Skip to main content
Top
Published in: Journal of Translational Medicine 1/2012

Open Access 01-12-2012 | Research

Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma

Authors: Yi Liang, Xue Hou, Qian Cui, Tie-Bang Kang, Jian-Hua Fu, Lan-Jun Zhang, Rong-Zhen Luo, Jie-Hua He, Yi-Xin Zeng, Hao-Xian Yang

Published in: Journal of Translational Medicine | Issue 1/2012

Login to get access

Abstract

Background

The correlation of S-phase kinase–associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival.

Methods

Tissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro.

Results

Skp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs.

Conclusions

Negative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells.
Appendix
Available only for authorised users
Literature
1.
go back to reference Younes M, Henson DE, Ertan A, Miller CC: Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol. 2002, 37: 1359-1365.CrossRefPubMed Younes M, Henson DE, Ertan A, Miller CC: Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol. 2002, 37: 1359-1365.CrossRefPubMed
2.
go back to reference Law S, Wong J: What is appropriate treatment for carcinoma of the thoracic esophagus?. World J Surg. 2001, 25: 189-195.CrossRefPubMed Law S, Wong J: What is appropriate treatment for carcinoma of the thoracic esophagus?. World J Surg. 2001, 25: 189-195.CrossRefPubMed
3.
go back to reference Rice TW, Rusch VW, Apperson-Hansen C, Allen MS, Chen LQ, Hunter JG, Kesler KA, Law S, Lerut TE, Reed CE: Worldwide esophageal cancer collaboration. Dis Esophagus. 2009, 22: 1-8.CrossRefPubMed Rice TW, Rusch VW, Apperson-Hansen C, Allen MS, Chen LQ, Hunter JG, Kesler KA, Law S, Lerut TE, Reed CE: Worldwide esophageal cancer collaboration. Dis Esophagus. 2009, 22: 1-8.CrossRefPubMed
4.
go back to reference Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A: AJCC Cancer Staging Manual. 2010, Springer, New York, 103-115. 7 Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A: AJCC Cancer Staging Manual. 2010, Springer, New York, 103-115. 7
5.
7.
go back to reference Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K, Massague J: Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature. 2007, 446: 765-770.CrossRefPubMed Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K, Massague J: Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature. 2007, 446: 765-770.CrossRefPubMed
8.
go back to reference Cardozo T, Pagano M: The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004, 5: 739-751.CrossRefPubMed Cardozo T, Pagano M: The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004, 5: 739-751.CrossRefPubMed
9.
go back to reference Petroski MD, Deshaies RJ: Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005, 6: 9-20.CrossRefPubMed Petroski MD, Deshaies RJ: Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005, 6: 9-20.CrossRefPubMed
10.
go back to reference Li JQ, Wu F, Masaki T, Kubo A, Fujita J, Dixon DA, Beauchamp RD, Ishida T, Kuriyama S, Imaida K: Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors. Int J Oncol. 2004, 25: 87-95.PubMed Li JQ, Wu F, Masaki T, Kubo A, Fujita J, Dixon DA, Beauchamp RD, Ishida T, Kuriyama S, Imaida K: Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors. Int J Oncol. 2004, 25: 87-95.PubMed
11.
go back to reference Radke S, Pirkmaier A, Germain D: Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene. 2005, 24: 3448-3458.CrossRefPubMed Radke S, Pirkmaier A, Germain D: Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene. 2005, 24: 3448-3458.CrossRefPubMed
12.
go back to reference Lim MS, Adamson A, Lin Z, Perez-Ordonez B, Jordan RC, Tripp S, Perkins SL, Elenitoba-Johnson KS: Expression of Skp2, a p27(Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27(Kip1) and proliferation index. Blood. 2002, 100: 2950-2956.CrossRefPubMed Lim MS, Adamson A, Lin Z, Perez-Ordonez B, Jordan RC, Tripp S, Perkins SL, Elenitoba-Johnson KS: Expression of Skp2, a p27(Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27(Kip1) and proliferation index. Blood. 2002, 100: 2950-2956.CrossRefPubMed
13.
go back to reference Drobnjak M, Melamed J, Taneja S, Melzer K, Wieczorek R, Levinson B, Zeleniuch JA, Polsky D, Ferrara J, Perez SR: Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin Cancer Res. 2003, 9: 2613-2619.PubMed Drobnjak M, Melamed J, Taneja S, Melzer K, Wieczorek R, Levinson B, Zeleniuch JA, Polsky D, Ferrara J, Perez SR: Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin Cancer Res. 2003, 9: 2613-2619.PubMed
14.
go back to reference Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY: Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2009, 73: 202-207.CrossRefPubMed Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY: Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2009, 73: 202-207.CrossRefPubMed
15.
go back to reference Fukuchi M, Masuda N, Nakajima M, Fukai Y, Miyazaki T, Kato H: Kuwano: Inverse correlation between expression levels of p27 and the ubiquitin ligase subunit Skp2 in early esophageal squamous cell carcinoma. Anticancer Res. 2004, 24: 777-783.PubMed Fukuchi M, Masuda N, Nakajima M, Fukai Y, Miyazaki T, Kato H: Kuwano: Inverse correlation between expression levels of p27 and the ubiquitin ligase subunit Skp2 in early esophageal squamous cell carcinoma. Anticancer Res. 2004, 24: 777-783.PubMed
16.
go back to reference Wang XC, Wu YP, Ye B, Lin DC, Feng YB, Zhang ZQ, Xu X, Han YL, Cai Y, Dong JT: Suppression of anoikis by SKP2 amplification and overexpression promotes metastasis of esophageal squamous cell carcinoma. Mol Cancer Res. 2009, 7: 12-22.CrossRefPubMed Wang XC, Wu YP, Ye B, Lin DC, Feng YB, Zhang ZQ, Xu X, Han YL, Cai Y, Dong JT: Suppression of anoikis by SKP2 amplification and overexpression promotes metastasis of esophageal squamous cell carcinoma. Mol Cancer Res. 2009, 7: 12-22.CrossRefPubMed
17.
go back to reference Rami-Porta R, Wittekind C, Goldstraw P: Complete resection in lung cancer surgery: proposed definition. Lung Cancer. 2005, 49: 25-33.CrossRefPubMed Rami-Porta R, Wittekind C, Goldstraw P: Complete resection in lung cancer surgery: proposed definition. Lung Cancer. 2005, 49: 25-33.CrossRefPubMed
18.
go back to reference Yang HX, Xu Y, Fu JH, Wang JY, Lin P, Rong TH: An Evaluation of the Number of Lymph Nodes Examined and Survival for Node-Negative Esophageal Carcinoma: Data from China. Ann Surg Oncol. 2010, 17: 1901-1911.CrossRefPubMed Yang HX, Xu Y, Fu JH, Wang JY, Lin P, Rong TH: An Evaluation of the Number of Lymph Nodes Examined and Survival for Node-Negative Esophageal Carcinoma: Data from China. Ann Surg Oncol. 2010, 17: 1901-1911.CrossRefPubMed
19.
go back to reference Zhu ZH, Sun BY, Ma Y, Shao JY, Long H, Zhang X, Fu JH, Zhang LJ, Su XD, Wu QL: Three immunomarker support vector machines-based prognostic classifiers for stage IB non-small-cell lung cancer. J Clin Oncol. 2009, 27: 1091-1099.CrossRefPubMed Zhu ZH, Sun BY, Ma Y, Shao JY, Long H, Zhang X, Fu JH, Zhang LJ, Su XD, Wu QL: Three immunomarker support vector machines-based prognostic classifiers for stage IB non-small-cell lung cancer. J Clin Oncol. 2009, 27: 1091-1099.CrossRefPubMed
20.
go back to reference Fermento ME, Gandini NA, Lang CA, Perez JE, Maturi HV, Curino AC, Facchinetti MM: Intracellular distribution of p300 and its differential recruitment to aggresomes in breast cancer. Exp Mol Pathol. 2010, 88: 256-264.CrossRefPubMed Fermento ME, Gandini NA, Lang CA, Perez JE, Maturi HV, Curino AC, Facchinetti MM: Intracellular distribution of p300 and its differential recruitment to aggresomes in breast cancer. Exp Mol Pathol. 2010, 88: 256-264.CrossRefPubMed
21.
go back to reference Xu HM, Liang Y, Chen Q, Wu QN, Guo YM, Shen GP, Zhang RH, He ZW, Zeng YX, Xie FY: Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China. Chin J Cancer. 2011, 30: 204-212.CrossRefPubMedPubMedCentral Xu HM, Liang Y, Chen Q, Wu QN, Guo YM, Shen GP, Zhang RH, He ZW, Zeng YX, Xie FY: Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China. Chin J Cancer. 2011, 30: 204-212.CrossRefPubMedPubMedCentral
22.
go back to reference Zhang H, Kobayashi R, Galaktionov K, Beach D: p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell. 1995, 82: 915-925.CrossRefPubMed Zhang H, Kobayashi R, Galaktionov K, Beach D: p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell. 1995, 82: 915-925.CrossRefPubMed
23.
go back to reference Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP: Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature. 2000, 408: 381-386.CrossRefPubMed Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP: Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature. 2000, 408: 381-386.CrossRefPubMed
24.
go back to reference Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M: Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002, 416: 703-709.CrossRefPubMed Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M: Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002, 416: 703-709.CrossRefPubMed
25.
go back to reference Gao D, Inuzuka H, Korenjak M, Tseng A, Wu T, Wan L, Kirschner M, Dyson N, Wei W: Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Mol Biol Cell. 2009, 20: 3305-3316.CrossRefPubMedPubMedCentral Gao D, Inuzuka H, Korenjak M, Tseng A, Wu T, Wan L, Kirschner M, Dyson N, Wei W: Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Mol Biol Cell. 2009, 20: 3305-3316.CrossRefPubMedPubMedCentral
26.
go back to reference Chan CH, Lee SW, Wang J, Lin HK: Regulation of Skp2 expression and activity and its role in cancer progression. Scientific World Journal. 2010, 10: 1001-1015.CrossRefPubMed Chan CH, Lee SW, Wang J, Lin HK: Regulation of Skp2 expression and activity and its role in cancer progression. Scientific World Journal. 2010, 10: 1001-1015.CrossRefPubMed
27.
go back to reference Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Hershko DD: The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005, 103: 1336-1346.CrossRefPubMed Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Hershko DD: The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005, 103: 1336-1346.CrossRefPubMed
28.
go back to reference Masuda TA, Inoue H, Sonoda H, Mine S, Yoshikawa Y, Nakayama K, Nakayama K, Mori M: Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 2002, 62: 3819-3825.PubMed Masuda TA, Inoue H, Sonoda H, Mine S, Yoshikawa Y, Nakayama K, Nakayama K, Mori M: Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 2002, 62: 3819-3825.PubMed
29.
go back to reference Ma XM, Liu Y, Guo JW, Liu JH, Zuo LF: Relation of overexpression of S phase kinase-associated protein 2 with reduced expression of p27 and PTEN in human gastric carcinoma. World J Gastroenterol. 2005, 11: 6716-6721.CrossRefPubMedPubMedCentral Ma XM, Liu Y, Guo JW, Liu JH, Zuo LF: Relation of overexpression of S phase kinase-associated protein 2 with reduced expression of p27 and PTEN in human gastric carcinoma. World J Gastroenterol. 2005, 11: 6716-6721.CrossRefPubMedPubMedCentral
30.
go back to reference Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M: Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 2006, 12: 1215-1220.CrossRefPubMed Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M: Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 2006, 12: 1215-1220.CrossRefPubMed
31.
go back to reference Slotky M, Shapira M, Ben-Izhak O, Linn S, Futerman B, Tsalic M, Hershko DD: The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Breast Cancer Res. 2005, 7: R737-R744.CrossRefPubMedPubMedCentral Slotky M, Shapira M, Ben-Izhak O, Linn S, Futerman B, Tsalic M, Hershko DD: The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Breast Cancer Res. 2005, 7: R737-R744.CrossRefPubMedPubMedCentral
32.
go back to reference Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC, Harper JW: Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res. 2002, 8: 3419-3426.PubMed Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC, Harper JW: Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res. 2002, 8: 3419-3426.PubMed
33.
go back to reference Ben-Izhak O, Lahav-Baratz S, Meretyk S, Ben-Eliezer S, Sabo E, Dirnfeld M, Cohen S, Ciechanover A: Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer. J Urol. 2003, 170: 241-245.CrossRefPubMed Ben-Izhak O, Lahav-Baratz S, Meretyk S, Ben-Eliezer S, Sabo E, Dirnfeld M, Cohen S, Ciechanover A: Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer. J Urol. 2003, 170: 241-245.CrossRefPubMed
34.
go back to reference Osoegawa A, Yoshino I, Tanaka S, Sugio K, Kameyama T, Yamaguchi M, Maehara Y: Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer. J Clin Oncol. 2004, 22: 4165-4173.CrossRefPubMed Osoegawa A, Yoshino I, Tanaka S, Sugio K, Kameyama T, Yamaguchi M, Maehara Y: Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer. J Clin Oncol. 2004, 22: 4165-4173.CrossRefPubMed
35.
go back to reference Zhu CQ, Blackhall FH, Pintilie M, Iyengar P, Liu N, Ho J, Chomiak T, Lau D, Winton T, Shepherd FA: Skp2 gene copy number aberrations are common in non-small cell lung carcinoma, and its overexpression in tumors with ras mutation is a poor prognostic marker. Clin Cancer Res. 2004, 10: 1984-1991.CrossRefPubMed Zhu CQ, Blackhall FH, Pintilie M, Iyengar P, Liu N, Ho J, Chomiak T, Lau D, Winton T, Shepherd FA: Skp2 gene copy number aberrations are common in non-small cell lung carcinoma, and its overexpression in tumors with ras mutation is a poor prognostic marker. Clin Cancer Res. 2004, 10: 1984-1991.CrossRefPubMed
Metadata
Title
Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma
Authors
Yi Liang
Xue Hou
Qian Cui
Tie-Bang Kang
Jian-Hua Fu
Lan-Jun Zhang
Rong-Zhen Luo
Jie-Hua He
Yi-Xin Zeng
Hao-Xian Yang
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2012
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-10-73

Other articles of this Issue 1/2012

Journal of Translational Medicine 1/2012 Go to the issue