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A disintegrin and metalloproteinase 8 (ADAM8) protein is a multi‐domain transmembrane glycoprotein which involves in extracellular matrix remodelling, cell adhesion, invasion and migration. ADAM8 and epithelial‐mesenchymal transition (EMT) play an important role in tumour invasion has been well established. However, the interaction between ADAM8 and EMT has remained unclear. The data of colon cancer patients obtained from TCGA (The Cancer Genome Atlas) and GTEx (Genotype‐Tissue Expression Project) were analysed by the bioinformatics research method. The expression of ADAM8 in colon cancer cells was up‐regulated and down‐regulated by transfecting with the expression plasmid and small interfering RNA, respectively. Transwell invasion assay, immunohistochemistry, immunocytochemistry, Western blotting and qRT‐PCR were utilized to study the effect of ADAM8 on colon cancer cell's EMT and its related mechanisms. Analysis of TCGA and GTEx data revealed that ADAM8 was linked to poor overall survival in colon cancer patients. Besides, ADAM8 was correlated with multiple EMT biomarkers (E‐cadherin, N‐cadherin, Vimentin, Snail2 and ZEB2). In vitro, we also proved that the up‐regulation of ADAM8 could promote EMT effect and enhance the invasive ability of colon cancer cells. On the contrary, the down‐regulation of ADAM8 in colon cancer cells attenuated these effects above. Further studies suggested that ADAM8 modulated EMT on colon cancer cells through TGF‐β/Smad2/3 signalling pathway. Our research suggested that ADAM8 could be a potential biomarker for the prognosis of colon cancer and induced EMT to promote the invasion of colon cancer cells via activating TGF‐β/Smad2/3 signalling pathway. [ABSTRACT FROM AUTHOR]

Aims: Many epidemiological studies have investigated the correlation between adiponectin, C1Q and collagen domain containing (ADIPOQ) single nucleotide polymorphisms (SNPs) and risk of colorectal cancer (CRC). Although conflicting results have been reported, there was dispute regarding two SNPs (rs2241766 T/G and rs1501299 G/T). Therefore, we conducted a meta-analysis to systematically assess the associations and try to find the reasons for the dispute. Methods: We searched PubMed, the Cochrane Library, Elsevier, Wiley Online Library, China National Knowledge Infrastructure, WanFang data and Chongqing VIP to search for all eligible case−control studies published up to January 2015. Effect sizes of odds ratios (OR) and 95 % confidence intervals (95 % CI) were calculated using a fixed- or random-effect model. Results: Ten case-control studies including 4377 cases and 5584 controls were selected. A significant difference was observed in Chinese (OR 0.76; 95 % CI 0.68, 0.85; P < 0.001) and Ashkenazi Jewish populations (OR 0.79; 95 % CI 0.63, 0.99; P = 0.04) for rs2241766 with dominant model (TT vs TG + GG). A significant difference was observed in the Chinese population (OR 1.23; 95 % CI 1.11, 1.37; P < 0.001) for rs1501299 with dominant model (TT vs TG + GG). In addition, intake of red meat showed a synergistic effect between ADIPOQ gene and risk of colorectal cancer (CRC). Conclusions: ADIPOQ SNPs rs2241766 T/G and rs 1501299 G/T have a population-specific correlation with risk of CRC. However, small sample studies may increase reporting bias, particularly if the total number of studies included in the analysis is small. [ABSTRACT FROM AUTHOR]

This study was designed to explore the correlation between expressions of SATB1 and S100A4 and their relationships to the clinicopathologic parameters of colorectal carcinoma ( CRC). Expressions of SATB1 and S100A4 were evaluated by immunohistochemistry in a cohort of 131 primary CRC patients undergone surgical resection from 2005 to 2007. SATB1 and S100A4 were positively expressed in 48.9% and 54.2% of CRC cases, respectively. SATB1 and S100A4 expressions in tumor tissues were significantly higher than those in the corresponding normal tissues. A positive correlation was observed between SATB1 and S100A4. Moreover, the levels of SATB1 and S100A4 were both significantly associated with invasion, lymph node status, and TNM stage of CRC, whereas S100A4 expression was also correlated with distant metastasis. Multivariate analysis revealed that SATB1 expression was an independent prognostic indicator for poor survival of CRC. Further survival analysis indicated that co-expression of SATB1 and S100A4 suggested a worse 5-year overall survival rate in CRC patients. Thus, combined analysis of SATB1 and S100A4 expressions may be valuable in determining the development and progression of CRC. Co-expression of SATB1 and S100A4 is an unfavorable prognostic indicator and may be useful in the follow-up of patients with CRC. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of Rapamycin on epithelial-mesenchymal transition(EMT) of LoVo colonic adenocarcinoma cells in vitro. Methods: Cultured LoVo colonic adenocarcinoma cells were divided into three groups: negative control group, EMT-inducing group(TGF-β1) and EMT-interfering group(TGF-β1 plus Rapamycin). E-cadherin expression in LoVo cells was detected by Western Blot, while the expression of vimentin was evaluated through immunocytochemistry. The Snail mRNA in LoVo cells was examined by RT-PCR. Results: TGF-β1 induced LoVo cell switching from polygonal to spindle-shaped. TGF-β1 enhanced the expression of vimentin, but lowered the level of E-cadherin. In contrast, Rapamycin impaired the transition induced by TGF-β1. Rapamycin dramatically abrogated TGF-β1-induced vimentin expression and restored E-cadherin expression in LoVo cells. Rapamycin significantly repressed the up-regulation of Snail mRNA expression induced by TGF-β1. Conclusion: Rapamycin dramatically abrogated TGF-β1 induced Snail mRNA expression in LoVo cells, hence inhibiting EMT of these cells in vitro. [Copyright &y& Elsevier]

Background: Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. Methods: We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting. Results: We found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-κB specific inhibitor and NF-κB specific shRNA (shP65) abrogated the COX2 induction caused by IL-33. Conclusion: IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-κB signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment. [ABSTRACT FROM AUTHOR]

Foxp3+CD4+regulatory T (Treg) cells are thought to express negligible levels of effector cytokines, and inhibit immune responses and inflammation. Here, we have identified a population of IL-8+Foxp3+CD4+T cells in human peripheral blood, which is selectively increased in the microenvironments of ulcerative colitis and colon carcinoma. Phenotypically, this population is minimally overlapping with IL-17+Foxp3+CD4+T cells, and is different from IL-8−Foxp3+CD4+T cells in the same microenvironment. 40–60% of IL-8+Foxp3+CD4+T cells exhibit naive phenotype and express CD127, whereas IL-8−Foxp3+CD4+cells are basically memory T cells and express minimal CD127. The levels of CXCR5 expression are higher in IL-8+Foxp3+cells than in IL-8−Foxp3+cells. IL-2 and TGFβ induce IL-8+Foxp3+T cells. Exogenous Foxp3 expression promotes IL-8+Foxp3+T cells and inhibits effector cytokine IFNγ and IL-2 expression. Furthermore, Foxp3 binds to IL-8 proximal promoter and increases its activity. Functionally, IL-8+Foxp3+T cells inhibit T cell proliferation and effector cytokine production, but stimulate inflammatory cytokine production in the colon tissues, and promote neutrophil trafficking through IL-8. Thus, IL-8+Foxp3+cells may be an “inflammatory” Treg subset, and possess inflammatory and immunosuppressive dual biological activities. Given their dual roles and localization, these cells may be in a unique position to support tumor initiation and development in human chronic inflammatory environment. [ABSTRACT FROM PUBLISHER]

Background: The epidermal growth factor receptor (EGFR) has played an important role in the growth and apoptosis of colon cancer. The RNA interference (RNAi) technique can suppress gene expression, but the effects of double combining sites RNAi targeting EGFR have not been well understood. Methods: pU6-EGFR-shRNA-1 and pU6-EGFR-shRNA-2 expressive vectors were transfected to the LoVo cells. Five groups were selected for the study: Group 1, the control cells; group 2, the negative control plasmid vector HK; group 3, pU6-EGFR-shRNA-1; group 4, pU6-EGFR-shRNA-2; group 5, pU6-EGFR-shRNA-1 and pU6-EGFR-shRNA-2, half for each. The mRNA and protein expression were assessed by Real Time quantitative PCR and Western blot. Apoptosis was determined via flow cytometry. IC50 and the inhibition ratio of 5-fluorouracil (5-FU) were carried out by CCK-8. Results: In groups 3, 4, and 5, the mRNA expression was decreased by (80.22 ± 3.42)%, (81.30 ± 2.83)%, and (90.58 ± 2.76)%, respectively, and the protein expression was decreased by (74.11 ± 4.02)%, (73.39 ± 2.30)%, and (90.39 ± 3.34)%, respectively. Meanwhile, the cell apoptosis increased by (10.43 ± 0.49)%, (10.13 ± 0.39)%, and (14.17 ± 0.53)%, respectively. The IC50 of 5-FU and cell inhibition ratio analysis demonstrated that there were significant differences between the following three: group 5, groups 3 and 4, and groups 1 and 2. Conclusions: Both pU6-EGFR-shRNA-1 and pU6-EGFR-shRNA-2 are capable of suppressing EGFR expression of the LoVo cell and can promote apoptosis and increase the cell toxicity of 5-FU. The double combining sites RNAi technique is significantly better than a single site. [Copyright &y& Elsevier]

Highlights: [•] HMGB1 in the peritoneal cavity of mice after surgical trauma was detected. [•] HMGB1 in the peritoneal cavity recruited myeloid derived suppressor cells. [•] Blocking HMGB1 reduced the recruitment of myeloid derived suppressor cells. [•] The recruited MDSCs favor postoperative peritoneal metastasis of colon cancer. [ABSTRACT FROM AUTHOR]

Background: Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. Methods: We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting. Results: We found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-κB specific inhibitor and NF-κB specific shRNA (shP65) abrogated the COX2 induction caused by IL-33. Conclusion: IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-κB signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment. [ABSTRACT FROM AUTHOR]