Skip to main content

Advertisement

SpringerLink
Log in

Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Phosphorylated p38 (p-p38) played a pivotal role in the regulation of disease progression and correlated with tumor prognosis. Here, we characterized the prognostic effect of p-p38 in colorectal cancer (CRC). Three hundred and sixteen CRC patients in stages I–III were recruited in this study. P-p38 expression was semi-quantitatively evaluated using tissue microarrays and immunohistochemistry staining. Overall survival (OS), disease-free survival (DFS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS) of patient subgroups, segregated by p-p38 expression level and clinical stage, were compared using Kaplan–Meier analysis. We found that p-p38 was overexpressed in 48.1 % (152/316) CRC tissues, whereas low or deficiently expressed in normal adjacent epithelia. Overexpression of p-p38 predicted poor OS (P < 0.001), DFS (P = 0.002), LFFS (P = 0.016), and DMFS (P = 0.025) in CRC. Importantly, patient subgroups in the early stage (stages I + II) and with low p-p38 had similar OS, PFS, LFFS, and DMFS probabilities to that of stage I, whereas those with high p-p38 were similar to stage III disease. In addition, for stage III disease, the subgroup with low p-p38 had a similar survival probability to that of stage I, whereas the subgroup with high p-p38 had the worst survival. Multivariate Cox analysis confirmed that p-p38 was indeed a significantly independent factor for death, recurrence, and distant metastases in CRC. Our results demonstrated that p-p38 was a negative independent prognostic factor for CRC. Complementing TNM staging with p-p38 might refine the risk definition more accurately for a subset of patients.

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
Fig. 4

Similar content being viewed by others

Abbreviations

p-p38:

Phosphorylated p38

CRC:

Colorectal cancer

OS:

Overall survival

DFS:

Disease-free survival

LFFS:

Local failure-free survival

DMFS:

Distant metastasis-free survival

TNM:

Tumor node metastasis

EGFR:

Epidermal growth factor receptor

MAPKs:

Mitogen-activated protein kinases

Reference

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Jessup JM, Gunderson LL, Greene FL, Washington MK, Compton CC, Sobin LH, et al. 2010 staging system for colon and rectal carcinoma. Ann Surg Oncol. 2011;18:1513–7.

  3. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010;375:1030–47.

    Article  PubMed  Google Scholar 

  4. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol. 2005;16:102–8.

    Article  PubMed  Google Scholar 

  5. Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009;9:489–99.

    Article  CAS  PubMed  Google Scholar 

  6. Zlobec I, Vuong T, Hayashi S, Haegert D, Tornillo L, Terracciano L, et al. A simple and reproducible scoring system for EGFR in colorectal cancer: application to prognosis and prediction of response to preoperative brachytherapy. Br J Cancer. 2007;96:793–800.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Baynes RD, Gansert J. Kras mutational status as a predictor of epidermal growth factor receptor inhibitor efficacy in colorectal cancer. Am J Ther. 2009;16:554–61.

    Article  PubMed  Google Scholar 

  8. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.

    Article  CAS  PubMed  Google Scholar 

  9. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.

    Article  PubMed  Google Scholar 

  10. Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996;8:402–11.

    Article  CAS  PubMed  Google Scholar 

  11. Crews CM, Erikson RL. Extracellular signals and reversible protein phosphorylation: what to make of it all. Cell. 1993;74:215–7.

    Article  CAS  PubMed  Google Scholar 

  12. Kumar B, Koul S, Petersen J, Khandrika L, Hwa JS, Meacham RB, et al. p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 2010;70:832–41.

    Article  CAS  PubMed  Google Scholar 

  13. Esteva FJ, Sahin AA, Smith TL, Yang Y, Pusztai L, Nahta R, et al. Prognostic significance of phosphorylated p38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma. Cancer. 2004;100:499–506.

    Article  CAS  PubMed  Google Scholar 

  14. Hipp S, Berg D, Ergin B, Schuster T, Hapfelmeier A, Walch A, et al. Interaction of snail and p38 mitogen-activated protein kinase results in shorter overall survival of ovarian cancer patients. Virchows Archiv. 2010;457:705–13.

    Article  CAS  PubMed  Google Scholar 

  15. Chiu SJ, Chao JI, Lee YJ, Hsu TS. Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase-dependent pathway in human colorectal cancer cells. Toxicol Lett. 2008;179:63–70.

    Article  CAS  PubMed  Google Scholar 

  16. Paillas S, Boissiere F, Bibeau F, Denouel A, Mollevi C, Causse A, et al. Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma. Cancer Res. 2011;71:1041–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. de la Cruz-Morcillo MA, Valero ML, Callejas-Valera JL, Arias-Gonzalez L, Melgar-Rojas P, Galan-Moya EM, et al. P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance. Oncogene. 2012;31:1073–85.

    Article  PubMed  Google Scholar 

  18. Fan XJ, Wan XB, Huang Y, Cai HM, Fu XH, Yang ZL, et al. Epithelial–mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer. Br J Cancer. 2012;106:1735–41.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Wan XB, Zhao Y, Fan XJ, Cai HM, Zhang Y, Chen MY, et al. Molecular prognostic prediction for locally advanced nasopharyngeal carcinoma by support vector machine integrated approach. PLoS One. 2012;7:e31989.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Leung SF, Zee B, Ma BB, Hui EP, Mo F, Lai M, et al. Plasma Epstein–Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol. 2006;24:5414–8.

    Article  CAS  PubMed  Google Scholar 

  21. Xu J, Wan XB, Huang XF, Chan KC, Hong MH, Wang LH, et al. Serologic antienzyme rate of Epstein–Barr virus DNase-specific neutralizing antibody segregates TNM classification in nasopharyngeal carcinoma. J Clin Oncol. 2010;28:5202–9.

    Article  PubMed  Google Scholar 

  22. Yu Y, Yin D, Hoque MO, Cao B, Jia Y, Yang Y, et al. AKT signaling pathway activated by HIN-1 methylation in non-small cell lung cancer. Tumour Biol. 2012;33:307–14.

    Article  CAS  PubMed  Google Scholar 

  23. Lee S, Song YA, Park YL, Cho SB, Lee WS, Lee JH, et al. Expression of kitenin in human colorectal cancer and its relation to tumor behavior and progression. Pathol Int. 2011;61:210–20.

    Article  CAS  PubMed  Google Scholar 

  24. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. P53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer cell. 2007;11:175–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Rudolf E, John S, Cervinka M. Irinotecan induces senescence and apoptosis in colonic cells in vitro. Toxicol Lett. 2012;214:1–8.

    Article  CAS  PubMed  Google Scholar 

  26. Grossmann I, de Bock GH, Meershoek-Klein Kranenbarg WM, van de Velde CJ, Wiggers T. Carcinoembryonic antigen (CEA) measurement during follow-up for rectal carcinoma is useful even if normal levels exist before surgery. A retrospective study of CEA values in the TME trial. Eur J Surg Oncol. 2007;33:183–7.

    Article  CAS  PubMed  Google Scholar 

  27. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9.

    Article  PubMed  Google Scholar 

  28. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the mosaic trial. J Clin Oncol. 2009;27:3109–16.

    Article  CAS  PubMed  Google Scholar 

  29. Sargent D, Sobrero A, Grothey A, O’Connell MJ, Buyse M, Andre T, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27:872–7.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Gunderson LL, Callister M, Marschke R, Young-Fadok T, Heppell J, Efron J. Stratification of rectal cancer stage for selection of postoperative chemoradiotherapy: current status. Gastrointes Cancer Res: GCR. 2008;2:25–33.

    Google Scholar 

  31. Sprenger T, Rothe H, Jung K, Christiansen H, Conradi LC, Ghadimi BM, et al. Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: do we have indications for individual risk stratification? World J Surg Oncol. 2010;8:27.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 81072042 to L. Wang, no. 81001086 to X.-J. Fan, and no. 81000934 to X.-B. Wan), Natural Science Foundation of Guangdong Province (no. 10251008901000008 to L. Wang), and Project for Outstanding Young and Creative Talent Training Plan in Higher Education Institutions of Guangdong Province (no. LYM10010 to X.-J. Fan).

Author information

Authors and Affiliations

  1. Gastrointestinal Institute of Sun Yat-sen University, the Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancunerheng Road, Guangzhou, 510655, Guangdong, China

    Xin-Juan Fan, Xin-Hui Fu, Pei-Huang Wu, Dian-Ke Chen, Pu-Ning Wang, Li Jiang, Dao-Hai Wang, Zhi-Ting Chen, Jian-Ping Wang & Lei Wang

  2. Department of Pathology, the Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancunerheng Road, Guangzhou, 510655, Guangdong, China

    Xin-Juan Fan & Yan Huang

  3. Department of Radiation Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancunerheng Road, 510655, Guangzhou, Guangdong, China

    Xiang-Bo Wan

Authors
  1. Xin-Juan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang-Bo Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin-Hui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pei-Huang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dian-Ke Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pu-Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dao-Hai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi-Ting Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian-Ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jian-Ping Wang or Lei Wang.

Additional information

X.-J.Fan and X.-B.Wan contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

ROC curve analysis of p-p38 cutoff point for overall survival (a), disease-free survival (b), local failure-free survival (c), and distant metastasis-free survival (d) using p-p38 expression scores (PPT 236 kb)

Table S1

DFS, LFFS, and DMFS comparison of subgroups with different clinical stages and with p-p38 within stages I–III (DOC 38 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, XJ., Wan, XB., Fu, XH. et al. Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer. Tumor Biol. 35, 10487–10495 (2014). https://doi.org/10.1007/s13277-014-2320-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2320-3

Keywords

Search

Navigation