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Expression of the MET oncogene correlates with upregulation of coagulation factor XII and procoagulant disorders in colorectal cancer

ABSTRACT: Cancer patients often develop hemostasis disorders whose pathogenesis is poorly understood. Previous work in mouse models has shown that these disorders can be sustained by the MET oncogene by transcriptional upregulation of hemostasis genes. Here we investigated the correlation between the procoagulant state of colorectal cancer patients, and overexpression of MET and hemostasis genes in the tumor. We found that, in a patient subset, blood levels of D-dimer and coagulation factor XII (F12) were frequently elevated, and reverted towards normality after surgery. Global expression profiling of tumor tissues and adjacent mucosae revealed a significant correlation between high D-dimer levels in the blood, and overexpression of MET in the tumor. An “hemostasis gene signature”, including F12, cyclo-oxygenase 2, thromboxane synthase-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator and protein C receptor was associated with MET overexpression. This association was confirmed in an independent 173-sample CRC dataset. The mechanistic link between MET signaling and F12 expression was established experimentally in cell lines. These data indicate that MET contributes to the pathogenesis of coagulation disorders in CRC by upregulation of hemostasis genes including F12, and provide a candidate biomarker for the CRC-associated procoagulant state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52060 | GEO | 2022/12/30

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is a genetically heterogeneous disease with several distinct morphological growth patterns. This study was aimed to investigate genes differentially expressed between ulcerative and polypoid colorectal CRC. cDNA microarray was first employed to compare the gene expression profiling of ulcerative and polypoid CRC with paired normal mucosa. Potential candidates identified by data filtering were further validated using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry. Epigenetic regulation of gene expression was investigated using methylation-specific PCR (MSP). cDNA microarray identified 11 up-regulated and 14 down-regulated genes differentially expressed in both types of tumor compared to matched normal mucosa. Among them, S100P was the only upregulated gene preferentially associated with polypoid CRC (p = 0.032), whereas no genes demonstrated significantly differential association with ulcerative CRC. S100P protein and mRNA expression level of polypoid CRC was significantly higher than that of ulcerative CRC (p < 0.05, respectively). Immunoreactivity of S100P protein was localized predominantly in the nuclei and to a less extent in the cytoplasm. Overexpression of S100P occurred early in the adenoma stage. 80% (24/30) and 20% (6/30) polypoid CRC showed diffusely strong and moderate overexpression, respectively. In contrast, S100P was diffusely and strongly expressed in 15% (6/40) ulcerative CRC, with 52.5% (21/40) and 32.5% (13/40) tumors having moderate and weak overexpression, respectively. S100P overexpression was preferentially associated with polypoid CRC (p < 0.001). The relative methylation level determined by MSP was not statistically different between polypoid and ulcerative CRC (43.36% vs. 49.10%, p = 0.168), indicating that promoter hypomethylation was directly related to upregulation of S100P mRNA. The gene expression profiling of ulcerative and polypoid CRC with paired normal mucosa were compared. Dye swapping experiments with ulcerative CRC vs normal mucosa or polypoid CRC vs normal mucosa were performed and we averaged the log ratios of the duplicated spots on each slide.

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Expression of the MET oncogene correlates with upregulation of coagulation factor XII and procoagulant disorders in colorectal cancer

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