Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer

Diagnostic Pathology

Rui Xie¹  Liqun Pang¹  Tianheng Ma¹  Chengcheng Gao¹ 

[1] Department of Gastroenterology, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu 223300, P. R. China

关键词: Prognosis;    Immunohistochemistry;    Phosphorylation;    p21-activated kinase 2;    Gastric cancer;   

Others  :  802485
DOI  :  10.1186/1746-1596-9-55

 received in 2014-02-03, accepted in 2014-03-03,  发布年份 2014

【 摘 要 】

Objective

p21-activated kinase (PAK) 2, as a member of the PAK family kinases, is involved in a number of hallmark processes including cell proliferation, survival, mitosis, apoptosis, motility and angiogenesis. However, the clinical significance of the activation of PAK2 in human gastric cancer has not been fully elucidated. The aim of this study was to investigate whether PAK2 expression and its phosphorylation status are correlated with tumor progression and prognosis in gastric cancer.

Methods

Expression patterns and subcellular localizations of PAK2 and Ser20-phosphorylated PAK2 (pSer20PAK2) in 82 gastric cancer patients were detected by immunohistochemistry.

Results

Both PAK2 and pSer20PAK2 immunostainings were localized in the cytoplasm of tumor cells of gastric cancer tissues. Compared with the normal gastric mucosa, the expression levels of PAK2 and pSer20PAK2 proteins were both significantly increased (both P < 0.001). Additionally, the patients displaying the over-expression of PAK2 and pSer20PAK2 proteins were dramatically associated with unfavorable clinicopathologic variables including higher tumor depth (P = 0.022 and 0.036, respectively), greater extent of lymph node metastasis ((P = 0.022 and 0.036, respectively), positive distant metastasis (P = 0.025 and 0.038, respectively) and advanced tumor stage (P = 0.018 and 0.031, respectively). Moreover, the patients overexpressing PAK2 and pSer20PAK2 proteins have poor overall survival rates relative to those without overexpression of these proteins. Furthermore, cox multi-factor analysis showed that PAK2 (p = 0.012) and pSer20PAK2 (p = 0.010) were independent prognosis factors for human gastric cancer.

Conclusion

Our data suggest for the first time that PAK2 activation may be associated with advanced tumor progression and poor prognosis of gastric cancer.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1236344107120406 webcite.

【 授权许可】

   
2014 Gao et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Alberts SR, Cervantes A, van de Velde CJ: Gastric cancer: epidemiology, pathology and treatment. Ann Oncol 2003, 14(Suppl 2):ii31-ii36.
• [2]Ye YW, Dong RZ, Zhou Y, Du CY, Wang CM, Fu H, Shi YQ: Prognostic analysis of familial gastric cancer in Chinese population. J Surg Oncol 2011, 104:76-82.
• [3]Zhang YZ, Zhang LH, Gao Y, Li CH, Jia SQ, Liu N, Cheng F, Niu DY, Cho WC, Ji JF, Zeng CQ: Discovery and validation of prognostic markers in gastric cancer by genome-wide expression profiling. World J Gastroenterol 2011, 17:1710-1717.
• [4]Ichikura T, Tomimatsu S, Okusa Y, Uefuji K, Tamakuma S: Comparison of the prognostic significance between the number of metastatic lymph nodes and nodal stage based on their location in patients with gastric cancer. J Clin Oncol 1993, 11:1894-1900.
• [5]Ye DZ, Field J: PAK signaling in cancer. Cell Logist 2012, 2:105-116.
• [6]Chan PM, Manser E: PAKs in human disease. Prog Mol Biol Transl Sci 2012, 106:171-187.
• [7]Whale A, Hashim FN, Fram S, Jones GE, Wells CM: Signalling to cancer cell invasion through PAK family kinases. Front Biosci (Landmark Ed) 2011, 16:849-864.
• [8]Kichina JV, Goc A, Al-Husein B, Somanath PR, Kandel ES: PAK1 as a therapeutic target. Expert Opin Ther Targets 2010, 14:703-725.
• [9]Coniglio SJ, Zavarella S, Symons MH: Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Mol Cell Biol 2008, 28:4162-4172.
• [10]Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, Tam KF, Ngan HY, Chan QK, Chan DC, Chan KY, Cheung AN: Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer 2010, 127:21-31.
• [11]Li X, Wen W, Liu K, Zhu F, Malakhova M, Peng C, Li T, Kim HG, Ma W, Cho YY, Bode AM, Dong Z, Dong Z: Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines. J Biol Chem 2011, 286:22291-22299.
• [12]Man G, Wei L, Haiming W, Guanjun W: The distinct expression patterns of claudin-10, −14, −17 and E-cadherin between adjacent non-neoplastic tissues and gastric cancer tissues. Diagn Pathol 2013, 8:205. BioMed Central Full Text
• [13]Geng M, Wang L, Chen X, Cao R, Li P: The association between chemosensitivity and Pgp, GST-π and Topo II expression in gastric cancer. Diagn Pathol 2013, 8:198. BioMed Central Full Text
• [14]Wang T, Xuan X, Li M, Gao P, Zheng Y, Zang W, Zhao G: Astragalus saponins affect proliferation, invasion and apoptosis of gastric cancer BGC-823 cells. Diagn Pathol 2013, 8:179. BioMed Central Full Text
• [15]Zhang G, Qu Y, Dang S, Yang Q, Shi B, Hou P: Variable copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in advanced gastric cancer patients. Diagn Pathol 2013, 8:173. BioMed Central Full Text
• [16]Jin J, Jin T, Quan M, Piao Y, Lin Z: Ezrin overexpression predicts the poor prognosis of gastric adenocarcinoma. Diagn Pathol 2012, 7:135. BioMed Central Full Text
• [17]Sotoudeh K, Hashemi F, Madjd Z, Sadeghipour A, Molanaei S, Kalantary E: The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays. Diagn Pathol 2012, 7:57. BioMed Central Full Text
• [18]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
• [19]Rennefahrt UE, Deacon SW, Parker SA, Devarajan K, Beeser A, Chernoff J, Knapp S, Turk BE, Peterson JR: Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem 2007, 282:15667-15678.
• [20]Tang Y, Yu J, Field J: Signals from the Ras, Rac, and Rho GTPases converge on the Pak protein kinase in Rat-1 fibroblasts. Mol Cell Biol 1999, 19:1881-1891.
• [21]Kiosses WB, Daniels RH, Otey C, Bokoch GM, Schwartz MA: A role for p21-activated kinase in endothelial cell migration. J Cell Biol 1999, 147:831-844.
• [22]Li T, Zhang J, Zhu F, Wen W, Zykova T, Li X, Liu K, Peng C, Ma W, Shi G, Dong Z, Bode AM, Dong Z: P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation. Carcinogenesis 2011, 32:659-666.