Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis

Abstract

BackgroundGastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients.MethodsExpression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays.ResultsNedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ2 = 21.885, p <0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p < 0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion.ConclusionsOur results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-248) contains supplementary material, which is available to authorized users.

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

“…NEDD4-1 is frequently overexpressed in many types of human cancers including gastric carcinomas [35], colorectal [36], breast [37] and non-small cell lung carcinomas [38]. Suppression of NEDD4-1 expression in cells derived from these cancers can significantly reduce tumor cell growth both in vitro and in animal models.…”

NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN

“…All cases were reviewed independently by two pathologists who were blinded to the clinicopathological data. The immunostaining was evaluated as previously reported [28]. Briefly, a mean percentage (0-100) of NEDD4-positive tumor cells was determined in at least five randomly selected areas at ×400 magnification (50-250 cancer cells per area).…”

The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma

“…While NEDD4-1 is an oncogene in most cancers, [16][17][18][19][20][21][22]33,34 it can also act as a tumor suppressor in some tumors 14,15,35,36 ; however, the role of NEDD4-1 in MM remains unclear. While NEDD4-1 is an oncogene in most cancers, [16][17][18][19][20][21][22]33,34 it can also act as a tumor suppressor in some tumors 14,15,35,36 ; however, the role of NEDD4-1 in MM remains unclear.…”

“…Aberrant NEDD4-1 expression has been observed in various tumors. While NEDD4-1 is an oncogene in most cancers, [16][17][18][19][20][21][22]33,34 it can also act as a tumor suppressor in some tumors 14,15,35,36 ; however, the role of NEDD4-1 in MM remains unclear. In our study, low NEDD4-1 expression was closely related to worse outcomes among MM patients.…”