Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer

Abstract

// Shu-Heng Jiang 1, 2, * , Yang Wang 1, 2, 4, * , Jian-Yu Yang 3, * , Jun Li 2, * , Ming-Xuan Feng 5 , Ya-Hui Wang 1, 2 , Xiao-Mei Yang 2 , Ping He 2 , Guang-Ang Tian 2 , Xiao-Xin Zhang 2 , Qing Li 1, 2 , Xiao-Yan Cao 2 , Yan-Miao Huo 3 , Min-Wei Yang 3 , Xue-Liang Fu 3 , Jiao Li 3 , De-Jun Liu 3 , Miao Dai 7 , Shan-Yun Wen 7 , Jian-Ren Gu 1, 2 , Jie Hong 6 , Rong Hua 3 , Zhi-Gang Zhang 2 , Yong-Wei Sun 3 1 Shanghai Medical College of Fudan University, Shanghai, P.R. China 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China 3 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China 4 Department of Urology, Shanghai No.5 People’s Hospital, Fudan University, Shanghai, P.R. China 5 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China 6 Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China 7 Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, P.R. China * These authors contributed equally to this work Correspondence to: Yong-Wei Sun, e-mail: syw0616@126.com Zhi-Gang Zhang, e-mail: zzhang@shsci.org Rong Hua, e-mail: lordhuarong@sohu.com Jie Hong, e-mail: jiehong97@gmail.com Keywords: EDIL3, prognosis, tumor growth, anoikis, pancreatic cancer Received: June 16, 2015      Accepted: November 28, 2015      Published: December 28, 2015 ABSTRACT Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients’ TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.