Skip to main content

Advertisement

SpringerLink
Log in

The prognostic significance of Smad3, Smad4, Smad3 phosphoisoform expression in esophageal squamous cell carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Smad3 functions as an integrator of diverse signaling, including transforming growth factor β signaling and the function of Smad3 is complexly regulated by differential phosphorylation at various sites of Smad3. Despite the importance of Smad3 and its various phosphoisoforms, their prognostic significance has rarely been studied. In this study, we demonstrated the prognostic significance of Smad3, its phosphoisoforms, and Smad4 expression by immunohistochemistry in 126 esophageal squamous cell carcinomas. The phosphoisoforms of Smad3 studied in this article included phosphorylation at C-terminal (pSmad3C)(Ser423/425) and phosphorylation at the linker region (pSmad3L)(Ser213). High expression of Smad3 was associated with shorter overall survival. Co-existence of high expression of pSmad3L(S213) and low expression of pSmad3C(S423/425) were associated with advanced N stage and an independent prognostic factor for overall [hazard ratio (HR) 2.03, 95 % confidence interval (CI) (1.10–3.75), p = 0.023] and disease-free survival [HR 2.41, 95 % CI (1.32–4.39), p = 0.004]. In conclusion, co-existence of high pSmad3L(Ser213) expression and low pSmad3C(Ser423/425) expression can be considered as immunohistochemical biomarkers for predicting prognosis as well as future therapeutic targets. In addition, our results of combinatory effect of differential phosphorylation of Smad3 on prognosis suggest the mode of action of Smad3 might be logically determined by its phosphorylation pattern.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Massague J. TGFbeta in Cancer. Cell. 2008;134:215–30.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Ross S, Hill CS. How the Smads regulate transcription. Int J Biochem Cell Biol. 2008;40:383–408.

    Article  PubMed  CAS  Google Scholar 

  3. Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, et al. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology. 2003;38:879–89.

    Article  PubMed  CAS  Google Scholar 

  4. Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang XF. Axin and GSK3-control Smad3 protein stability and modulate TGF-signaling. Genes Dev. 2008;22:106–20.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Kamaraju AK, Roberts AB. Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem. 2005;280:1024–36.

    Article  PubMed  CAS  Google Scholar 

  6. Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004;430:226–31.

    Article  PubMed  CAS  Google Scholar 

  7. Matsuura I, Wang G, He D, Liu F. Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. Biochemistry. 2005;44:12546–53.

    Article  PubMed  CAS  Google Scholar 

  8. Millet C, Yamashita M, Heller M, Yu LR, Veenstra TD, Zhang YE. A negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204. J Biol Chem. 2009;284:19808–16.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Mori S, Matsuzaki K, Yoshida K, Furukawa F, Tahashi Y, Yamagata H, et al. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene. 2004;23:7416–29.

    Article  PubMed  CAS  Google Scholar 

  10. Nagata H, Hatano E, Tada M, Murata M, Kitamura K, Asechi H, et al. Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma. Hepatology. 2009;49:1944–53.

    Article  PubMed  CAS  Google Scholar 

  11. Wang G, Matsuura I, He D, Liu F. Transforming growth factor-{beta}-inducible phosphorylation of Smad3. J Biol Chem. 2009;284:9663–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Matsuzaki K. Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis. Histol Histopathol. 2006;21:645–62.

    PubMed  CAS  Google Scholar 

  13. Matsuzaki K, Kitano C, Murata M, Sekimoto G, Yoshida K, Uemura Y, et al. Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer. Cancer Res. 2009;69:5321–30.

    Article  PubMed  CAS  Google Scholar 

  14. Yamagata H, Matsuzaki K, Mori S, Yoshida K, Tahashi Y, Furukawa F, et al. Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis. Cancer Res. 2005;65:157–65.

    PubMed  CAS  Google Scholar 

  15. Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology. 2007;46:48–57.

    Article  PubMed  CAS  Google Scholar 

  16. Murata M, Matsuzaki K, Yoshida K, Sekimoto G, Tahashi Y, Mori S, et al. Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B. Hepatology. 2009;49:1203–17.

    Article  PubMed  CAS  Google Scholar 

  17. Sekimoto G, Matsuzaki K, Yoshida K, Mori S, Murata M, Seki T, et al. Reversible Smad-dependent signaling between tumor suppression and oncogenesis. Cancer Res. 2007;67:5090–6.

    Article  PubMed  CAS  Google Scholar 

  18. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. Lyon: International Agency of Research on Cancer; 2009.

    Google Scholar 

  19. Hongo M, Nagasaki Y, Shoji T. Epidemiology of esophageal cancer: orient to occident. Effects of chronology, geography and ethnicity. J Gastroenterol Hepatol. 2009;24:729–35.

    Article  PubMed  Google Scholar 

  20. Lao-Sirieix P, Fitzgerald RC. Screening for oesophageal cancer. Nat Rev Clin Oncol. 2012;9:278–87.

    Article  PubMed  Google Scholar 

  21. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  22. Cheng MF, Tzao C, Tsai WC, Lee WH, Chen A, Chiang H, et al. Expression of EMMPRIN and matriptase in esophageal squamous cell carcinoma: correlation with clinicopathological parameters. Dis Esophagus. 2006;19:482–6.

    Article  PubMed  Google Scholar 

  23. Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ, Levin B. bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 1995;55:237–41.

    PubMed  CAS  Google Scholar 

  24. Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659–93.

    Article  PubMed  CAS  Google Scholar 

  25. Fukuchi M, Kato H, Kuwano H. TGF-β signaling in esophageal squamous cell carcinoma. Esophagus. 2005;2:15–9.

    Article  Google Scholar 

  26. Fukai Y, Fukuchi M, Masuda N, Osawa H, Kato H, Nakajima T, et al. Reduced expression of transforming growth factor-beta receptors is an unfavorable prognostic factor in human esophageal squamous cell carcinoma. Int J Cancer. 2003;104:161–6.

    Article  PubMed  CAS  Google Scholar 

  27. Fukuchi M, Fukai Y, Masuda N, Miyazaki T, Nakajima M, Sohda M, et al. High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Res. 2002;62:7162–5.

    PubMed  CAS  Google Scholar 

  28. Fukuchi M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Sohda M, et al. Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma. Int J Cancer. 2004;108:818–24.

    Article  PubMed  CAS  Google Scholar 

  29. Matsuzaki K. Smad phospho-isoforms direct context-dependent TGF-beta signaling. Cytokine Growth Factor Rev. 2013;24:385–99.

    Article  PubMed  CAS  Google Scholar 

  30. Kim SH, Kim KH, Ahn S, Hyeon J, Park CK. Smad3 and Smad3 phosphoisoforms are prognostic markers of gastric carcinoma. Dig Dis Sci. 2013;58:989–97.

    Article  PubMed  CAS  Google Scholar 

  31. Kim SH, Ahn S, Park CK. Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy. Hepatobiliary Pancreat Dis Int. 2012;11:51–9.

    Article  PubMed  CAS  Google Scholar 

  32. Han G, Wang XJ. Roles of TGFbeta signaling Smads in squamous cell carcinoma. Cell Biosci. 2011;1:41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Yamazaki K, Masugi Y, Effendi K, Tsujikawa H, Hiraoka N, Kitago M, et al. Upregulated SMAD3 promotes epithelial-mesenchymal transition and predicts poor prognosis in pancreatic ductal adenocarcinoma. Lab Invest. 2014;94:683–91.

    Article  PubMed  CAS  Google Scholar 

  34. Park JH, Lee C, Suh JH, Chae JY, Moon KC. Nuclear expression of Smad proteins and its prognostic significance in clear cell renal cell carcinoma. Hum Pathol. 2013;44:2047–54.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI11C17620000) and this study was also supported by Samsung Biomedical Research Institute grant “(SS1B30131).”

Conflict of interest

There is not any commercial interest in the subject of study and the source of any financial or material support.

Author information

Authors and Affiliations

  1. Department of Pathology and Translational Genomics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, 50 Ilwon-dong, Gangnam-gu, Seoul, 135-710, Korea

    Soo Youn Cho, Sang Yun Ha, Cheol-Keun Park & Seok-Hyung Kim

  2. Department of Pathology, Cancer Research Institute, School of Medicine, Chungnam National University, 6 Munhwa 1-dong, Jung-gu, Daejeon, 301-747, Korea

    Song-Mei Huang & Kyung-Hee Kim

  3. Department of Molecular Biology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea

    Jeong Hoon Kim, Myung Soo Kang, Hae-yong Yoo & Hyeon-ho Kim

  4. Department of Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Korea

    Sung-Hee Um

Authors
  1. Soo Youn Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Yun Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Song-Mei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeong Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Myung Soo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hae-yong Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyeon-ho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cheol-Keun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung-Hee Um
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kyung-Hee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seok-Hyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kyung-Hee Kim or Seok-Hyung Kim.

Additional information

Soo Youn Cho and Sang Yun Ha have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cho, S.Y., Ha, S.Y., Huang, SM. et al. The prognostic significance of Smad3, Smad4, Smad3 phosphoisoform expression in esophageal squamous cell carcinoma. Med Oncol 31, 236 (2014). https://doi.org/10.1007/s12032-014-0236-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0236-9

Keywords

Search

Navigation