ABSTRACT
The objective of the present study was to investigate the expression of B7 homologue 3 (B7H3) in muscleinvasive bladder cancer (MIBC) tissues, evaluate its correlation with patient clinicopathological characteristics, and to explore the effect of B7H3 on MIBC cells. B7H3 expression levels in tumor tissues from 115 patients undergoing radical cystectomy for MIBC were detected by immunohistochemical staining, followed by analysis of the association with clinicopathological characteristics and survival. A B7H3silenced cell line was established by RNA interference (RNAi). Alterations in cell proliferation, cell cycle, migration and invasion were analyzed in vitro. The proteins associated with cancer cell behavior were detected by western blot analysis. In addition, we utilized a xenograft tumor assay in nude mice to test the inhibitory effect of B7H3 shRNA on MIBC in vivo. The results revealed that, among the 115 patients, the B7H3 expression level was significantly associated with an increased incidence of distant metastasis (P=0.014) and vascular invasion (P=0.031), whereas it was not statistically associated with sex, age, pathologic grade, tumor stage, recurrence and lymphatic metastasis. Overall survival (OS) and progressionfree survival (PFS) were significantly worse for patients with high B7H3 expression (P<0.001 and P<0.001, respectively) among the 115 MIBC patients. Suppression of B7H3 significantly inhibited the proliferation, caused G2 phase arrest, as well as declined migration and invasion abilities in vitro. The protein expression of Ki67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP2) and MMP9 were decreased in the T24/B7H3 shRNA group compared with the control (P<0.05, respectively). Finally, we were able to inhibit tumor development by decreasing B7H3 expression in vivo. In conclusion, a high expression level of B7H3 in MIBC tissues is associated with a poor clinicopathological status and poor prognosis, and promotes the development of MIBC in vitro and in vivo. Thus, B7H3 may be a potential novel biomarker for the poor prognosis of MIBC patients.
Subject(s)
B7 Antigens/metabolism , Muscles/pathology , Urinary Bladder Neoplasms/pathology , Aged , Animals , B7 Antigens/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cystectomy , Disease Progression , Disease-Free Survival , Female , G2 Phase Cell Cycle Checkpoints , Humans , Incidence , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Invasiveness/pathology , Neovascularization, Pathologic/epidemiology , Neovascularization, Pathologic/pathology , Prognosis , RNA, Small Interfering/metabolism , Survival Analysis , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/surgery , Xenograft Model Antitumor AssaysABSTRACT
The coinhibitory molecules, B7-H3 and B7-H4, have shown negative regulation in T cell activation and tumor-associated macrophage (TAM) polarization in tumor-specific immunity. Here, we investigated the expression of B7-H3 and B7-H4 in human and murine esophageal squamous cell carcinoma (ESCC) tissues to define their clinical significance and mechanism in a tumor microenvironment. In the present study, B7-H3 and B7-H4 were expressed in 90.6 and 92.7 % samples, respectively. High B7-H3 and B7-H4 expression was associated with advanced TNM stage and lymph node metastasis (p < 0.05, respectively). Patients with both B7-H3 and B7-H4 high-expressed tumors had the poorest prognosis (26.7 months), whereas those with both low-expressed tumors had the best survival (56.7 months). B7-H3 and B7-H4 expression were inclined to be positively related to the infiltration intensity of Treg cells and TAMs (p < 0.05, respectively), and B7-H3 expression is negatively associated with the intensity of CD8(+) T cells (p < 0.05). In 4-nitroquinoline 1-oxide (4-NQO)-induced murine models, high B7-H3 expression could only be detected at carcinoma stage, but abnormal B7-H4 expression appeared a little earlier at dysplasia stage. In vitro studies revealed that knockdown of B7-H3 on tumor cells suppressed ESCC cell migration and invasion, while knockdown of B7-H4 could inhibit ESCC cell growth. Overall, B7-H3 and B7-H4 are involved in ESCC progression and development and their coexpression could be valuable prognostic indicators. Interference of these negative regulatory molecules might be a new strategy for treating ESCC.
