Skip to main content
Log in

Imbalanced expression of mitogen-activated protein kinase phosphatase-1 and phosphorylated extracellular signal-regulated kinases in lung squamous cell carcinoma

  • Published:
Journal of Zhejiang University SCIENCE B Aims and scope Submit manuscript

Abstract

Objective

Mitogen-activated protein kinases (MAPKs) are correlated with a more malignant phenotype in many cancers. This study was designed to evaluate the predictive value of the expression of MAPK phosphatase-1 (MKP-1) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), as the key regulatory mechanism of the MAPKs, in lung squamous cell carcinoma (SCC).

Methods

We assessed the expressions of MKP-1 and p-ERK1/2 in twenty subjects at different differentiation degree of SCC and five normal lungs by immunohistochemistry and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis.

Results

Immunohistochemistry and real-time RT-PCR assay showed that the expression of MKP-1 was gradually decreased as tissue type went from normal lung tissues to increasingly undifferentiated carcinoma, and it was negatively correlated with tumor differentiation (P<0.01). However, the expression of p-ERK1/2 or ERK1/2 was gradually increased as tissue type went from normal lung tissues to increasingly undifferentiated carcinoma, and it was positively correlated with tumor differentiation (P<0.01).

Conclusions

Our data indicates the relevance of MKP-1 and p-ERK1/2 in SCC as a potential positive and negative prognostic factor. The imbalanced expression of MKP-1 and p-ERK1/2 may play a role in the development of SCC and these two molecules may be new targets for the therapy and prognosis of SCC.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adeyinka, A., Nui, Y., Cherlet, T., Snell, L., Watson, P.H., Murphy, L.C., 2002. Activated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin. Cancer Res., 8(6): 1747–1753.

    PubMed  CAS  Google Scholar 

  • Bermudez, O., Pages, G., Gimond, C., 2010. The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am. J. Physiol. Cell Physiol., 299(2):C189–C202. [doi:10.1152/ajpcell.00347.2009]

    Article  PubMed  CAS  Google Scholar 

  • Blackhall, F.H., Pintilie, M., Michael, M., Leighl, N., Feld, R., Tsao, M.S., Shepherd, F.A., 2003. Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer. Clin. Cancer Res., 9(6):2241–2247.

    PubMed  CAS  Google Scholar 

  • Bogoyevitch, M.A., 2006. The isoform-specific functions of the c-Jun N-terminal kinases (JNKs): differences revealed by gene targeting. Bioessays, 28(9):923–934. [doi:10.1002/bies.20458]

    Article  PubMed  CAS  Google Scholar 

  • Bogoyevitch, M.A., Arthur, P.G., 2008. Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim. Biophys. Acta, 1784(1):76–93. [doi:10.1016/j.bbapap.2007.09.013]

    PubMed  CAS  Google Scholar 

  • Chang, L.F., Karin, M., 2001. Mammalian MAP kinase signalling cascades. Nature, 410(6824):37–40. [doi:10.1038/35065000]

    Article  PubMed  CAS  Google Scholar 

  • Chen, H., Zhu, G., Li, Y., Padia, R.N., Dong, Z., Pan, Z.K., Liu, K., Huang, S., 2009. Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res., 69(24): 9228–9235. [doi:10.1158/0008-5472.CAN-09-1950]

    Article  PubMed  CAS  Google Scholar 

  • Denkert, C., Schmitt, W.D., Berger, S., Reles, A., Pest, S., Siegert, A., Lichtenegger, W., Dietel, M., Hauptmann, S., 2002. Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int. J. Cancer, 102(5):507–513. [doi:10.1002/ijc.10746]

    Article  PubMed  CAS  Google Scholar 

  • Dickinson, R.J., Keyse, S.M., 2006. Diverse physiological functions for dual-specificity MAP kinase phosphatases. J. Cell Sci., 119(22):4607–4615. [doi:10.1242/jcs.03266]

    Article  PubMed  CAS  Google Scholar 

  • Dunn, K.L., Espino, P.S., Drobic, B., He, S., Davie, J.R., 2003. The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem. Cell Biol., 83(1):1–14. [doi:10.1139/o04-121]

    Article  Google Scholar 

  • Eralp, Y., Derin, D., Ozluk, Y., Yavuz, E., Guney, N., Saip, P., Muslumanoglu, M., Igci, A., Kücücük, S., Dincer, M., Aydiner, A., Topuz, E., 2008. MAPK overexpression is associated with anthracycline resistance and increased risk for recurrence in patients with triple-negative breast cancer. Ann. Oncol., 19(4):669–674. [doi:10.1093/annonc/mdm522]

    Article  PubMed  CAS  Google Scholar 

  • Farooq, A., Zhou, M.M., 2004. Structure and regulation of MAPK phosphatases. Cell. Signal., 16(7):769–779. [doi:10.1016/j.cellsig.2003.12.008]

    Article  PubMed  CAS  Google Scholar 

  • Gailhouste, L., Ezan, F., Bessard, A., Frémin, C., Rageul, J., Langouët, S., Baffet, G., 2010. RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. Int. J. Cancer, 126(6):1367–1377. [doi:10.1002/ijc.24950]

    PubMed  CAS  Google Scholar 

  • Greenberg, A.K., Basu, S., Hu, J., Yie, T.A., Tchou-Wong, K.M., Rom, W.N., Lee, T.C., 2002. Selective p38 activation in human non-small cell lung cancer. Am. J. Respir. Cell Mol. Biol., 26(5):558–564.

    PubMed  CAS  Google Scholar 

  • Herbst, R.S., Heymach, J.V., Lippman, S.M., 2008. Lung cancer. N. Engl. J. Med., 359(13):1367–1380. [doi:10.1056/NEJMra0802714]

    Article  PubMed  CAS  Google Scholar 

  • Hu, J.A., Li, Y., Fang, J., 2010. Effect of ERK inhibitor on pulmonary metastasis of inoculated human adenoid cystic carcinoma cells in nude mice. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 109(1):117–123. [doi:10.1016/j.tripleo.2009.07.052]

    Article  PubMed  Google Scholar 

  • Huang, D., Ding, Y., Luo, W.M., Bender, S., Qian, C.N., Kort, E., Zhang, Z.F., VandenBeldt, K., Duesbery, N.S., Resau, J.H., Teh, B.T., 2008. Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Res., 68(1):81–88. [doi:10.1158/0008-5472.CAN-07-5311]

    Article  PubMed  CAS  Google Scholar 

  • Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Thun, M.J., 2009. Cancer statistics. CA Cancer. J. Clin., 59(4): 225–249. [doi:10.3322/caac.20006]

    Article  PubMed  Google Scholar 

  • Johnson, G.L., Lapadat, R., 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 298(5600):1911–1912. [doi:10.1126/science.1072682]

    Article  PubMed  CAS  Google Scholar 

  • Mavria, G., Vercoulen, Y., Yeo, M., Paterson, H., Karasarides, M., Marais, R., Bird, D., Marshall, C.J., 2006. ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis. Cancer Cell, 9(1):33–44. [doi:10.1016/j.ccr.2005.12.021]

    Article  PubMed  CAS  Google Scholar 

  • Moro, L., Arbini, A.A., Marra, E., Greco, M., 2007. Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2. Int. J. Oncol., 30(1):217–224.

    PubMed  CAS  Google Scholar 

  • Mukohara, T., Kudoh, S., Yamauchi, S., Kimura, T., Yoshimura, N., Kanazawa, H., Hirataa, K., Wanibuchib, H., Fukushimab, S., Inouec, K., et al., 2003. Expression of epidermal growth factor receptor (EGFR) and downstream-activated peptides in surgically excised non-small-cell lung cancer (NSCLC). Lung Cancer, 41(2): 123–130. [doi:10.1016/S0169-5002(03)00225-3]

    Article  PubMed  Google Scholar 

  • Murphy, L.O., Blenis, J., 2006. MAPK signal specificity: the right place at the right time. Trends Biochem. Sci., 31(5):268–275. [doi:10.1016/j.tibs.2006.03.009]

    Article  PubMed  CAS  Google Scholar 

  • Owens, D.M., Keyse, S.M., 2007. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene, 26(22):3203–3213. [doi:10.1038/sj. onc.1210412]

    Article  PubMed  CAS  Google Scholar 

  • Roux, P.P., Blenis, J., 2004. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev., 68(2): 320–344. [doi:10.1128/MMBR.68.2.320-344.2004]

    Article  PubMed  CAS  Google Scholar 

  • Serini, S., Trombino, S., Oliva, F., Piccioni, E., Monego, G., Resci, F., Boninsegna, A., Picci, N., Ranelletti, F.O., Calviello, G., 2008. Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression. Apoptosis, 13(9):1172–1183. [doi:10.1007/s10495-008-0246-1]

    Article  PubMed  CAS  Google Scholar 

  • Shaul, Y.D., Seger, R., 2007. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim. Biophys. Acta, 1773(8):1213–1226. [doi:10.1016/j.bbamcr.2006.10.005]

    Article  PubMed  CAS  Google Scholar 

  • Tsujita, E., Taketomi, A., Gion, T., Kuroda, Y., Endo, K., Watanabe, A., Nakashima, H., Aishima, S., Kohnoe, S., Maehara, Y., 2005. Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma. Oncology, 69(4):342–347. [doi:10.1159/000089766]

    Article  PubMed  CAS  Google Scholar 

  • Wada, T., Penninger, J.M., 2004. Mitogen-activated protein kinases in apoptosis regulation. Oncogene, 23(16): 2838–2849. [doi:10.1038/sj.onc.1207556]

    Article  PubMed  CAS  Google Scholar 

  • Ward, Y., Wang, W., Woodhouse, E., Linnoila, I., Liotta, L., Kelly, K., 2001. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol. Cell. Biol., 21(17): 5958–5969. [doi:10.1128/MCB.21.17.5958-5969.2001]

    Article  PubMed  CAS  Google Scholar 

  • Widmann, C., Gibson, S., Jarpe, M.B., Johnson, G.L., 1999. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev., 79(1):143–180.

    PubMed  CAS  Google Scholar 

  • Wong, H.R., Dunsmore, K.E., Page, K., Shanley, T.P., 2005. Heat shock-mediated regulation of MKP-1. Am. J. Physiol. Cell Physiol., 289(5):C1152–C1158. [doi:10.1152/ajpcell.00138.2005]

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hua-hao Shen.

Additional information

The two authors contributed equally to this work

Project supported by the National Natural Science Foundation of China (No. 30900654), the Science and Technology Department of Zhejiang Province (No. 2009R10031), and the Health Bureau of Zhejiang Province (No. 2009QN010), China

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, K., Zhang, M., Qian, Yy. et al. Imbalanced expression of mitogen-activated protein kinase phosphatase-1 and phosphorylated extracellular signal-regulated kinases in lung squamous cell carcinoma. J. Zhejiang Univ. Sci. B 12, 828–834 (2011). https://doi.org/10.1631/jzus.B1100165

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1631/jzus.B1100165

Key words

CLC number

Navigation