Cholangiocarcinoma (CCA) is a notoriously lethal epithelial cancer originating from the biliary system.As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage, the disease leads to a fairly poor prognosis.As the incidence of CCA is increasing, although the mortality rate remains stable, and few other definite etiologies have yet to be established, renewing our knowledge of its fundamental carcinogenesis is advisable.The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA.This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA.
Inflammation-related animal model is necessary to better understanding the association of inflammation with tumorigenesis. Although mouse models of inflammation-related lung tumorigenesis on A/J mice strain have been set up in previous study, there is no report on the model on C57BL/6J mice. In this study, C57BL/6J mice were randomly divided into two groups and instilled with benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS) with different treatments. Mice in Group I were instilled intratracheally with B(a)p (1 mg/mouse) and LPS (5 µg/mouse), once a week for 4 times, on Tuesday and Friday, respectively [the week of the last time of B(a)p treatment named Week 0]. At Week 4, mice continued to be treated with LPS, once every four weeks for 5 times. Mice in Group II were exposed to B(a)p (1 mg/mouse, once a week for 4 times) and 3 weeks later instilled intratracheally with LPS (2.5 µg/mouse) once every three weeks for 5 times. At Week 30, the incidence, number, size and histopathology of lung tumor in two models were compared. The tumor incidence (96.97%) and mean tumor count (13.0 ± 12.4) of mice in Group II were significantly increased compared with those in Group I (69.23%, 4.9 ± 5.1), respectively. In addition, smaller tumors (≤1 mm) were more abundant in Group II than Group I. Histopathological examination found the tumors induced by B(a)p plus LPS in Group II were more advanced tumors. In conclusion, a better mouse model of inflammation-related lung tumorigenesis induced by B(a)p plus LPS in C57BL/6J mice was set up successfully.
Core 1 β 1,3-galactosyltransferase 1 (C1GALT1) acts as an important glycosyltransferase in the occurrence and development of tumor glycosylation. However, the regulatory mechanisms of C1GALT1 in thyroid cancer (TC) is still unclear. In this study, we discovered that the expression level of C1GALT1 was significantly increased in thyroid adenocarcinoma tissues and cell lines (p < 0.01). Meanwhile, gene silencing of C1GALT1 inhibited the proliferation (CCK-8 assay), migration (wound healing), and invasion (Transwell) of TC cells (p < 0.05). Further investigation indicated that miR-141-3p had a negative correlation with C1GALT1 and suppressed cancer carcinogenesis in TC cells. Moreover, we first found that glucose transporter 1 (GLUT1) was a downstream element of C1GALT1 and was positively correlated with C1GALT1 levels in TC. The GLUT1 could reverse the inhibitory effects of siRNA C1GALT1 on cell development (p < 0.05). These data suggest that the miR-141-3p/C1GALT1/GLUT1 axis plays an essential role during TC progression and may be a probable biomarker or therapeutic target for thyroid cancer patients.
Glycogen storage disease (GSD) type VI is a rare disease caused by the inherited deficiency of liver phosphorylase.The proband, a 61-month-old Chinese boy, manifested intermittent hematochezia, growth retardation, hepatomegaly, damage of liver function, mild hypoglycemia, and hyperlactatemia. The other patient was a 107-month-old Chinese girl with growth retardation, hepatomegaly, mild hypoglycemia, and hyperlactatemia. In order to further confirm the diagnosis, we conducted a liver biopsy and detected blood samples for their gene using IDT exon chip capture and high-throughput sequencing.According to the clinical symptoms, physical examination, laboratory examinations, liver biopsy, and the genetic test finding, the 2 patients were diagnosed GSD VI.They were treated mainly with uncooked cornstarch.There were 2 mutations of PYGL gene in this pedigree. c.2467C>T (p. Q823X) and c.2178-2A>C occurred both in the proband and his second sister.As a novel mutation, c.2178-2A>C enriches the mutation spectrum of PYGL gene. The different degrees of elevated lactate is an unusual phenotype in GSD VI patients. It is not clear if this is caused by the new mutation of c. 2178-2A > C. Long-term complications remains to be observed.
Glycerol 3-phosphate dehydrogenase 1 (GPD1) acts as a tumor suppressor in various types of cancer. However, the mechanisms of GPD1 anti-tumor remain unclear in breast cancer. This study aims to explore the function and clinical relevance of GPD1 in breast cancer. We confirmed that GPD1 inhibited the ability of proliferation, migration, and invasion in GPD1 overexpression breast cancer cells by CCK-8, wound healing, and Transwell assays, respectively. We found that GPD1 overexpression activated the lipid synthesis pathway and PI3K/AKT signaling pathway. The inhibitory effect of GPD1 on breast cancer cells was also weakened after treatment with LY294002, a PI3K/AKT pathway inhibitor. These results indicated that GPD1 suppressed the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid signaling pathways. Meanwhile, we detected that the relationship between GPD1 level and survival rate presents a positive correlation in breast cancer patients from the Cancer Genome Atlas (TCGA) database. Therefore, GPD1 can be a prognostic biomarker and target in developing therapeutic strategies for breast cancer patients.
Objective . This study aimed to clarify the clinical features, the serum level of autoantibodies, and cytokine of myositis patients with anti-EJ antibody, which targets glycyl tRNA-synthetase (GlyRS). Methods . Sera of 236 Chinese patients with myositis were screened for anti-EJ by a novel immunoprecipitation assay of flag-tagged GlyRS. Anti-EJ positive patients are evaluated for the clinical features and cytokine profile. Results . The sera from 4 of 236 adult myositis patients were found to carry the anti-EJ using established novel immunoprecipitation assay and immunoblotting. The prevalence of anti-EJ in our cohorts is about 1.7%. The decline of anti-EJ level was detected in two patients during disease remission. Interstitial lung disease and muscle weakness, but not skin involvement, are common clinical features of anti-EJ positive patients. Moreover, using a cytokine profile analyses, we found that the serum levels of IP-10, IL-6, MCP-1, and VEGF were significantly elevated in patients with anti-EJ and gradually decreased during disease remission of two patients, whereas IL-8 level was obviously reduced in these patients. Conclusion . The novel immunoprecipitation assay is suitable to detect and monitor the levels of anti-EJ autoantibody. The serum levels of anti-EJ, IP-10, IL-6, MCP-1, and VEGF may be related to disease activity in myositis patients with anti-EJ antibodies.
Inflammatory micro-environment has been proposed to play a critical role in lung tumorigenesis. NLRP3 is known as an intracellular receptor involving inflammation and has been reported which is increasingly associated with tumor development, but the role in inflammation-driven lung cancer has not been fully clarified. In this study, we investigated whether lipopolysaccharide (LPS)-induced pulmonary inflammation could contribute to lung tumorigenesis induced by benzo(a)pyrene [B(a)p] in C57BL/6J mice and the role of NLRP3 in the pathogenesis.NLRP3-/- mice and C57BL/6J mice (wide-type, WT) were instilled intratracheally with B(a)p (1 mg/mouse) once a week for 4 times [the week of the last time of B(a)p treatment named Week 0], and mice were then instilled intratracheally with LPS at Week 3, 2.5 μg/mouse, once every three weeks for 5 times. At Week 30, the incidence, number, size and histopathology of lung tumor were analyzed.Mice exposed to B(a)p or B(a)p plus LPS could induce lung tumors, whereas LPS or vehicles treatment could not induce lung tumorigenesis. In WT mice, B(a)p plus LPS exposure significantly increased tumor incidence, mean tumor count and tumor size of visible tumors of lungs compared with B(a)p treatment alone, and NLRP3 deletion inhibited lung tumorigenesis induced by B(a)p or B(a)p plus LPS. Histopathological examination found LPS-induced pulmonary inflammatory changes enhanced lung tumorigenesis induced by B(a)p in WT mice, deletion of NLRP3 improved the inflammatory changes induced by LPS and the number and size of pathological tumor nests induced by B(a)p or B(a)p plus LPS. In addition, we found B(a)p treatment and B(a)p plus LPS treatment predominately induced the development of adenoma.LPS enhanced B(a)p-induced lung tumorigenesis in WT and NLRP3-/- mice of C57BL/6J strain, and NLRP3 deletion inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS.
In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.
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