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

Shu-Heng Jiang,Yang Wang,Miao Dai,Ping He,Qing Li,Rong Hua,Guang-Ang Tian,Jun Li,Jie Hong,Jiao Li,Xiao‐Xin Zhang ,Jianren Gu ,Xianghui Cao ,Jianyu Yang ,Dejun Liu ,Minwei Yang ,Zhigang Zhang ,Xueliang Fu ,Min Feng ,Yan‐Miao Huo ,Xiaomei Yang ,Yahui Wang ,Wen T Shen ,Yongwei Sun

doi:10.18632/oncotarget.6772

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly malignancies with frequent metastasis and recurrence [1]
The results showed that EDIL3 expression was significantly up-regulated in pancreatic ductal adenocarcinoma (PDAC) tissues comparing with paired normal pancreatic tissues using GSE15471 (Figure 1A, n = 39, p = 1.33E-11) and GSE28735 (Figure 1B, n = 45, p = 3.73E-8)
In the commercial tissue microarrays (TMA) (TMA1, OD-CT-DgPan01-006), we found that EDIL3 was significantly up-regulated in chronic pancreatitis (CHP) tissues and PDAC tissues compared with normal pancreas (NP) (Figure 1F)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly malignancies with frequent metastasis and recurrence [1]. The disappointing survival rates for pancreatic cancer indicate the aggressive nature of this deadly disease. To overcome this global challenging problem, a thorough understanding of the molecular mechanisms underlying the progression of pancreatic cancer is urgently needed [4, 5]. Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), known as developmentally regulated endothelial cell locus 1 (DEL-1), is a secreted (ECM) protein that composed of three epidermal growth factor (EGF) domains and two discoidin I-Like repeats [7]. Down-regulation of EDIL3 inhibits tumor growth by antiangiogenesis and anti-proliferation [12]. Little is known about the expression pattern and cellular functions of EDIL3 in pancreatic cancer

Methods

Results

Conclusion