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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma

Authors: Ying Zhang, Ommoleila Molavi, Min Su, Raymond Lai

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Loss of STAT1 (Signal Transducer and Activator of Transcription-1) has been implicated in the pathobiology of a number of cancer types. Nonetheless, the biological and clinical significance of STAT1 in esophageal squamous cell carcinomas (ESCC) has not been comprehensively studied.

Methods

Using immunohistochemistry, we detected the STAT1 expression in a cohort of ESCC patients; In-vitro experiments, we used enforced gene transfection of STAT1C into two STAT1- weak/negative ESCC cell lines and siRNA knockdown of STAT1 in two STAT1-strong ESCC cell lines to detect STAT1 function in ESCC.

Results

We found that the expression of STAT1 was heterogeneous in ESCC, with 64 (49.0%) strongly positive cases, 59 (45.0%) weakly positive cases and 8 (6.1%) negative cases. STAT1 expression inversely correlated with the depth of tumor invasion and tumor size (p=0.047 and p=0.029, respectively, Chi square). Furthermore, patients with STAT1-strong/weak tumors had a significantly longer survival compared to those with STAT1-negative tumors (33.6 months versus 13.1 months, p=0.019). In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011). Our in-vitro experiments revealed that STAT1 is proapoptotic and inhibitory to cell-cycle progression and colony formation. Lastly, we found evidence that STAT1 signaling in ESCC cells down-regulated the expression and/or activity of NF-κB and STAT3, both of which are known to have oncogenic potential.

Conclusion

To conclude, our findings suggest that STAT1 is a tumor suppressor in ESCC. Loss of STAT1, which is frequent in ESCC, contributes to the pathogenesis of these tumors.
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Literature
1.
Li J, Yu B, Song L, Eschrich S, Haura EB: Effects of IFN-gamma and Stat1 on gene expression, growth, and survival in non-small cell lung cancer cells. J Interferon Cytokine Res. 2007, 27 (3): 209-220. 10.1089/jir.2006.0111.CrossRefPubMed
2.
Adámková L, Soucková K, Kovarík J: Transcription protein STAT1: biology and relation to cancer. Folia Biol (Praha). 2007, 53 (1): 1-6.
3.
Calò V, Migliavacca M, Bazan V, Macaluso M, Macaluso M, Buscemi M, Gebbia N, Russo A: STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. 2003, 197: 157-168. 10.1002/jcp.10364.CrossRefPubMed
4.
Battle TE, Frank DA: The role of STATs in apoptosis. Curr Mol Med. 2002, 2: 381-392. 10.2174/1566524023362456.CrossRefPubMed
5.
Max Parkin D, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002 CA cancer. J Clin. 2002, 2005 (55): 74-108.
6.
Su M, Liu M, Tian DP, Li XY, Zhang GH, Yang HL, Fan X, Huang HH, Gao YX: Temporal trends of esophageal cancer during 1995-2004 in Nanao Island, an extremely high-risk area in China. Eur J Epidemiol. 2007, 22 (1): 43-48. 10.1007/s10654-006-9086-x.CrossRefPubMed
7.
Zhang HZ, Jin GF, Shen HB: Epidemiologic differences in esophageal cancer between Asian and Western populations. Chin J Cancer. 2012, 31 (6): 281-286. 10.5732/cjc.011.10390.CrossRefPubMedPubMedCentral
8.
Polednak AP: Trends in survival for both histologic types of esophageal cancer in US surveillance, epidemiology and end results areas. Int J Cancer. 2003, 105 (1): 98-100. 10.1002/ijc.11029.CrossRefPubMed
9.
Kaganoi J, Watanabe G, Okabe M, Nagatani S, Kawabe A, Shimada Y, Imamura M, Sakai Y: STAT1 activation-induced apoptosis of esophageal squamous cell carcinoma cells in vivo. Ann Surg Oncol. 2007, 14 (4): 1405-1415. 10.1245/s10434-006-9274-7.CrossRefPubMed
10.
Watanabe G, Kaganoi J, Imamura M, Shimada Y, Itami A, Uchida S, Sato F, Kitagawa M: Progression of esophageal carcinoma by loss of EGF-STAT1 pathway. Cancer J. 2001, 7 (2): 132-139.PubMed
11.
Armanious H, Gelebart P, Mackey J, Ma Y, Lai R: STAT3 upregulates the protein expression and transcriptional activity of beta-catenin in breast cancer. Int J Clin Exp Pathol. 2010, 3 (7): 654-664.PubMedPubMedCentral
12.
Armanious H, Gelebart P, Anand M, Belch A, Lai R: Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway. Blood. 2011, 117 (23): 6237-6246. 10.1182/blood-2010-10-313940.CrossRefPubMed
13.
Sironi JJ, Ouchi T: STAT1-induced apoptosis is mediated by caspases 2, 3, and 7. J. Biol Chem. 2004, 279 (6): 4066-4074.CrossRefPubMed
14.
15.
Dimco G, Knight RA, Latchman DS, Stephanou A: STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest. Cell Cycle. 2010, 9: 4638-4649. 10.4161/cc.9.23.13955.CrossRefPubMed
16.
Suk K, Chang I, Kim YH, Kim S, Kim JY, Kim H, Lee MS: Interferon gamma (IFN gamma) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. J Biol Chem. 2001, 276 (16): 13153-13159. 10.1074/jbc.M007646200.CrossRefPubMed
17.
Tian F, Zang WD, Hou WH, Liu HT, Xue LX: Nuclear factor-kB signaling pathway constitutively activated in esophageal squamous cell carcinoma cell lines and inhibition of growth of cells by small interfering RNA. Acta Biochim Biophys Sin (Shanghai). 2006, 38 (5): 318-326. 10.1111/j.1745-7270.2006.00166.x.CrossRef
18.
Tian F, Zhang C, Tian W, Jiang Y, Zhang X: Comparison of the effect of p65 siRNA and curcumin in promoting apoptosis in esophageal squamous cell carcinoma cells and in nude mice. Oncol Rep. 2012, 28 (1): 232-240.PubMed
19.
Kienan V, Brec V, Ng W, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M: Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J. Biol. Chem. 2003, 278: 2758-2766. 10.1074/jbc.M209572200.CrossRef
20.
Qing Y, Stark GR: Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem. 2004, 279 (40): 41679-41685. 10.1074/jbc.M406413200.CrossRefPubMed
21.
Pensa S, Regis G, Boselli D, Novelli F, Valeria Poli: STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?. JAK-STAT Pathway in Disease. Edited by: Anastasis Stephanou. 2009, 100-113.
22.
Kim HS, Lee MS: STAT1 as a key modulator of cell death. Cell Signal. 2007, 19 (3): 454-465. 10.1016/j.cellsig.2006.09.003.CrossRefPubMed
23.
Durbin JE, Hackenmiller R, Simon MC, Levy DE: Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996, 84 (3): 443-450. 10.1016/S0092-8674(00)81289-1.CrossRefPubMed
24.
Lee CK, Rao DT, Gertner R, Gimeno R, Frey AB, Levy DE: Distinct requirements for IFNs and STAT1 in NK cell function. J Immunol. 2000, 165 (7): 3571-3577. 10.4049/jimmunol.165.7.3571.CrossRefPubMed
25.
Lee CK, Smith E, Gimeno R, Gertner R, Levy DE: STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol. 2000, 164 (3): 1286-1292. 10.4049/jimmunol.164.3.1286.CrossRefPubMed
26.
Deng H, Zhen H, Fu Z, Huang X, Zhou H, Liu L: The antagonistic effect between STAT1 and Survivin and its clinical significance in gastric cancer. Oncol Lett. 2012, 3 (1): 193-199.PubMed
27.
Kovarik J, Boudny V, Kocak I, Lauerova L, Fait V, Vagundova M: Malignant melanoma associates with deficient IFN-induced STAT 1 phosphorylation. Int J Mol Med. 2003, 12: 335-340.PubMed
28.
Bowman T, Garcia R, Turkson J, Jove R: STATs in oncogenesis. Oncogene. 2000, 19: 2474-2488. 10.1038/sj.onc.1203527.CrossRefPubMed
29.
Dimberg LY, Dimberg A, Ivarsson K, Fryknäs M, Rickardson L, Tobin G, Ekman S, Larsson R, Gullberg U, Nilsson K, Öberg F, Wiklund HJ: Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer. 2012, 12: 318-10.1186/1471-2407-12-318.CrossRefPubMedPubMedCentral
30.
Wang BY, Goan YG, Hsu PK, Hsu WH, Wu YC: Tumor length as a prognostic factor in esophageal squamous cell carcinoma. Ann Thorac Surg. 2011, 91: 887-893. 10.1016/j.athoracsur.2010.11.011.CrossRefPubMed
31.
Wang Z: The Invasion, Lymphatic Metastasis and Prognostic in ESCC. Master thesis. 2011, Guangxi Medical College
32.
Meyer S, Wild PJ, Vogt T, Bataille F, Ehret C, Gantner S, Landthaler M, Klinkhammer-Schalke M, Hofstaedter F, Bosserhoff AK: Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma. Exp Dermatol. 2010, 19 (8): e251-e257.CrossRefPubMed
33.
Ichiba M, Miyazaki Y, Kitamura S, Kiyohara T, Shinomura Y, Matsuzawa Y: Epidermal growth factor inhibits the growth of TE8 esophageal cancer cells through the activation of STAT1. J Gastroenterol. 2002, 37 (7): 497-503. 10.1007/s005350200077.CrossRefPubMed
34.
Sasagawa T, Hlaing M, Akaike T: Synergistic induction of apoptosis in murine hepatoma Hepa1-6 cells by IFN-gamma and TNF-alpha. Biochem Biophys Res Commun. 2000, 272 (3): 674-680. 10.1006/bbrc.2000.2835.CrossRefPubMed
35.
Sutherland RL, Musgrove EA: Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models. Breast Cancer Res. 2002, 4: 14-17.CrossRefPubMed
36.
Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, Huang K, Tong Q: MicroRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One. 2013, 8 (1): 55719-10.1371/journal.pone.0055719.CrossRef
37.
Campo E, Raffeld M, Jaffe ES: Mantle-cell lymphoma. Semin Hematol. 1999, 36 (2): 115-127.PubMed
38.
Inomata M, Uchino S, Tanimura H, Shiraishi N, Adachi Y, Kitano S: Amplification and overexpression of cyclin D1 in aggressive human esophageal cancer. Oncol Rep. 1998, 5 (1): 171-176.PubMed
39.
Zhao J, Li L, Wei S, Gao Y, Chen Y, Wang G, Wu Z: Clinicopathological and prognostic role of cyclin D1 in esophageal squamous cell carcinoma: a meta- analysis. Dis Esophagus. 2012, 25 (6): 520-526. 10.1111/j.1442-2050.2011.01278.x.CrossRefPubMed
40.
Abdel-Latif MM, O'Riordan J, Windle HJ, Carton E, Ravi N, Kelleher D, Reynolds JV: NF-κB activation in esophageal adenocarcinoma: relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy. Ann Surg. 2004, 239 (4): 491-500. 10.1097/01.sla.0000118751.95179.c6.CrossRefPubMedPubMedCentral
41.
Su C, Chen Z, Luo H, Su Y, Liu W, Cai L, Wang T, Lei Y, Zhong B: Different patterns of NF-κB and Notch1 signaling contribute to tumor-induced lymphangiogenesis of esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2011, 30: 85-10.1186/1756-9966-30-85.CrossRefPubMedPubMedCentral
42.
Krämer OH, Baus D, Knauer SK, Stein S, Jäger E, Stauber RH, Grez M, Pfitzner E, Heinzel T: Acetylation of Stat1 modulates NF-kappaB activity. Genes Dev. 2006, 20 (4): 473-485. 10.1101/gad.364306.CrossRefPubMedPubMedCentral
43.
Wang Y, Wu TR, Cai S, Welte T, Chin YE: Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation. Mol Cell Biol. 2000, 20 (13): 4505-4512. 10.1128/MCB.20.13.4505-4512.2000.CrossRefPubMedPubMedCentral
44.
Gelebart P, Zak Z, Anand M, Dien-Bard J, Amin HM, Lai R: Interleukin-21 effectively induces apoptosis in mantle cell lymphoma through a STAT1-dependent mechanism. Leukemia. 2009, 23 (10): 1836-1846. 10.1038/leu.2009.100.CrossRefPubMed
45.
Zhang Y, Du XL, Wang CJ, Lin DC, Ruan X, Feng YB, Huo YQ, Peng H, Cui JL, Zhang TT, Wang YQ, Zhang H, Zhan QM, Wang MR: Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells. Gastroenterology. 2012, 142 (3): 521-530. 10.1053/j.gastro.2011.11.023.CrossRefPubMed
46.
Sakamoto C: STAT1 and STAT3 might be regulated differently in esophageal squamous cell carcinoma. J Gastroenterol. 2002, 37 (7): 575-577. 10.1007/s005350200090.CrossRefPubMed
47.
Ho HH, Ivashkiv LB: Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem. 2006, 281 (20): 14111-14118. 10.1074/jbc.M511797200.CrossRefPubMed
48.
Costa-Pereira AP, Tininini S, Strobl B, Alonzi T, Schlaak JF, Is'harc H, Gesualdo I, Newman SJ, Kerr IM, Poli V: Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc Natl Acad Sci USA. 2002, 99 (12): 8043-8047. 10.1073/pnas.122236099.CrossRefPubMedPubMedCentral
49.
Regis G, Pensa S, Boselli D, Novelli F, Poli V: Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol. 2008, 19 (4): 351-359. 10.1016/j.semcdb.2008.06.004.CrossRefPubMed
50.
Thyrell L, Arulampalam V, Hjortsberg L, Farnebo M, Grandér D, Pokrovskaja Tamm K: Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity. Exp Cell Res. 2007, 313 (19): 4015-4024. 10.1016/j.yexcr.2007.08.007.CrossRefPubMed
51.
Khodarev NN, Beckett M, Labay E, Darga T, Roizman B, Weichselbaum RR: STAT1 is overexpressed in tumors eslected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc Natl Acad Sci USA. 2004, 101 (6): 1714-1719. 10.1073/pnas.0308102100.CrossRefPubMedPubMedCentral
52.
Buettner R, Mora LB, Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002, 8 (4): 945-954.PubMed
53.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D: Molecular portraits of human breast tumours. Nature. 2000, 406: 747-752. 10.1038/35021093.CrossRefPubMed
54.
Greenwood C, Metodieva G, Al-Janabi K, Lausen B, Alldridge L, Leng L, Bucala R, Fernandez N, Metodiev MV: STAT1 and CD74 overexpression is codependent and linked to increase invasion and lymph node metastasisintriple-negative breast cancer. J Proteomics. 2012, 75 (10): 3031-3040. 10.1016/j.jprot.2011.11.033.CrossRefPubMed
55.
Yao R, Wang Y, Lubet RA, You M: Differentially expressed genes associated with mouse lung tumor progression. Oncogene. 2002, 21 (37): 5814-5821. 10.1038/sj.onc.1205422.CrossRefPubMed
56.
Duarte CW, Willey CD, Zhi D, Cui X, Harris JJ, Vaughan LK, Mehta T, McCubrey RO, Khodarev NN, Weichselbaum RR, Gillespie GY: Expression signature of IFN/STAT1signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PLoS One. 2012, 7 (1): e29653-10.1371/journal.pone.0029653.CrossRefPubMedPubMedCentral
Metadata
Title
The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma
Authors
Ying Zhang
Ommoleila Molavi
Min Su
Raymond Lai
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-791

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