Protein Arginine Methyltransferase-5 Overexpression Is Frequently Observed in Non-Small Cell Lung Carcinomas
Konstantin Shilo, Xin Wu, Smita Sharma, Meng Welliver, Wenrui Duan, Miguel Villalona, Jun Fukuoka, Chenglong Li, Said Sif, Robert Baiocchi, Gregory Otterson. Ohio State University, Columbus, OH; Toyama University, Toyama, Japan
Background: Protein arginine methyltransferase-5 (PRMT5) is a chromatin remodeling enzyme capable of methylation of histone and non-histone proteins and is involved in a wide range of cellular processes. As such its overexpression has been linked to the tumor suppressor genes silencing, enhanced tumor cells growth and survival in lymphomas, gliomas and melanomas. The enzyme's active site is an attractive target for anti-cancer therapies and has prompted in silico development of a novel PRMT5 specific inhibitor (OSU BLL1). Since only limited data is available regarding PRMT5 role in lung cancer, the goals of this study were to evaluate PRMT5 expression in a large cohort of patients with non-small cell lung carcinomas (NSCLC) and its potential suitability for targeted therapy.
Design: Clinicopathological features of tissue microarray based samples of 300 patients with NSCLC were analyzed with regard to PRMT5 expression (1:70, rabbit polyclonal, Abcam, Cambridge, MA). The results were evaluated in comparison to normal lung parenchyma and recorded as negative, cytoplasmic, and cytoplasmic plus nuclear. The patterns of PRMT5 expression were also evaluated in NSCLC cell lines (NCI-H1299, A549, NCI-H520) as well as in 6 surgically resected NSCLC. Possible correlations were assessed utilizing SYSTAT13.0 (SPSS Inc., Chicago, IL).
Results: PRMT5 was identified in the majority of NSCLC with cytoplasmic expression seen in 188 (83.2%) and nuclear expression in 125 (55.3%) of 226 cases but not in normal alveolar parenchyma (44/44). Nuclear PRMT5 was more frequently observed in squamous cell carcinomas (64.9%, 74/114) than in adenocarcinomas (45.5%, 51/112), p=0.006. The patterns of expression (cytoplasmic vs. nuclear) correlated with tumor type but not with patients' age, gender, tumor grade, stage or outcome. Both cytoplasmic and nuclear PRMT5 was present in NSCLC cell lines (3/3) and surgically resected NSCLC (6/6). Additionally, nuclear PRMT5 was also identified in the areas adjacent to tumors in reactive type 2 pneumocytes, respiratory epithelium, and alveolar macrophages but not in normal alveolar parenchyma away from tumors (6/6).
Conclusions: PRMT5 overexpression is observed in a high percentage of pulmonary NSCLC, suggesting its role in pulmonary carcinogenesis. While PRMT5 is present in the cytoplasm of a majority of NSCLC, its nuclear localization is more variable and is more frequently detected in squamous cell carcinoma. Further study of the role of PRMT5 in lung carcinogenesis and as a potential target for chemotherapy is warranted.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 295, Wednesday Afternoon