Combinations of laminin 5 with PTEN, p-EGFR and p-Akt define a group of distinct molecular subsets indicative of poor prognosis in patients with non-small cell lung cancer

An,She-Juan; Lin,Qiu-Xiong; Chen,Zhi-Hong; Su,Jian; Cheng,Hua; Xie,Zhi; Zhang,Xu-Chao; Zhou,Hai-Yu; Huang,Ying; Chen,Shi-Liang; Guo,Wei-Bang; Wu,Yi-Long

doi:10.3892/etm.2012.577

Combinations of laminin 5 with PTEN, p-EGFR and p-Akt define a group of distinct molecular subsets indicative of poor prognosis in patients with non-small cell lung cancer

Authors:
- She-Juan An
- Qiu-Xiong Lin
- Zhi-Hong Chen
- Jian Su
- Hua Cheng
- Zhi Xie
- Xu-Chao Zhang
- Hai-Yu Zhou
- Ying Huang
- Shi-Liang Chen
- Wei-Bang Guo
- Yi-Long Wu
View Affiliations

Affiliations: Guangdong Lung Cancer Institute, Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Published online on: May 16, 2012 https://doi.org/10.3892/etm.2012.577
Pages: 226-230

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

Laminin 5 (Ln5) is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. This study explored the expression of Ln5 and the role of its relationships with PTEN, phospho-EGFR (p-EGFR) and phospho-Akt (p-Akt) in the prognosis of patients with non-small cell lung cancer (NSCLC). The protein expression of Ln5, PTEN, p-EGFR and p-Akt was assessed by immunohistochemical analysis, and their relationships to prognosis were analyzed. Protein expression of Ln5, p-EGFR and p-Akt was detected in 61.2 (60/98), 60.2 (59/98) and 45.3% (43/95) of patients with NSCLC, respectively. Loss of PTEN expression was found in 67.7% of tumors (65/96). Ln5 expression was related to patient gender, histology and p-Akt expression (χ2=3.901, 4.549 and 6.985, respectively; P=0.048, 0.033 and 0.008, respectively). Patients with positive Ln5 expression had marginally poorer survival than Ln5-negative patients (median survival time 56.4 months vs. not reached; χ2=3.346; P=0.067). Overall survival was significantly different in patients with positive Ln5 expression combined with loss of PTEN, positive p-EGFR expression or positive p-Akt expression. Cox regression analysis showed that stage, co-expression of Ln5 and p-Akt, and PTEN were the three most independent prognostic factors for patients with NSCLC (χ2=27.906; P<0.0005). The results highlight the complex relationships between extracellular matrix proteins and key signaling pathway molecules in tumorigenesis. Changes in the expression of Ln5 plus PTEN, p-EGFR or p-Akt define a distinct subset of lung cancers. Patients with such cancers have poorer survival and require early treatment that impacts survival.

View Figures

View References

1.	Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
2.	Bremnesa RM, Sirerab R and Camps C: Circulating tumour-derived DNA and RNA markers in blood: a tool for early detection, diagnostics, and follow-up? Lung Cancer. 49:1–12. 2005. View Article : Google Scholar : PubMed/NCBI
3.	Al-Saad S, Donnem T, Al-Shibli K, Persson M, Bremnes RM and Busund LT: Diverse prognostic roles of Akt isoforms, PTEN and PI3K in tumor epithelial cells and stromal compartment in non-small cell lung cancer. Anticancer Res. 29:4175–4183. 2009.PubMed/NCBI
4.	Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
5.	Kalikaki A, Koutsopoulos A, Hatzidaki D, et al: Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and K-RAS mutation status. Lung Cancer. 69:110–115. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Miyazaki K: Laminin-5 (laminin-332): unique biological activity and role in tumor growth and invasion. Cancer Sci. 97:91–98. 2006. View Article : Google Scholar : PubMed/NCBI
7.	Fukai Y, Masuda N, Kato H, et al: Correlation between laminin-5 gamma2 chain and epidermal growth factor receptor expression in esophageal squamous cell carcinomas. Oncology. 69:71–80. 2005. View Article : Google Scholar : PubMed/NCBI
8.	Yurchenco PD and Cheng YS: Self-assembly and calcium-binding sites in laminin A three-arm interaction model. J Biol Chem. 268:17286–17299. 1993.PubMed/NCBI
9.	Engel J: Domain organizations of modular extracellular matrix proteins and their evolution. Matrix Biol. 15:295–299. 1996. View Article : Google Scholar : PubMed/NCBI
10.	Lee SY, Kim MJ, Jin G, et al: Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers. J Thorac Oncol. 5:1734–1740. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Li F, Liu Y, Chen H, Liao D, Shen Y, Xu F and Wang J: EGFR and COX-2 protein expression in non-small cell lung cancer and the correlation with clinical features. J Exp Clin Cancer Res. 30:272011. View Article : Google Scholar : PubMed/NCBI
12.	Yoshizawa A, Fukuoka J, Shimizu S, et al: Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res. 16:240–248. 2010. View Article : Google Scholar : PubMed/NCBI
13.	Tang JM, He QY, Guo RX and Chang XJ: Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 51:181–191. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Menard S, Castronovo V, Tagliabue E and Sobel ME: New insights into the metastasis-associated 67 kD laminin receptor. J Cell Biochem. 67:155–165. 1997. View Article : Google Scholar : PubMed/NCBI
15.	Moriya Y, Niki T, Yamada T, Matsuno Y, Kondo H and Hirohashi S: Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size. An immunohistochemical analysis of 102 cases. Cancer. 91:1129–1141. 2001. View Article : Google Scholar : PubMed/NCBI
16.	Giannelli G, Azzariti A, Fransvea E, Porcelli L, Antonaci S and Paradiso A: Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells. Br J Cancer. 91:1964–1969. 2004.PubMed/NCBI
17.	Hamasaki H, Koga K, Aoki M, et al: Expression of laminin 5-γ2 chain in cutaneous squamous cell carcinoma and its role in tumour invasion. Br J Cancer. 105:824–832. 2011.
18.	Kodama K, Ishii G, Miyamoto S, et al: Laminin 5 expression protects against anoikis at aerogenous spread and lepidic growth of human lung adenocarcinoma. Int J Cancer. 116:876–884. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Yuen HW, Ziober AF, Gopal P, et al: Suppression of laminin-5 expression leads to increased motility, tumorigenicity, and invasion. Exp Cell Res. 309:198–210. 2005. View Article : Google Scholar : PubMed/NCBI
20.	Uramoto H, Shimokawa H, Hanagiri T, Kuwano M and Ono M: Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. Lung Cancer. 73:361–365. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Wang L, Yue W, Zhang L, Zhao X, Wang Y and Xu S: mTOR and PTEN expression in non-small cell lung cancer: analysis by real-time fluorescence quantitative polymerase chain reaction and immunohistochemistry. Surg Today. 42:419–425. 2012. View Article : Google Scholar : PubMed/NCBI