SHP2 promotes laryngeal cancer growth through the Ras/Raf/Mek/Erk pathway and serves as a prognostic indicator for laryngeal cancer

Gu,Jia; Han,Tao; Ma,Rui-Hang; Zhu,Yu-Lin; Jia,Yi-Na; Du,Jing-Jing; Chen,Yu; Jiang,Xue-Jun; Xie,Xiao-Dong; Guo,Xing

doi:10.3892/ijo.2013.2191

SHP2 promotes laryngeal cancer growth through the Ras/Raf/Mek/Erk pathway and serves as a prognostic indicator for laryngeal cancer

Authors:
- Jia Gu
- Tao Han
- Rui-Hang Ma
- Yu-Lin Zhu
- Yi-Na Jia
- Jing-Jing Du
- Yu Chen
- Xue-Jun Jiang
- Xiao-Dong Xie
- Xing Guo
View Affiliations

Affiliations: Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, P.R. China, Department of Oncology, General Hospital of Shenyang Military Region, Shenyang 110016, P.R. China, Department of Operation Room, General Hospital of Shenyang Military Region, Shenyang 110016, P.R. China
Published online on: November 28, 2013 https://doi.org/10.3892/ijo.2013.2191
Pages: 481-490

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The overall survival rate and prognosis of patients with laryngeal cancer are not optimistic despite advances in therapeutic techniques. Gene expression prognostic models enable the development of more appropriate treatment strategies. The human gene PTPN11 encoding a non-receptor protein tyrosine phosphatase, Src homology phosphotyrosine phosphatase 2 (SHP2), is a well-documented proto-oncogene in various malignancies. This study investigated the role of SHP2 expression and associated clinical manifestations in laryngeal cancer using a tissue microarray of 112 pairs of laryngeal cancer samples and corresponding adjacent normal mucosae. SHP2 expression increased in laryngeal cancer, and this result was associated with the poor survival rate of laryngeal cancer patients. Moreover, increased SHP2 expression remarkably promoted the growth of laryngeal cancer cells in vitro and tumorigenicity of laryngeal cancer cells in vivo. The Ras/Raf/Mek/Erk pathway was also found to be involved in the SHP2-induced growth of laryngeal cancer cells. Overall, our findings indicated that SHP2 plays an important role in laryngeal cancer tumorigenesis and that its expression is negatively correlated with the prognosis of patients. Thus, SHP2 may be a promising combinational therapeutic target for treatment of laryngeal cancer. The interference of SHP2 expression can serve as a novel strategy for laryngeal cancer treatment.

View Figures

View References

1.	Li XY, Guo X, Feng S, et al: Relationship between a family history of malignancy and the incidence of laryngeal carcinoma in the Liaoning province of China. Clin Otolaryngol. 34:127–131. 2009. View Article : Google Scholar : PubMed/NCBI
2.	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar
3.	Loyo M and Pai SI: The molecular genetics of laryngeal cancer. Otolaryngol Clin North Am. 41:v657–v672. 2008. View Article : Google Scholar
4.	Hoffman HT, Porter K, Karnell LH, et al: Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival. Laryngoscope. 116:1–13. 2006. View Article : Google Scholar : PubMed/NCBI
5.	Neel BG, Gu H and Pao L: The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 28:284–293. 2003.
6.	Lai LA, Zhao C, Zhang EE and Feng GS: The Shp-2 tyrosine phosphatase. Protein Phosphatases. Arino J and Alexander D: Springer-Verlag; Berlin, Heidelberg: pp. 275–299. 2004, View Article : Google Scholar
7.	Tartaglia M and Gelb BD: Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet. 48:81–96. 2005. View Article : Google Scholar : PubMed/NCBI
8.	Bentires-Alj M, Gil SG, Chan R, et al: A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 12:114–121. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Higuchi M, Tsutsumi R, Higashi H and Hatakeyama M: Conditional gene silencing utilizing the lac repressor reveals a role of SHP-2 in cagA-positive Helicobacter pylori pathogenicity. Cancer Sci. 95:442–447. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Higashi H, Tsutsumi R, Muto S, et al: SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 295:683–686. 2002. View Article : Google Scholar : PubMed/NCBI
11.	Takahashi A, Tsutsumi R, Kikuchi I, et al: SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell. 43:45–56. 2011. View Article : Google Scholar : PubMed/NCBI
12.	Chan RJ and Feng GS: PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 109:862–867. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Wen W, Han T, Chen C, et al: Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling. Mol Cancer Ther. 12:1796–1804. 2013. View Article : Google Scholar : PubMed/NCBI
14.	Broich G, Lavezzi AM, Biondo B and Pignataro LD: PCNA - a cell proliferation marker in vocal cord cancer. Part II: recurrence in malignant laryngeal lesions. In Vivo. 10:175–178. 1996.PubMed/NCBI
15.	Dobrossy L: Epidemiology of head and neck cancer: magnitude of the problem. Cancer Metastasis Rev. 24:9–17. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Manes S, Mira E, Gomez-Mouton C, Zhao ZJ, Lacalle RA and Martinez AC: Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mol Cell Biol. 19:3125–3135. 1999.PubMed/NCBI
17.	Tartaglia M, Mehler EL, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 29:465–468. 2001. View Article : Google Scholar : PubMed/NCBI
18.	Aceto N, Sausgruber N, Brinkhaus H, et al: Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat Med. 18:529–537. 2012. View Article : Google Scholar
19.	Grossmann KS, Rosario M, Birchmeier C and Birchmeier W: The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res. 106:53–89. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Cunnick JM, Meng S, Ren Y, et al: Regulation of the mitogen-activated protein kinase signaling pathway by SHP2. J Biol Chem. 277:9498–9504. 2002. View Article : Google Scholar : PubMed/NCBI
21.	Dittrich A, Quaiser T, Khouri C, Gortz D, Monnigmann M and Schaper F: Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling. Mol Biosyst. 8:2119–2134. 2012. View Article : Google Scholar : PubMed/NCBI
22.	Tseng PC, Huang WC, Chen CL, et al: Regulation of SHP2 by PTEN/AKT/GSK-3beta signaling facilitates IFN-gamma resistance in hyperproliferating gastric cancer. Immunobiology. 217:926–934. 2012. View Article : Google Scholar : PubMed/NCBI
23.	Chan G, Kalaitzidis D and Neel BG: The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 27:179–192. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Feng GS: Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res. 17:37–41. 2007. View Article : Google Scholar : PubMed/NCBI
25.	Wu R, Duan L, Ye L, et al: S100A9 promotes the proliferation and invasion of HepG2 hepatocellular carcinoma cells via the activation of the MAPK signaling pathway. Int J Oncol. 42:1001–1010. 2013.PubMed/NCBI
26.	Chung EJ, Urick ME, Kurshan N, et al: MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands. Int J Oncol. 42:2028–2036. 2013.PubMed/NCBI
27.	Pradier R, Gonzalez A, Matos E, et al: Prognostic factors in laryngeal carcinoma. Experience in 296 male patients. Cancer. 71:2472–2476. 1993. View Article : Google Scholar : PubMed/NCBI
28.	Jin YT, Kayser S, Kemp BL, et al: The prognostic significance of the biomarkers p21^WAF1/CIP1, p53, and bcl-2 in laryngeal squamous cell carcinoma. Cancer. 82:2159–2165. 1998. View Article : Google Scholar : PubMed/NCBI
29.	Tandon S, Tudur-Smith C, Riley RD, Boyd MT and Jones TM: A systematic review of p53 as a prognostic factor of survival in squamous cell carcinoma of the four main anatomical subsites of the head and neck. Cancer Epidemiol Biomarkers Prev. 19:574–587. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Fujii S, Uryu H, Akashi K, et al: Clinical significance of KRAS gene mutation and epidermal growth factor receptor expression in Japanese patients with squamous cell carcinoma of the larynx, oropharynx and hypopharynx. Int J Clin Oncol. 118:454–463. 2013. View Article : Google Scholar : PubMed/NCBI