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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.


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.


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 10 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.


Wang H.,Zhejiang University | Wang H.,Key Laboratory of Disease Proteomics of Zhejiang Province | Zhang D.,Zhejiang University | Zhang D.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 8 more authors.
Journal of Cellular and Molecular Medicine | Year: 2015

Hepatic lipase (LIPC) is a key rate-limiting enzyme in lipoprotein catabolism pathways involved in the development of obesity. The C-514T polymorphism in the promoter region is associated with decreased LIPC activity. We performed a case-controlled study (850 obese children and 2119 controls) and evaluated the association between LIPC C-514T polymorphism, obesity and plasma lipid profile in Chinese children and adolescents. Additionally, we conducted a meta-analysis of all results from published studies as well as our own data. A significant association between the polymorphism and obesity is observed in boys (P = 0.042), but not in girls. And we observed a significant relationship of the polymorphism with total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) independent of obesity in boys. The T allele carriers have higher levels of low density lipoprotein cholesterol (LDL-C) in obese boys, and triglyceride (TG), TC and LDL-C in non-obese girls (all P < 0.05). In the meta-analysis, under dominant model the T allele increased body mass index (BMI) level in boys, while it decreased BMI in girls, and increased the levels of TC both in the overall and subgroups, TG and HDL-C in the overall and boys, and LDL-C in the overall (all P < 0.05). Our results suggest that the T allele might carry an increased risk of obesity in Chinese boys. The meta-analysis suggests that T allele acts as a risk allele for higher BMI levels in male childhood, while it is a protective allele in female childhood. And the polymorphism is associated with the levels of plasma lipids, which may be modulated by obesity and gender. © 2015 John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.


Wang J.,Zhejiang University | Wang J.,The First Hospital of Jiaxing | Tang J.,Zhejiang University | Lai M.,Zhejiang University | And 3 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.


Zhang H.,Zhejiang University | Zhang H.,Key Laboratory of Disease Proteomics of Zhejiang Province | Tang J.,Zhejiang University | Li C.,Zhejiang University | And 10 more authors.
Cancer Letters | Year: 2015

Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer. © 2014 Elsevier Ireland Ltd.


Wang L.,Zhejiang University | Wang L.,Key Laboratory of Disease Proteomics of Zhejiang Province | Lin D.,Qingdao University | Fu Y.,Zhejiang University | And 2 more authors.
Pathology Research and Practice | Year: 2016

Aim To assess the expression pattern of aldehyde dehydrogenase 1A1 (ALDH1A1) in the normal–adenoma–primary carcinoma–liver metastasis sequence, and investigate its association with clinicopathological features and outcomes. Methods Immunohistochemistry for ALDH1A1 was performed on two cohorts. One used tissue microarrays (TMAs) of 395 primary colorectal carcinomas, and the other used whole-tissue sections from 217 adenomas, 265 primary carcinomas, and 72 liver metastatic carcinomas. Both the epithelial and stromal expression of ALDH1A1 were evaluated. Both cytoplasmic and nuclear expression were assessed in epithelial cells. Results In the TMA and whole-tissue cohorts, univariate analysis indicated that the cytoplasmic expression of ALDH1A1 cannot be considered as a prognosis marker of CRCs. In the whole-tissue cohort, nuclear expression was found in a small subgroup of CRC patients. Here, both univariate and multivariate analysis showed that nuclear expression was significantly associated with longer disease-specific survival. In addition, we found that nuclear expression in low-grade adenoma was predominant over high-grade adenoma, primary CRC and the correpsonding liver metastasis. Conclusions Whole-tissue is better than TMA for the detection of ALDH1A1 nuclear staining in CRC patients, and nuclear expression is associated with a better outcome. Cytoplasmic expression is not a suitable prognostic marker of CRC. © 2016 Elsevier GmbH


Li H.,Zhejiang University | Li H.,Key Laboratory of Disease Proteomics of Zhejiang Province | Xu F.,Zhejiang University | Xu F.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 7 more authors.
Cell Adhesion and Migration | Year: 2016

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy. © 2016 Taylor & Francis


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.


Zhou D.,Zhejiang University | Zhou D.,Key Laboratory of Disease Proteomics of Zhejiang Province | Li Z.,Zhejiang University | Li Z.,Key Laboratory of Disease Proteomics of Zhejiang Province | And 9 more authors.
Oncotarget | Year: 2015

Some single nucleotide polymorphisms (SNPs) influence the existence of CpG sites, the basis of DNA modification such as methylation and hydroxymethylation. These polymorphisms can lead to gain or loss of CpG sites and were defined as CpG site related SNPs (cgSNPs) in this study. The cgSNPs change DNA sequence and might potentially affect DNA modification such as methylation. However, the functional consequence of cgSNPs is poorly understood. We observed that a considerable proportion (23.0%) of common variants were cgSNPs in human genome. Mutations involving loss of CpG sites were associated with reduced levels of methylation (~20.2%) using The Cancer Genome Atlas (TCGA) data. Using public databases (SCAN and seeQTL) of expression quantitative trait loci (eQTLs), we found that the cgSNPs were significantly enriched in eQTLs via logistic regression and simulation test. Furthermore, we observed that cgSNPs were more likely to be trait-associated loci especially cancers using a catalog of published genome-wide association studies (GWAS) recorded by National Human Genome Research Institute (NHGRI). Our results indicated that cgSNP might be meaningful as annotation either in SNP functional prediction or in screening for trait-associated SNPs.

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