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Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer.

ABSTRACT: BACKGROUND:Circadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single-nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients. METHODS:Nine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan-Meier curve were used for prognosis analysis. RESULTS:Among the nine SNPs, rs11133399 in CLOCK, rs1044432 and rs2279284 in BAML1 were significantly associated with GC overall survival and recurrence-free survival. The unfavorable genotypes of these SNPs showed a cumulative effect on GC prognosis. Multivariate assessment model indicated that these SNPs, in conjunction with clinical variables, enhanced the power to predict GC prognosis. In addition, survival tree analysis revealed the genotype of rs11133399 as a primary risk factor contributing to the prognosis of GC patients. Functional assays showed that the G allele in rs11133399 significantly enhanced luciferase reporter activity than A allele. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, suggesting that this SNP might affect the prognosis of GC through its influence on the expression of CLOCK gene. CONCLUSIONS:Our data indicate that SNPs in CPFL genes might contribute to the clinical outcome of GC through their impact on gene expression. Further studies are needed to elucidate its underlying molecular mechanisms.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6488121 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer.

Chen Yibing Y Wang Dandan D Song Yucen Y Zhang Xiaofei X Jiao Zhihui Z Dong Juqin J Lü Lin L Zou Zhengzhi Z Du Wei W Qu Falin F

Cancer medicine 20190307 4

<h4>Background</h4>Circadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single-nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients.<h4>Methods</h4>Nine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan-Meier curve were use ...[more]

PMID: 30843665

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Project description:BackgroundHypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood.MethodsHypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment.ResultsOur results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient's pessimistic outcome.ConclusionOur work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

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Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer.

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Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer.

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