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Background: X-box-binding protein 1 (XBP1) and N-acetyltransferase 1 (NAT1) are involved in oncogenesis and progression of many human cancer types. However, the roles of XBP1 and NAT1 in gallbladder cancer (GBC) are never reported.Methods: We examined XBP1 and NAT1 expression in GBC and matched adjacent non-tumor tissues via Western blotting. Then, we assayed XBP1 and NAT1 expression in 215 GBCs, including 69 squamous cell/adenosquamous carcinomas (SC/ASCs) and 146 adenocarcinomas (ACs) with immunohistochemistry. Their prognostic and clinicopathological significance was further evaluated using the χ2 test or Fisher's exact test, Kaplan–Meier univariate survival analysis, and log-rank tests.Results: XBP1 expression was upregulated, and NAT1 expression was downregulated in GBC. Immunohistochemical results showed that XBP1 expression was negatively associated with NAT1 expression in GBC, including SC/ASC and AC. The rate of patients with an age of more than 45 years, positivity of lymph node metastasis, and invasion were significantly higher in SC/ASC than those in AC (all P < 0.05). The percentage of XBP1-positive and NAT1-negative expression was significantly higher in the cases with poor differentiation, advanced tumor, nodes, and metastases (TNM) stage, lymph node metastasis, invasion, and only receiving biopsy in GBC, SC/ASC, and AC (all P < 0.05). XBP1-positive and NAT1-negative expression was positively related to larger tumor size (>3 cm) in GBC and AC. There was a negative association between XBP1 and NAT1 expression in GBC, SC/ASC, and AC (all P < 0.05). Positive XBP1 and negative NAT1 expression was closely associated with decreased overall survival in GBC, SC/ASC, and AC patients (all P < 0.05). The multivariate Cox regression analysis showed that positive XBP1 or negative NAT1 expression was an independent factor for poor prognosis in gallbladder SC/ASC and AC patients.Conclusions: This study indicates that positive XBP1 and negative NAT1 expression are closely associated with the clinicopathological and biological behaviors and poor prognosis in GBC.

Gallbladder cancer is a relatively uncommon human malignant tumor with an extremely poor prognosis. Currently, no biomarkers can accurately diagnose gallbladder cancer and predict patients’ prognosis. XRCC1 is involved in tumorigenesis, progression, and chemo-resistance of several human cancers, but the role of XRCC1 in gallbladder cancer is never reported. In this study, we investigated the expression of XRCC1 and its clinicopathological and prognostic significance in gallbladder cancer, and explored the biological role of XRCC1 in gallbladder cancer cells. We found that XRCC1 was significantly up-regulated in gallbladder cancer in protein and mRNA levels. Positive XRCC1 expression was correlated with aggressive clinicopathological features and was an independent poor prognostic factor in gallbladder cancer. The ROC curves suggested that XRCC1 expression had potential clinicopathological diagnostic value in gallbladder cancer. In vitro, XRCC1 was overexpression in CD133+GBC-SD cells compared to GBC-SD cells. In functional experiment, XRCC1 knockdown had a non-significant impact on proliferation, migration, invasion, and apoptosis of CD133+GBC-SD cells. But, XRCC1 knockdown could significantly improve the sensitivity of CD133+GBC-SD cells to 5-Fluorouracil via promoting cell necrosis and apoptosis. Thus, this study indicates that XRCC1 may be a promising predictive biomarker of gallbladder cancer and a potential therapeutic target for gallbladder cancer.