Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line.
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ABSTRACT:
SUBMITTER: To KF
PROVIDER: S-EPMC2409891 | biostudies-other | 2004 Oct
REPOSITORIES: biostudies-other
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Project description:BackgroundDNA methylation controls the transcription of genes and is involved in the development of lung cancer. Our preliminary bioinformatics prediction revealed that sperm associated antigen 6 (SPAG6) was considerably hypermethylated in lung squamous cell carcinoma (LUSC). Thus, this study aimed to probe the mechanism underlying its hypermethylation.MethodsThe effect of DNA methylation of SPAG6 on its expression in LUSC was analyzed. The contributors to SPAG6 DNA hypermethylation were sought. CCK-8, EdU, and Transwell assays were carried out to assess the malignant phenotype of LUSC cells. KEGG pathway enrichment analysis was used to screen for pathways affected by SPAG6, which were confirmed by dual-luciferase assays. Bioinformatics analysis was conducted to dissect the impact of SPAG6 on the immune response and cancer cell stemness in LUSC.ResultsDNA methyltransferase 3b (DNMT3b)-mediated hypermethylation of the SPAG6 promoter in LUSC led to SPAG6 downregulation. SPAG6 reverted the malignant phenotype of LUSC cells. SPAG6 regulated the JAK/STAT pathway by inhibiting the transcription of STAT1 and STAT3. The expression of SPAG6 was positively related to immune infiltration in LUSC and inversely related to the expressions of the immunosuppressive genes CTLA4 and PDCD1. SPAG6 expression was negatively correlated with cancer cell stemness in LUSC, and its expression inhibited the expressions of Nanog, ALDH1, and Sox2, markers of cancer cell stemness.ConclusionsDNMT3b-mediated SPAG6 promoter hypermethylation activates the JAK/STAT pathway to promote LUSC progression.
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Project description:The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.
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Project description:Background: Esophagus cancer is a malignant tumor with a high incidence rate, and radiation is an important modality for esophageal cancer therapy. However, therapeutic failure in the treatment of ESCC is often attributed to an inherent radio-resistance of the tumor cells. This study discusses effect and mechanism of carbon ion exerts tumor-inhibiting proliferation via down-regulation of LIF in esophageal squamous cell carcinoma. Methods: Colony formation, CCK8 and EdU assays were used to detect cell survival and proliferation after 0 and 2Gy carbon ion irradiation of ECA109 cells. Proteomics changes were probed in response to carbon ion irradiation using quantitative proteomics approach incorporating TMT isotope tags. Then, candidate genes were identified via bioinformatics analysis methods and microarray results were verified by real-time qPCR. Paired ESCC tumor tissues and adjacent non-tumor samples from 17 patients were collected and used for detecting expression by immunohistochemistry. Furthermore, small interfering RNA (siRNA) was transfected into ECA109 and KYSE150 cells and cell proliferation was analyzed by EdU assay. Flow cytometry and Western blot were performed to measure the and apoptosis and JAK-STAT3 protein expression level of ECA109 and KYSE150 cells combined drugs after siLIF transfection. Results: When compared with the control (0Gy), Inhibition of ECA109 cell proliferation and clonogenic survival by 2 Gy carbon ions, radiation group screened 360 differentially expressed proteins, 156 of which were up-regulated and 144 were down-regulated. Downregulation of LIF expression by siRNA enhances apoptotic in the ECA109 and KYSE150 cells, significantly inhibited esophageal squamous cell carcinoma cells proliferation. In ESCC cells, the JAK/STAT3 signaling pathway is inhibited in a LIF-dependent manner, resulting in the expression of STAT3 downstream target genes. Carbon ions combined with siLIF inhibited cell proliferation more significantly. The inhibitory cell proliferation effect was more pronounced by the combined intervention of carbon ion irradiation with siLIF. LIF expression was 18.51±9.84 and 5.82±4.50 in 17 paired ESCC tissues and adjacent non-cancerous tissues, respectively. LIF protein expression was lower in ESCC than in the adjacent normal tissue. Conclusion: The findings of this study reveal that Carbon ion knockdown was shown to downregulate LIF in ESCC cells. LIF is involved in ESCC proliferation and inhibited the ESCC cell proliferation by activating the STAT3 signaling pathways.
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