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In the original publication of this manuscript [1], there are three errors in Fig. 1. The identified errors do not affect the conclusions of the work. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that interferon-γ (IFN-γ)-induced galectin-9 expression in Kupffer cells plays an essential role in modulatingthe microenvironment of hepatitis-associated hepatocellular carcinoma (HCC). However, whether or not IFN-γ induces galectin-9 expression in HCC cells, its biological role and regulatory mechanism in HCC development and progression are poorly defined. Methods: Quantitative PCR and western blotting analysis were used to detect galectin-9 and EZH2 levels in HCC cell lines stimulated with IFN-γ. Bioinformatics analysis and luciferase reporter assay were utilized to confirmthe binding ofmiR-22 to the 3' untranslated region (3'-UTR) of galectin-9. The methylation status of miR-22 promoter was analyzed by MSP (Methylation specific PCR) and BSP (bisulfite sequencing PCR), while chromatin immunoprecipitation (ChIP) assay identify the occupation status of EZH2 and H3K27me3 at the promoter. Furthermore, the effect of ectopic expression of galectin-9 and miR-22 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, transwell assays and flow cytometric analysis, respectively. Results: IFN-γ induces up-regulation of galectin-9 and EZH2 in HCC cell lines. Galectin-9 is a target of miR-22 and EZH2 facilitates galectin-9 expression by tri-methylation of H3K27 on miR-22 promoter but not hyper-methylation status of DNA. MiR-22 overexpression suppressed HCC cell growth, invasion, and metastasis both in vitro and in vivo. Interestingly, galectin-9 also exhibited antitumor effects, and restoring galectin-9 expression in miR-22 overexpressing cells strengthened its antitumor effects. Conclusions: These findings indicated that EZH2 facilitates galectin-9 expression by epigenetically repressing miR-22 and that galectin-9, which is known as an immunosuppressant, also functions as a tumor suppressor in HCC. [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]

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]