determined by cDNA microarray. Clin Cancer Res. 2002;8:3475–9.PubMed
4.
go back to reference Mori M, Mimori K, Yoshikawa Y, et al. Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. Surgery. 2002;131:S39–47.CrossRefPubMed Mori M, Mimori K, Yoshikawa Y, et al. Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. Surgery. 2002;131:S39–47.CrossRefPubMed
5.
go back to reference Ohmachi T, Tanaka F, Mimori K, et al. Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res. 2006;12:3057–63.CrossRefPubMed Ohmachi T, Tanaka F, Mimori K, et al. Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res. 2006;12:3057–63.CrossRefPubMed
6.
go back to reference Mimori K, Kataoka A, Yoshinaga K, et al. Identification of molecular markers for metastasis-related genes in primary breast cancer cells. Clin Exp Metastasis. 2005;22:59–67.CrossRefPubMed Mimori K, Kataoka A, Yoshinaga K, et al. Identification of molecular markers for metastasis-related genes in primary breast cancer cells. Clin Exp Metastasis. 2005;22:59–67.CrossRefPubMed
7.
go back to reference Chang AC, Reddel RR. Identification of a second stanniocalcin cDNA in mouse and human: stanniocalcin 2. Mol Cell Endocrinol. 1998;141:95–9.CrossRefPubMed Chang AC, Reddel RR. Identification of a second stanniocalcin cDNA in mouse and human: stanniocalcin 2. Mol Cell Endocrinol. 1998;141:95–9.CrossRefPubMed
8.
go back to reference Welcsh PL, Lee MK, Gonzalez-Hernandez RM, et al. BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc Natl Acad Sci USA. 2002;99:7560–5.CrossRefPubMed Welcsh PL, Lee MK, Gonzalez-Hernandez RM, et al. BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc Natl Acad Sci USA. 2002;99:7560–5.CrossRefPubMed
9.
go back to reference Esseghir S, Kennedy A, Seedhar P, et al. Identification of NTN4, TRA1, and STC2 as prognostic markers in breast cancer in a screen for signal sequence encoding proteins. Clin Cancer Res. 2007;13:3164–73.CrossRefPubMed Esseghir S, Kennedy A, Seedhar P, et al. Identification of NTN4, TRA1, and STC2 as prognostic markers in breast cancer in a screen for signal sequence encoding proteins. Clin Cancer Res. 2007;13:3164–73.CrossRefPubMed
10.
go back to reference Buckanovich RJ, Sasaroli D, O’Brien-Jenkins A, et al. Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol. 2007;25:852–61.CrossRefPubMed Buckanovich RJ, Sasaroli D, O’Brien-Jenkins A, et al. Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol. 2007;25:852–61.CrossRefPubMed
11.
go back to reference Meyer HA, Tolle A, Jung M, et al. Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma. Eur Urol. 2009;55:669–78.CrossRefPubMed Meyer HA, Tolle A, Jung M, et al. Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma. Eur Urol. 2009;55:669–78.CrossRefPubMed
12.
go back to reference Staehler M. Editorial comment on: Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma. Eur Urol. 2009;55:678.CrossRefPubMed Staehler M. Editorial comment on: Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma. Eur Urol. 2009;55:678.CrossRefPubMed
13.
go back to reference Tamura K, Furihata M, Chung SY, et al. Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer. Cancer Sci. 2009;100:914–9.CrossRefPubMed Tamura K, Furihata M, Chung SY, et al. Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer. Cancer Sci. 2009;100:914–9.CrossRefPubMed
14.
go back to reference Volland S, Kugler W, Schweigerer L, Wilting J, Becker J. Stanniocalcin 2 promotes invasion and is associated with metastatic stages in neuroblastoma. Int J Cancer. 2009;125:2049–57.CrossRefPubMed Volland S, Kugler W, Schweigerer L, Wilting J, Becker J. Stanniocalcin 2 promotes invasion and is associated with metastatic stages in neuroblastoma. Int J Cancer. 2009;125:2049–57.CrossRefPubMed
15.
go back to reference Sobin LH, Fleming ID. TNM classification of malignant tumors. 5th ed. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4. Sobin LH, Fleming ID. TNM classification of malignant tumors. 5th ed. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4.
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference Nishida K, Mine S, Utsunomiya T, et al. Global analysis of altered gene expressions during the process of esophageal squamous cell carcinogenesis in the rat: a study combined with a laser microdissection and a cDNA microarray. Cancer Res. 2005;65:401–9.PubMed Nishida K, Mine S, Utsunomiya T, et al. Global analysis of altered gene expressions during the process of esophageal squamous cell carcinogenesis in the rat: a study combined with a laser microdissection and a cDNA microarray. Cancer Res. 2005;65:401–9.PubMed
18.
go back to reference Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nat Genet. 2001;29:365–71.CrossRefPubMed Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nat Genet. 2001;29:365–71.CrossRefPubMed
19.
go back to reference Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med. 1990;9:811–8.CrossRefPubMed Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med. 1990;9:811–8.CrossRefPubMed
20.
go back to reference Arigami T, Natsugoe S, Uenosono Y, et al. Lymphatic invasion using D2–40 monoclonal antibody and its relationship to lymph node micrometastasis in pN0 gastric cancer. Br J Cancer. 2005;93:688–93.CrossRefPubMed Arigami T, Natsugoe S, Uenosono Y, et al. Lymphatic invasion using D2–40 monoclonal antibody and its relationship to lymph node micrometastasis in pN0 gastric cancer. Br J Cancer. 2005;93:688–93.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference Shibata K, Tanaka S, Shiraishi T, Kitano S, Mori M. G-protein gamma 7 is down-regulated in cancers and associated with p 27kip1-induced growth arrest. Cancer Res. 1999;59:1096–101.PubMed Shibata K, Tanaka S, Shiraishi T, Kitano S, Mori M. G-protein gamma 7 is down-regulated in cancers and associated with p 27kip1-induced growth arrest. Cancer Res. 1999;59:1096–101.PubMed
23.
go back to reference Ito T, Hashimoto Y, Tanaka E, et al. An inducible short-hairpin RNA vector against osteopontin reduces metastatic potential of human esophageal squamous cell carcinoma in vitro and in vivo. Clin Cancer Res. 2006;12:1308–16.CrossRefPubMed Ito T, Hashimoto Y, Tanaka E, et al. An inducible short-hairpin RNA vector against osteopontin reduces metastatic potential of human esophageal squamous cell carcinoma in vitro and in vivo. Clin Cancer Res. 2006;12:1308–16.CrossRefPubMed
24.
go back to reference Kita Y, Natsugoe S, Okumura H, et al. Expression of osteopontin in oesophageal squamous cell carcinoma. Br J Cancer. 2006;95:634–8.CrossRefPubMed Kita Y, Natsugoe S, Okumura H, et al. Expression of osteopontin in oesophageal squamous cell carcinoma. Br J Cancer. 2006;95:634–8.CrossRefPubMed
25.
go back to reference Xi L, Luketich JD, Raja S, et al. Molecular staging of lymph nodes from patients with esophageal adenocarcinoma. Clin Cancer Res. 2005;11:1099–109.PubMed Xi L, Luketich JD, Raja S, et al. Molecular staging of lymph nodes from patients with esophageal adenocarcinoma. Clin Cancer Res. 2005;11:1099–109.PubMed
26.
go back to reference Hosch SB, Izbicki JR, Pichlmeier U, et al. Expression and prognostic significance of immunoregulatory molecules in esophageal cancer. Int J Cancer. 1997;74:582–7.CrossRefPubMed Hosch SB, Izbicki JR, Pichlmeier U, et al. Expression and prognostic significance of immunoregulatory molecules in esophageal cancer. Int J Cancer. 1997;74:582–7.CrossRefPubMed
27.
go back to reference Akimoto T, Nonaka T, Harashima K, et al. Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line: the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity. Int J Radiat Biol. 2004;80:483–92.CrossRefPubMed Akimoto T, Nonaka T, Harashima K, et al. Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line: the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity. Int J Radiat Biol. 2004;80:483–92.CrossRefPubMed
28.
go back to reference Ding Y, Shimada Y, Gorrin-Rivas MJ, et al. Clinicopathological significance of human macrophage metalloelastase expression in esophageal squamous cell carcinoma. Oncology. 2002;63:378–84.CrossRefPubMed Ding Y, Shimada Y, Gorrin-Rivas MJ, et al. Clinicopathological significance of human macrophage metalloelastase expression in esophageal squamous cell carcinoma. Oncology. 2002;63:378–84.CrossRefPubMed
29.
go back to reference Yoshikawa R, Yanagi H, Shen CS, et al. ECA39 is a novel distant metastasis-related biomarker in colorectal cancer. World J Gastroenterol. 2006;12:5884–9.PubMed Yoshikawa R, Yanagi H, Shen CS, et al. ECA39 is a novel distant metastasis-related biomarker in colorectal cancer. World J Gastroenterol. 2006;12:5884–9.PubMed
30.
go back to reference Oue N, Hamai Y, Mitani Y, et al. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 2004;64:2397–405.CrossRefPubMed Oue N, Hamai Y, Mitani Y, et al. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 2004;64:2397–405.CrossRefPubMed
31.
go back to reference Seya T, Tanaka N, Shinji S, et al. Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis. Oncol Rep. 2006;16:1225–30.PubMed Seya T, Tanaka N, Shinji S, et al. Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis. Oncol Rep. 2006;16:1225–30.PubMed
32.
go back to reference Hu L, Lau SH, Tzang CH, et al. Association of Vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene. 2004;23:298–302.CrossRefPubMed Hu L, Lau SH, Tzang CH, et al. Association of Vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene. 2004;23:298–302.CrossRefPubMed
33.
go back to reference Wagner GF, Jaworski E. Calcium regulates stanniocalcin mRNA levels in primary cultured rainbow trout corpuscles of stannius. Mol Cell Endocrinol. 1994;99:315–22.CrossRefPubMed Wagner GF, Jaworski E. Calcium regulates stanniocalcin mRNA levels in primary cultured rainbow trout corpuscles of stannius. Mol Cell Endocrinol. 1994;99:315–22.CrossRefPubMed
34.
go back to reference Deol HK, Varghese R, Wagner GF, Dimattia GE. Dynamic regulation of mouse ovarian stanniocalcin expression during gestation and lactation. Endocrinology. 2000;141:3412–21.CrossRefPubMed Deol HK, Varghese R, Wagner GF, Dimattia GE. Dynamic regulation of mouse ovarian stanniocalcin expression during gestation and lactation. Endocrinology. 2000;141:3412–21.CrossRefPubMed
35.
go back to reference Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405–14.PubMed Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405–14.PubMed
36.
go back to reference Raya A, Kawakami Y, Rodriguez-Esteban C, et al. Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature. 2004;427:121–8.CrossRefPubMed Raya A, Kawakami Y, Rodriguez-Esteban C, et al. Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature. 2004;427:121–8.CrossRefPubMed
37.
go back to reference Stolk M, Leon-Ponte M, Merrill M, Ahern GP, O’Connell PJ. IP3Rs are sufficient for dendritic cell Ca2+ signaling in the absence of RyR1. J Leukoc Biol. 2006;80:651–8.CrossRefPubMed Stolk M, Leon-Ponte M, Merrill M, Ahern GP, O’Connell PJ. IP3Rs are sufficient for dendritic cell Ca2+ signaling in the absence of RyR1. J Leukoc Biol. 2006;80:651–8.CrossRefPubMed
38.
go back to reference Rossi D, Murayama T, Manini I, et al. Expression and functional activity of ryanodine receptors (RyRs) during skeletal muscle development. Cell Calcium. 2007;41:573–80.CrossRefPubMed Rossi D, Murayama T, Manini I, et al. Expression and functional activity of ryanodine receptors (RyRs) during skeletal muscle development. Cell Calcium. 2007;41:573–80.CrossRefPubMed
39.
go back to reference Choi JH, Park JT, Davidson B, et al. Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 2008;68:5716–23.CrossRefPubMed Choi JH, Park JT, Davidson B, et al. Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 2008;68:5716–23.CrossRefPubMed
40.
go back to reference Banasiak KJ, Xia Y, Haddad GG. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog Neurobiol. 2000;62:215–49.CrossRefPubMed Banasiak KJ, Xia Y, Haddad GG. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog Neurobiol. 2000;62:215–49.CrossRefPubMed
41.
go back to reference Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001;11:293–9.CrossRefPubMed Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001;11:293–9.CrossRefPubMed
42.
go back to reference Ito D, Walker JR, Thompson CS, et al. Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol Cell Biol. 2004;24:9456–69.CrossRefPubMed Ito D, Walker JR, Thompson CS, et al. Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol Cell Biol. 2004;24:9456–69.CrossRefPubMed
43.
go back to reference Law AY, Wong CK. Stanniocalcin-2 is a HIF-1 target gene that promotes cell proliferation in hypoxia. Exp Cell Res. 2010;316:466–76.CrossRefPubMed Law AY, Wong CK. Stanniocalcin-2 is a HIF-1 target gene that promotes cell proliferation in hypoxia. Exp Cell Res. 2010;316:466–76.CrossRefPubMed
Metadata
Title
STC2: A Predictive Marker for Lymph Node Metastasis in Esophageal Squamous-Cell Carcinoma
Authors
Yoshiaki Kita, MD, PhD
Koshi Mimori, MD, PhD
Masaaki Iwatsuki, MD, PhD
Takehiko Yokobori, MD, PhD
Keisuke Ieta, MD, PhD
Fumiaki Tanaka, MD, PhD
Hideshi Ishii, MD, PhD
Hiroshi Okumura, MD, PhD
Shoji Natsugoe, MD, PhD
Masaki Mori, MD, PhD, FACS
Publication date
01-01-2011
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 1/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-010-1271-1

Other articles of this Issue 1/2011

Annals of Surgical Oncology 1/2011 Go to the issue