Search

Sodium taurocholate cotransporting polypeptide (NTCP) is identified as the functional receptor for HBV entry, which is responsible for upregulated HBV transcription in the HBV life cycle. Besides, NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma (HCC). Thereby, NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy. Herein, we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7, which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro. Additionally, CETSA assay, molecular docking, and MD simulation validated that B7 could bind to NTCP. Furthermore, western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells. Taken together, our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.

BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C.

Microarray studies revealed down-regulation of PCDH9 mRNA level in lymph node metastasis of gastric cancer compared with the primary tumors. The expression of PCDH9 protein and its clinicopathological relevance were assessed on tissue microarrays of 1072 cases of gastric cancer. Its prognostic value was further evaluated on a small cohort of 175 gastric cancers. PCDH9 was down-regulated during the development and progression of gastric cancer. The overall rates of PCDH9 expression in normal, primary tumor, nodal and hepatic metastatic tissues were 100 % (1072/1072), 48.0 % (515/1072), 20.1 % (34/169), and 5.6 % (1/18), respectively. Positive staining of PCDH9 protein was significantly reversely correlated with tumor size, tumor differentiation, tumor invasion, lymph node metastasis, and disease progression. The Cox proportional hazards model revealed that the PCDH9 was an independent prognostic factor for gastric cancer. Therefore, decreased expression of PCDH9 is frequent in human gastric cancer metastasis and PCDH9 expression is an independent prognostic factor, suggesting that PCDH9 could be a promising biomarker of this malignancy.

Pancreatic cancer is one of the most lethal cancers worldwide. CD86 (B7-2) is a costimulatory molecule on antigen-presenting cells and plays critical roles in tumor immunity. It has been reported that polymorphisms in CD86 gene can be involved in the development of various cancers. Here, we investigated the association of two CD86 polymorphisms, +1057G/A (rs1129055) and +2379G/C (rs17281995), with pancreatic cancer in the Chinese population. The two polymorphisms were identified in 369 pancreatic cancer patients and 412 healthy controls using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Data were analyzed by chi-square test and adjusted for body mass index, smoking, drinking, and diabetes status. Results showed that the frequency of the +1057A allele was significantly higher in pancreatic cancer cases than in controls (59.8 vs. 52.8 %, p = 0.021). Comparison of genotype frequencies showed that +1057GA and +1057AA genotypes were significantly increased in the pancreatic cancer group (odds ratio (OR) = 1.52; 95 % confidence interval (CI), 1.09–2.38; p = 0.026; and OR = 1.90; 95 % CI, 1.21–3.01; p = 0.007). We did not find any association between the +2379G/C polymorphism and pancreatic cancer. Analysis of haplotypes indicated that the AG (+1057, +2379) haplotype was correlated with the susceptibility to this disease (p = 0.019). These results suggest that the CD86 +1057G/A polymorphism and AG (+1057, +2379) haplotype are genetic risk factors for pancreatic cancer.