Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development.

Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFß-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.

Association between inflammatory biomarkers and progression of intracranial large artery stenosis after ischemic stroke.

BACKGROUND: Proinflammatory state has been implicated as a pathogenetic mechanism in the progression of intracranial large artery atherosclerosis (ILA). High levels of inflammatory biomarkers in healthy populations and in patients with acute stroke or acute coronary syndrome are known to be associated with subsequent stroke events. This study investigated the relationship between circulating biomarkers measured early after stroke onset and future ILA progression. METHODS: In 48 patients with acute ischemic stroke, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2 and MMP-9 were measured within 48 hours after onset. Baseline severity and ILA progression were assessed by serial magnetic resonance angiography (MRA). The median follow-up period for MRA was 3.1 years. Hazard ratio (HR) was calculated using the Cox proportional hazard model adjusted for traditional risk factors, and accuracy of predicted ILA progression was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: ILA progression was observed in 6 of 48 patients (12.5%). After adjusting for age, sex, and presence of hypertension, baseline ILA severity score (HR 2.814; 95% confidence interval [CI] 1.172-6.754) and IL-6 (HR 1.215; 95% CI 1.002-1.473) were significantly associated with ILA progression. Area under the ROC curve (AUC) for prediction of ILA progression by traditional risks, baseline ILA severity score and IL-6, was 0.647. When IL-6 was removed from this model, AUC remained at 0.631. CONCLUSIONS: In addition to traditional risk factors and baseline radiologic findings, circulating levels of IL-6 measured soon after stroke onset are associated with future ILA progression.

[Effects of early statin treatment on inflammatory biomarkers and clinical deterioration in patients with acute ischemic stroke].

We prospectively studied the effects of early statin treatment on stroke-induced changes in the levels of inflammatory biomarkers. Patients admitted within 48 hours after the onset of ischemic stroke were enrolled. They were divided into 2 groups according to their lipid profiles and history of statin treatment. In patients who had received statin treatment prior to admission and those who had abnormal lipid profiles on admission, daily treatment with 10 mg atorvastatin was initiated within 48 hours after the onset of stroke (Statin group; n = 45). In patients who had normal lipid profiles on admission, statin was not administered for at least 2 weeks after admission (Non-Statin group; n = 101). The serum concentrations of interleukin (IL)-6, IL-10, IL-18, matrix metalloproteinase (MMP)-2, MMP-9, and high sensitive C-reactive protein were measured on days 1, 3, 7, and 14. In percentage changes in serially measured circulating IL-6 levels, a significant interaction between group and repeated measures (group X time factor) was demonstrated (p = 0.047). Frequency of neurological deterioration episodes (NIHSS score > or = 2) during 14 days after admission was lower in the Statin group than in the Non-Statin group, however the difference did not reach statistically significant level (7.9% vs 20.2%, p = 0.118). The initiation of usual dose of atorvastatin early after the onset of ischemic stroke significantly decreased the elevation of IL-6 and may protect against the early neurological deterioration. Circulating levels of IL-6 may be one of the candidates for monitoring the acute effects of statin. Further studies wherein IL-6 levels are monitored in larger samples would be feasible for investigating the effect of early treatment with usual dose of atorvastatin on the functional outcome.

Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer.

It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.