The inducible T-cell co-stimulator (ICOS) belongs to the B7-CD28 immunoglobulin superfamily, which is currently the subject of intense study due to great successes gained in treatment of different malignancies by disrupting their family members. However, the role of ICOS played in colorectal cancer (CRC) remains poorly understood. A tissue microarray (n = 310) was stained with the ICOS specific antibody and ICOS expression is decreased in patients with either lymphatic or distant metastasis and inversely associated with CEA level and TNM stage of CRC patients. Importantly, high ICOS expression is significantly correlated with overall survival (OS) of CRC patients (n = 230, p < 0.001), and ICOS expression is also proved to be an independent prognostic factor by multivariate analysis. Surgical excised CRC specimens (n = 26) were enzymatically digested to get the tumor-infiltrating leukocytes and ICOS is mainly expressed on CD4+ T cells and its ligand ICOSL is detected on macrophages and tumor cells. ICOS expression level is associated with increased cytotoxic T lymphocyte antigen (CTLA)-4 (p < 0.001) and programmed death (PD-1) (p = 0.005) expression on T cells and more infiltrated CD8+ T cells (p < 0.001). Interestingly, ICOS+CD4+ cells isolated from tumor tissues have high T-bet and interferon (IFN)γ expression, the characteristics of Th1 cells, compared to ICOS−CD4+ cells. In addition, the correlation between the percentage of ICOS+CD4+ T cells in tumor tissue and peripheral blood was detected. Conclusively, expression of ICOS is associated with improved survival in CRC and percentage of ICOS+CD4+ cells acting as Th1 cells in either primary tumor tissue or peripheral blood may be a clinical biomarker for good prognosis of CRC patients.

Aberrantly expressed microRNAs contribute to the initiation and progression of human cancers. However, the underlying functions of microRNA-187 (miR-187) in colorectal cancer (CRC) remain largely unexplored. Here, we demonstrated that miR-187 was significantly down-regulated in CRC tissues and cell lines compared to their normal counterparts. By Kaplan-Meier analysis, we revealed that decreased miR-187 expression was closely associated with shorter overall survival and relapse-free survival of patients with CRC. By gain- and loss-of-function studies, we showed that miR-187 remarkably suppressed CRC cell proliferation, migration, invasion, and promoted cell apoptosis. Furthermore, bioinformatics analysis and luciferase reporter assay identified that CD276 was the direct functional target of miR-187 in CRC. Genetic silencing of CD276 recapitulated similar phenotype as observed in over-expression of miR-187, and restoration of CD276 completely rescued the inhibitory effect of miR-187 in CRC cells. Taken together, our study implied the essential roles of miR-187 in suppressing CRC progression, and a novel link between miR-187 and CD276 in CRC.

ATPase family AAA domain-containing 2 (ATAD2) has been identified as a critical modulator involved in cell proliferation and invasion. The purpose of this study was to explore the expression of ATAD2 in CRC tissues as well as its relationship with degree of malignancy. Data containing three independent investigations from Oncomine database demonstrated that ATAD2 is overexpressed in CRC compared with normal tissue, and similar result was also found in 32 pairs of CRC tissues by qPCR. The protein expression of ATAD2 was examined in six CRC cell lines and 300 CRC specimens. The results showed that high expression of ATAD2 was significantly correlated with tumor size (P < 0.001), serum CEA (P = 0.012), lymph node metastasis (P = 0.018), liver metastasis (P = 0.025), and clinical stage (P = 0.004). Kaplan-Meier method suggested that higher ATAD2 protein expression significantly associated with the overall survival (OS) of CRC patients (P < 0.001) and was an independent predictor of poor OS. Functional studies showed that suppression of ATAD2 expression with siRNA could significantly inhibit the growth in SW480 and HCT116 cells. These results indicated that ATAD2 could serve as a prognostic marker and a therapeutic target for CRC.

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