Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder

Abstract

The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder have not been well documented because it is a rare subtype of gallbladder cancer. In this study, the protein expression of Nectin-2 and DDX3 in 46 SC/ASCs and 80 adenocarcinomas was measured using immunohistochemistry. We demonstrated that positive Nectin-2 and DDX3 expression was significantly associated with large tumor size, high TNM stage, and lymph node metastasis of SC/ASC and AC. Positive Nectin-2 and DDX3 expression was significantly associated with invasion and surgical curability of AC. Univariate Kaplan-Meier analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with post-operative survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and no surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well as poor-prognosis of gallbladder cancer.

Keywords: DDX3; Gallbladder cancer; Nectin-2; adenocarcinoma; adenosquamous carcinoma; metastasis; prognosis; squamous cell carcinoma.

Figure 1

Nectin-2 and DDX3 expression in SC/ASC. EnVision immunohistochemistry, original magnification x200. Nectin-2 and DDX3 positive reaction was mainly localized in the cytoplasm. A: Positive Nectin-2 expression in moderately differentiated SC/ASC. B: Negative Nectin-2 expression in well differentiated SC/ASC. C: Positive DDX3 expression in moderately differentiated SC/ASC. D: Negative DDX3 expression in well differentiated SC/ASC.

Figure 2

Nectin-2 and DDX3 expression in AC. EnVision immunohistochemistry, original magnification x200. Nectin-2 and DDX3 positive reaction was mainly localized in the cytoplasm. A: Positive Nectin-2 expression in moderatelydifferentiated AC. B: Negative Nectin-2 expression in well differentiated AC. C: Positive DDX3 expression inmoderately differentiated AC. D: Negative DDX3 expression in well differentiated AC.

Figure 3

Nectin-2 and DDX3 expression and survival in patients with SC/ASC of gallbladder. A: Kaplan-Meier plots of overall survival in patients with SC/ASC and with Nectin-2 positive and negative expression. B: Kaplan-Meier plots of overall survival in patients with SC/ASC and with DDX3 positive and negative expression.

Figure 4

Nectin-2 and DDX3 expression and survival in patients with AC of gallbladder. A: Kaplan-Meier plots of overall survival in patients with AC and with Nectin-2 positive and negative expression. B: Kaplan-Meier plots of overall survival in patients with AC and with DDX3 positive and negative expression.