Tetraspanins are believed to interact with specific partner proteins forming tetraspanin-enriched microdomains and regulate some aspects of partner protein functions. However, the role of Tspan5 during pathological processes, particularly in cancer biology, remains unknown. Here we report that Tspan5 is significantly downregulated in gastric cancer (GC) and closely associated with clinicopathological features including tumour size and TNM stage. The expression of Tspan5 is inversely correlated with patient overall survival and is an independent prognostic factor in GC. Upregulation of Tspan5 in tumour cells results in inhibition of cell proliferation and colony formation in vitro and suppression of xenograft growth of GC by reducing tumour cell proliferation in vivo. Thus, Tspan5 functions as a tumour suppressor in stomach to control the tumour growth. Mechanistically, Tspan5 inhibits the cell cycle transition from G1-S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Reconstitution of either cyclin D1 or CDK4 in Tspan5-overexpressing GC cells rescues the inhibitory phenotype produced by Tspan5, suggesting that cyclin D1/CDK4 play a dominant role in mediating the suppression of tumour growth by Tspan5 in GC. Our results suggest that Tspan5 may serve as a prognostic biomarker for predicting outcome of GC patients and provide new insights into the pathogenesis of GC and rational for the development of clinical intervention strategies against GC.

CD24 is involved in tumor progression of various cancers, but the effects of CD24 on tumor angiogenesis in colorectal cancer are still unknown. We aimed to investigate the underlying mechanism and role of CD24 on colorectal cancer (CRC) angiogenesis. Our data showed that the microvessal density (MVD) was related to the expression of CD24 in primary and metastasis CRC. Silencing of CD24 could dramatically decrease human umbilical vein endothelial cell (HUVEC) migration, invasion and tubule formation, but trivially affected cell proliferation. We also mechanically showed that silencing CD24 could downregulate the expression of VEGF via inhibiting the phosphorylation and translocation of STAT3. Moreover, Hsp90 was identified as the down-interaction protein of CD24 with co-immunoprecipitation assay and systematic mass spectrometry. Immunofluorescence results showed Hsp90 partly co-localized with CD24 in CRC cell membrane and there was a positive correlation between CD24 and Hsp90 expression in CRC tissues. We gradually evidenced that Hsp90 modulated the stability and degradation of CD24 in a proteasome-depended manner, and transferred the signal transmission from CD24 to STAT3. 17-AAG, a specific Hsp90, could abrogate the CD24 induce- HUVEC migration, invasion and tubule formation in vitro and in vivo. Collectively, our results suggested that CD24 induced CRC angiogenesis in Hsp90-dependent manner and activated STAT3-mediated transcription of VEGF. We provided a new insight into the regulation mechanism of tumor angiogenesis by exploring the role of CD24 in angiogenesis.

Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 × 10-8) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 × 10-8). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 × 10-7) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 × 10-6) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC.

Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3'UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance.

While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.

Prognosis of age at diagnosis for gastric cancer (GC) has been investigated in a few studies with inconclusive results. To assess the survival of GC across different age groups, we searched the Surveillance, Epidemiology, and End Results (SEER) database (1988-2010) and identified 10,092 patients undergoing gastrectomy. Analyses of the associations between age and 5-year GC-specific survival (GCSS) were carried out using the Kaplan-Meier method and Cox regression model. When the 50-59 year age group was used as reference group, patients younger than 50 years suffered similar survival rates, and the risk of death increased for patients older than 60 years (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.02-1.20), peaking for ages > 80 years (HR, 1.60; 95% CI, 1.46-1.76). Overall, HRs of 5-year GCSS increased steadily with age, even when age was evaluated as a continuous variable. We assessed the survival differences associated with age between three groups, using the cut-off ages of 30 and 50 years. Compared with the elderly group, a high survival rate was observed in the mid-age group, but not in the youngest group. Stratified analysis for sex, race, tumor site, histology and clinical stage yielded consistent results. This study shows that the prognosis of GC varies with age, and young GC patients appear to have a favorable GCSS after surgical treatment. Further studies are warranted to verify our findings.

B7-H3, first recognized as a co-stimulatory molecule, is abnormally expressed in cancer tissues and is associated with cancer metastasis and a poor prognosis. However, as an initial event of metastasis, the relationship between the Epithelial-Mesenchymal Transition (EMT ) in cancer cells and B7-H3 has still not been investigated. In this study, we first analyzed B7-H3 expression by immunohistochemistry in colorectal cancer tissues. B7-H3 was expressed in the cancer cell membrane and was associated with the T stage of colorectal cancer; it also showed a positive correlation with MMP2 and MMP9 expression in cancer tissues. Over-expression of B7-H3 in SW480 cells allowed cancer cells to invade and metastasize more than the control cells, whereas invasion and metastasis capabilities were decreased after B7-H3 was knocked down in Caco-2 cells. We further showed that B7-H3 down-regulated the expression of E-cadherin and β-catenin and up-regulated N-cadherin and Vimentin expression, implying that B7-H3 promoted the EMT in colorectal cancer cells. We also checked another character of the EMT, the stemness of cancer cells. CD133, CD44 and Oct4 were significantly elevated after the SW480 cells were transfected with B7-H3 and reduced in Caco-2 cells after B7-H3 was inhibited. In subsequent studies, we proved that B7-H3 upregulated the expression of Smad1 via PI3K-Akt. In conclusion, B7-H3 promotes the EMT in colorectal cancer cells by activating the PI3K-Akt pathway and upregulating the expression of Smad1.

Wip1 has been shown to correlate with the metastasis/invasion of several tumors. This study was designed to investigate the clinical significance and biological function of Wip1 in intrahepatic cholangiocarcinoma (ICC). The expression of Wip1 was investigated in sixty human ICC biopsy samples by immunohistochemistry. Transient and stable knockdown of Wip1 in two human ICC cells (ICC-9810 and SSP25) were established using short hairpin RNA expression vector. Immunohistochemistry revealed that Wip1 was up-regulated in human ICC tissues (47/60, 78.3%). High levels of Wip1 in human ICC correlated with metastasis to the lymph metastasis (P=0.022). Genetic depletion of Wip1 in ICC cells resulted in significantly inhibited proliferation and invasion compared with controls. Most importantly, Wip1 down-regulation impaired tumor migration capacity of ICC cells in vivo. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) is an important target of Wip1. Consistently, in human ICC tissues, Wip1 level was positively correlated with MMP-2 expression. Taken together, our founding indicates that Wip1 may be a crucial regulator in the tumorigenicity and invasion of human ICC, Wip1 exerts its pro-invasion function at least in part through the MMP-2 signaling pathway, suggesting Wip1 as a potential therapeutic target for ICC.

Quaking(QKI) is an RNA binding protein, and it has been shown to serve as a tumor suppressor. However, the expression and functions of QKI in osteosarcoma progression remain poorly understood. In this study, we aimed to explore the expression of QKI2 in osteosarcoma tissues and to determine the mechanisms underlying aberrant QKI2 expression and the effect of QKI2 on osteosarcoma progression. We found that QKI2 was significantly down-regulated in osteosarcoma tissues compared with adjacent normal bone tissues. Using a series of molecular biological techniques, we demonstrated that all members of the miR-17-92 cluster were up-regulated and contributed to the down-regulation of QKI2 expression in osteosarcoma. Functional examination showed that QKI2 inhibited the proliferation, migration and invasion of osteosarcoma cells via decreasing the expression of β-catenin. Conclusively, we revealed that the regulatory axis consisting of the miR-17-92 cluster/QKI2/β-catenin plays a crucial role in the development and progression of osteosarcoma.