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Yue M.,Zhejiang University | Luo D.,Zhejiang University | Liu S.Y.P.,Zhejiang University | Zhou Q.,Zhejiang University | And 8 more authors.
Blood | Year: 2016

The sterile-20 kinase misshapen/Nck-interacting kinase (NIK)-related kinase 1 (MINK1) is involved in many important cellular processes such as growth, cytoskeletal rearrangement, and motility. Here, with MINK1-deficient (MINK12/2) mice, we showed that MINK1 plays an important role in hemostasis and thrombosis via the regulation of platelet functions. In the tail-bleeding assay, MINK12/2 mice exhibited a longer bleeding time thanwild-type(WT) mice (575.2 6 59.7 seconds vs 419.6 6 66.9 seconds). In a model of ferric chloride-induced mesenteric arteriolar thrombosis, vessel occlusion times were twiceaslonginMINK12/2 mice as in WT mice. In an in vitro microfluidic whole-blood perfusion assay, thrombus formation on a collagen matrix under arterial shear conditions was significantly reduced in MINK12/2 platelets. Moreover, MINK12/2 platelets demonstrated impaired aggregation and secretion in response to low doses of thrombin and collagen. Furthermore, platelet spreading on fibrinogen was largely hampered in MINK12/2 platelets. The functional differences of MINK12/2 platelets could be attributed to impaired adenosine 59-diphosphate secretion. Signaling events associated with MINK1 appeared to involve extracellular signal-regulated kinase, p38, and Akt. Hence, MINK1 may be an important signaling molecule that mediates mitogen-activated protein kinase signaling and participates in platelet activation and thrombus formation. (Blood. 2016;127(7):927-937). © 2016 by The American Society of Hematolog. Source

Wang J.,Zhejiang University | Tang J.,Zhejiang University | Lai M.,Zhejiang University | Lai M.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 2 more authors.
Mutation Research - Reviews in Mutation Research | Year: 2014

Epigenetics is the study of inherited changes in phenotype or gene expression that do not alter DNA sequence. Recently, scientists have focused their attention on 5-hydroxymethylcytosine (5hmC), a newly discovered epigenetic marker, also known as sixth DNA base of the genome. In mammals, this novel epigenetic marker is derived from 5-methylcytosine (5mC) in a process catalyzed by ten-eleven translocation (TET) enzymes. Although 5hmC has only been subjected to study for a short while, a great deal of data has been accumulated regarding its generation, distribution, demethylation, function, and disease implications. All this information suggested that 5hmC acts not only as an intermediate in the DNA demethylation process but also as an independent epigenetic marker, playing an important role in the regulation of gene expression. This review focuses on recent progress in the study of the relationship between 5hmC and human diseases, such as cancer and Rett syndrome (RTT). © 2014 Elsevier B.V. Source

Cao H.,Zhejiang University | Cao H.,Key Laboratory of Disease Proteomics of Zhejiang Province | Xu E.,Zhejiang University | Xu E.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 6 more authors.
Pathology Research and Practice | Year: 2015

Tumor metastasis is a multi-step process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. And metastasis is the major cause of death in the vast majority of cancer patients. However, the mechanisms underlying each step remain obscure. In the past decade, a developmental program epithelial-to-mesenchymal transition (EMT) has been increasingly recognized to play pivotal and intricate roles in promoting carcinoma invasion and metastasis. The EMT process is very complex and controlled by various families of transcriptional regulators through different signaling pathways. In this system review, we focus on the molecular network of the EMT program and its malignant phenotypes associated with metastasis in colorectal cancer (CRC), including cancer stem cells, tumor budding, circulating tumor cells and drug resistance. A better understanding of the molecular regulation of the dynamic EMT program during tumor metastasis will help to provide much-needed therapeutic interventions to target this program when treating metastatic CRC. © 2015 Elsevier GmbH. Source

Li C.,Zhejiang University | Li C.,Key Laboratory of Disease Proteomics of Zhejiang Province | Wang X.,Peking Union Medical College | Casal I.,CSIC - Biological Research Center | And 9 more authors.
Journal of Cellular and Molecular Medicine | Year: 2016

Although various studies have demonstrated that growth differentiation factor 15 (GDF15) might be a potential diagnostic and prognostic marker in colorectal cancer (CRC) patients, the results are inconsistent and the statistical power of individual studies is also insufficient. An original study was conducted to explore the diagnostic and prognostic value of serum GDF15 in CRC patients. We also conducted a meta-analysis study which aimed to summarize the diagnostic and prognostic performance of serum GDF15 in CRC. We searched PubMed and ISI Web of Knowledge up to 1 November 2014 for eligible studies. In order to explore the diagnostic performance of GDF15, standardized mean difference (SMD) and their 95% confidence intervals (CI) were estimated and receiver-operating characteristic (ROC) curves were constructed. For prognostic meta-analysis, study-specific hazard ratios (HRs) of serum GDF15 for survival were summarized. A total of eight studies were included in the meta-analyses. Our results revealed that serum GDF15 levels in CRC patients were higher than those in healthy controls (SMD = 1.08, 95% CI: 0.56–1.59, P < 0.001). For discriminating CRC from healthy controls, the AUC of GDF15 was 0.816 (95% CI: 0.792–0.838). The sensitivity and specificity were 58.9% (95% CI: 55.0–62.8) and 92.08% (95% CI: 89.2–94.4), respectively, when a cut-off value of 1099 pg/ml was established. Besides, higher GDF15 expression level was associated with worse overall survival for CRC patients (pooled HR = 2.09, 95% CI: 1.47–2.96). In conclusion, the present meta-analysis suggests that serum GDF15 may be a useful diagnostic and prognostic biomarker for CRC. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Source

Li Z.,Zhejiang University | Li Z.,Key Laboratory of Disease Proteomics of Zhejiang Province | Yu D.,Zhejiang University | Yu D.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 12 more authors.
Oncotarget | Year: 2015

Colorectal cancer (CRC) is a complex disease with an estimated heritability of approximately 35%. However, known CRC-related common single nucleotide polymorphisms (SNPs) can only explain ~0.65% of the heritability. This "missing heritability" may be explained partially by rare copy number variants (CNVs). In this study, we performed a genome-wide scan using Illumina Human-Omni Express BeadChip, 694 sporadic CRC cases and 1641 controls were eventually included in our analysis after quality control. The global burden analysis revealed a 1.53-fold excess of rare CNVs in CRC cases compared with controls (P < 1 × 10-6), and the difference being more pronounced for genic rare CNVs and CNVs overlapped with coding regions (1.65-fold and 1.84-fold, respectively, both P < 1 × 10-6). Interestingly, both the cases in the lowest and middle tertile of age carried a higher burden of rare CNVs comparing to the highest tertile. Furthermore, 639 CNV-disrupted genes exclusive to CRC cases were found to be significantly enriched in gene ontology (GO) terms concerning nucleosome assembly and olfactory receptor activity. Our study was the first to evaluate the burden of rare CNVs in sporadic CRC and suggested that rare CNVs contributed to the missing heritability of CRC. Source

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