Publications by authors named "Sibo Zhu"

32 Publications

Association between oral microflora and gastrointestinal tumors (Review).

Oncol Rep 2021 Aug 16;46(2). Epub 2021 Jun 16.

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China.

The oral cavity contains the highest density and the most species of microorganisms compared with other parts of the body. Recent studies have determined that the species and abundance of oral microflora are closely associated with the development of upper gastrointestinal tumors, including oral, esophageal and gastric cancer. Additionally, differential abundant microbiota in patients with cancer and abnormal microorganisms inside the tumor tissue have been identified as critical markers of tumorigenesis. There is evidence to suggest that certain genera, including , along with various species, such as , can increase the risk of oral cancer. Furthermore,   is a risk factor for esophageal carcinoma, while   infections are a main cause of gastric cancer. Currently, as far as carcinogenic mechanisms of oral microorganisms are concerned, it has been hypothesized that the production of carcinogenic substances, chronic inflammation and altered cell metabolisms may be mechanisms by which oral microorganisms influence the development of upper gastrointestinal cancer. Certain phrases, including 'oral microbes', 'oral microorganism', 'oral microbiology', 'oral microflora', 'oral cancer', 'oral carcinoma', 'carcinoma of mouth', 'esophagus cancer', 'esophageal cancer', 'esophageal carcinoma', 'carcinoma of esophagus', 'gastric cancer', 'gastric carcinoma', 'stomach cancer', 'cancer of the stomach', 'carcinogenic mechanism' and 'carcinogenesis', were searched as key words in PubMed and Web of Science for articles published between 1975 to 2020. A total of 1,512 studies were obtained. After further searching the abstracts for key words, such as oral microorganisms, oral cancer, esophagus cancer, gastric cancer and carcinogenic mechanisms, 137 studies were selected. The current review systematically and comprehensively summarized the association between the oral microbiota and oral, esophageal and gastric cancer. Additionally, the current review described the carcinogenic mechanisms of oral microbes and attempted to identify common molecular mechanisms among different types of tumor. The association between upper gastrointestinal cancer therapy and oral microflora was also assessed. The present review may be used as a reference for future diagnosis and therapeutics for upper gastrointestinal tumors.
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http://dx.doi.org/10.3892/or.2021.8111DOI Listing
August 2021

Relating the transcriptome and microbiome by paired terminal ileal Crohn disease.

iScience 2021 Jun 5;24(6):102516. Epub 2021 May 5.

Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China.

Management of terminal ileal Crohn disease (CD) is difficult due to fibrotic prognosis and failure to achieve mucosal healing. A limited number of synchronous analyses have been conducted on the transcriptome and microbiome in unpaired terminal ileum tissues. Therefore, our study focused on the transcriptome and mucosal microbiome in terminal ileal tissues of patients with CD with the aim of determining the role of cross-talk between the microbiome and transcriptome in the pathogenesis of terminal ileal CD. Mucosa-attached microbial communities were significantly associated with segmental inflammation status. Interaction-related transcription factors (TFs) are the panel nodes for cross-talk between the gene patterns and microbiome for terminal ileal CD. The transcriptome and microbiome in terminal ileal CD can be differently related to the local inflammatory status, and specific differentially expressed genes may be targeted for mucosal healing. TFs connect gene patterns with the microbiome by reflecting environmental stimuli and signals from microbiota.
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http://dx.doi.org/10.1016/j.isci.2021.102516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170125PMC
June 2021

TRPM2 promotes pancreatic cancer by PKC/MAPK pathway.

Cell Death Dis 2021 Jun 7;12(6):585. Epub 2021 Jun 7.

General Surgery Department, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

The mechanism of pancreatic cancer (PA) is not fully understanded. In our last report, TRPM2 plays a promising role in pancreatic cancer. However, the mechanism of TRPM2 is still unknown in this dismal disease. This study was designed to investigate the role and mechanism of TRPM2 in pancreatic cancer. TRPM2 overexpressed and siRNA plasmid were created and transfected with pancreatic cancer cell line (BxPC-3) to construct the cell model. We employed CCK-8, Transwell, scratch wound, and nude mice tumor-bearing model to investigate the role of TRPM2 in pancreatic cancer. Besides, we collected the clinical data, tumor tissue sample (TT) and para-tumor sample (TP) from the pancreatic cancer patients treated in our hospital. We analyzed the mechanism of TRPM2 in pancreatic cancer by transcriptome analysis, western blot, and PCR. We blocked the downstream PKC/MEK pathway of TRPM2 to investigate the mechanism of TRPM2 in pancreatic cancer by CCK8, scratch wound healing, and transwell assays. Overexpressed TRPM2 could promote pancreatic cancer in proliferation, migration, and invasion ability in no matter the cell model or nude mice tumor-bearing model. TRPM2 level is highly negative correlated to the overall survival and progression-free survival time in PA patients, however, it is significantly increased in PA tissue as the tumor stage increases. The transcriptome analysis, GSEA analysis, western-blot, and PCR results indicate TRPM2 is highly correlated with PKC/MAPK pathways. The experiments of PKC/MEK inhibitors added to TRPM2 overexpressed BxPC-3 cell showed that significant inhibition of PA cells happened in CCK8, transwell, and wound-healing assay. TRPM2 may directly activate PKCα by calcium or indirectly activate PKCε and PKCδ by increased DAG in PA, which promote PA by downstream MAPK/MEK pathway activation.
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http://dx.doi.org/10.1038/s41419-021-03856-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184946PMC
June 2021

A global metagenomic map of urban microbiomes and antimicrobial resistance.

Cell 2021 Jun 26;184(13):3376-3393.e17. Epub 2021 May 26.

Weill Cornell Medicine, New York, NY, USA; The Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, NY, USA.

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.
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http://dx.doi.org/10.1016/j.cell.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238498PMC
June 2021

Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.

Breast Cancer Res 2021 May 1;23(1):53. Epub 2021 May 1.

State Key Laboratory of Genetic Engineering, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China.

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.
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http://dx.doi.org/10.1186/s13058-021-01428-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088670PMC
May 2021

The gut microbiome in subclinical atherosclerosis: a population-based multi-phenotype analysis.

Rheumatology (Oxford) 2021 Mar 26. Epub 2021 Mar 26.

State Key Laboratory of Genetic Engineering and Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China.

Background: The altered microbiota, considered as quantitative traits, has also been identified to play pivotal roles in the host vascular physiology and might contribute to diseases. To understand the role of gut microbiota on vascular physiology in the sub-clinical elderly population and how lifestyles affect the composition of host gut microbiota to further impact the pathogenesis of vascular diseases.

Methods: Performed a population-based fecal metagenomic study over 569 elderly asymptomatic sub-clinical individuals in rural China. An association network was built based on clinical measurements and detailed epidemiologic questionnaires, including blood chemistry, arterial stiffness, carotid ultrasonography, and metagenomic datasets.

Results: Carotid arterial atherosclerosis indices, including intima-media thickness (IMT), were shown essentially in the network, and were significantly associated with living habits, socio-economic status, and diet. Using mediation analysis, we found that higher frequency of taking fresh fruits, fresh vegetables, and more exercise significantly reduces carotid arteries atherosclerosis in terms of IMT, PSV and EDV values the through the mediation of Alistepes, Oligella, and Prevotella. The gut microbes explained 16.5% of the mediation effect of lifestyles on the pathogenesis of carotid atherosclerosis. After adjusted, Faecalicatena (OR = 0.20∼0.30) was shown protective in the formation of carotid athersclerosis independently, while Libanicoccus (OR = 2.39∼2.43) were hazardous to carotid arterial IMTs. KEGG/KO analyses revealed a loss of anti-inflammation function in IMT subjects.

Conclusions: Our study provided a Chinese population-wide phenotype-metagenomic network, revealing association and mediation effect of gut microbiota on carotid artery atherosclerosis, hinting at a therapeutic and preventive potential of microbiota in vascular diseases.
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http://dx.doi.org/10.1093/rheumatology/keab309DOI Listing
March 2021

Loss of retinoic acid receptor-related receptor alpha (Rorα) promotes the progression of UV-induced cSCC.

Cell Death Dis 2021 03 4;12(3):247. Epub 2021 Mar 4.

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.
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http://dx.doi.org/10.1038/s41419-021-03525-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933246PMC
March 2021

Inhibition of phospholipases suppresses progression of psoriasis through modulation of inflammation.

Exp Biol Med (Maywood) 2021 Jun 27;246(11):1253-1262. Epub 2021 Feb 27.

Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China.

Abnormal lipid metabolism is regarded as a crucial cause of psoriasis. The specific mechanism of how phospholipase PLA2G4B mediates local immune dysfunction and skin lesions remains unclear. The aim of this study was to explore the mechanisms of anti-psoriasis and immune suppression effect by inhibiting PLA2G4B in psoriasis progression. We successfully transfected si-PLA2G4B in a murine keratinocyte cell-line PAM212 to verify the effect of progression by PLA2G4B. The Imiquimod psoriasis mouse model was then successfully constructed, followed by emulsion wrapped PLA2G4B-siRNA applied to the skin lesions. The phenotype, pathology, immunofluorescence staining of PLA2G4B, IL17, CD3, and CD1b, and bulk transcriptome analysis were performed to decipher the effect and mechanism of si-PLA2G4B. Interfering with PLA2G4B significantly inhibited the proliferation and migration of PAM212. The interference of PLA2G4B showed a therapeutic effect on psoriasis, comparable to that of betamethasone. The phenotype and pathology revealed reduced keratinocytes in the si-PLA2G4B group compared to the model mice. Immunofluorescence showed that CD1b, CD3+ T cells, and IL17 were suppressed in the skin lesions. RNA-seq and deconvolution revealed that immune cells such as myeloid dendritic cell and T cell CD8+ naive were inactivated. Th17 reduce the release of inflammatory factors such as IL17 and IL36. Pathway analysis revealed the potential therapeutic mechanism involved in the inhibition of sphingolipid or ceramide secretion. This study verified the anti-psoriatic effect of using si-PLA2G4B. The immune response was alleviated after administration. This phospholipase inhibition-based therapy sheds light on the pharmaceutical potential against psoriasis.
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http://dx.doi.org/10.1177/1535370221993424DOI Listing
June 2021

Single-cell analysis reveals the intra-tumor heterogeneity and identifies MLXIPL as a biomarker in the cellular trajectory of hepatocellular carcinoma.

Cell Death Discov 2021 Jan 18;7(1):14. Epub 2021 Jan 18.

Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.

Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensable tool to explore the genetic characteristics of HCC at a more detailed level. In this study, we profiled the gene expression of single cells from human HCC tumor and para-tumor tissues using the Smart-seq 2 sequencing method. Based on differentially expressed genes, we identified heterogeneous subclones in HCC tissues, including five HCC and two hepatocyte subclones. We then carried out hub-gene co-network and functional annotations analysis followed pseudo-time analysis with regulated transcriptional factor co-networks to determine HCC cellular trajectory. We found that MLX interacting protein like (MLXIPL) was commonly upregulated in the single cells and tissues and associated with a poor survival rate in HCC. Mechanistically, MLXIPL activation is crucial for promoting cell proliferation and inhibits cell apoptosis by accelerating cell glycolysis. Taken together, our work identifies the heterogeneity of HCC subclones, and suggests MLXIPL might be a promising therapeutic target for HCC.
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http://dx.doi.org/10.1038/s41420-021-00403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814056PMC
January 2021

Comprehensive analysis of metastatic gastric cancer tumour cells using single-cell RNA-seq.

Sci Rep 2021 01 13;11(1):1141. Epub 2021 Jan 13.

Department of Oncology, Changhai Hospital, Second Military Medical University, No. 168 Changhai Road, Shanghai, 200433, China.

Gastric cancer (GC) is a leading cause of cancer-induced mortality, with poor prognosis with metastasis. The mechanism of gastric carcinoma lymph node metastasis remains unknown due to traditional bulk-leveled approaches masking the roles of subpopulations. To answer questions concerning metastasis from the gastric carcinoma intratumoural perspective, we performed single-cell level analysis on three gastric cancer patients with primary cancer and paired metastatic lymph node cancer tissues using single-cell RNA-seq (scRNA-seq). The results showed distinct carcinoma profiles from each patient, and diverse microenvironmental subsets were shared across different patients. Clustering data showed significant intratumoural heterogeneity. The results also revealed a subgroup of cells bridging the metastatic group and primary group, implying the transition state of cancer during the metastatic process. In the present study, we obtained a more comprehensive picture of gastric cancer lymph node metastasis, and we discovered some GC lymph node metastasis marker genes (ERBB2, CLDN11 and CDK12), as well as potential gastric cancer evolution-driving genes (FOS and JUN), which provide a basis for the treatment of GC.
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http://dx.doi.org/10.1038/s41598-020-80881-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806779PMC
January 2021

Mechanisms and Future of Non-Small Cell Lung Cancer Metastasis.

Front Oncol 2020 11;10:585284. Epub 2020 Nov 11.

School of Life Sciences, Fudan University, Shanghai, China.

Lung cancer, renowned for its fast progression and metastatic potency, is rising to become a leading cause of death globally. It has been long observed that lung cancer is particularly ept in spawning distant metastasis at its early stages, and it can readily colonize virtually any human organ. In recent years, cancer research has shed light on why lung cancer is endowed with its exceptional ability to metastasize. In this review, we will take a comprehensive look at the current research on lung cancer metastasis, including molecular pathways, anatomical features and genetic traits that make lung cancer intrinsically metastatic, as we go from lung cancer's general metastatic potential to the particular metastasis mechanisms in multiple organs. We highly concerned about the advanced discovery and development of lung cancer metastasis, indicating the importance of lung cancer specific gene mutations, heterogeneity or biomarker discovery, and discussing potential opportunities and challenges. We will also introduce some current treatments that targets certain metastatic strategies of non-small cell lung cancer (NSCLC). Advances made in these regards could be critical to our current knowledge base of lung cancer metastasis.
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http://dx.doi.org/10.3389/fonc.2020.585284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686569PMC
November 2020

Risk factors and socio-economic burden in pancreatic ductal adenocarcinoma operation: a machine learning based analysis.

BMC Cancer 2020 Nov 27;20(1):1161. Epub 2020 Nov 27.

Department of Anesthesiology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Background: Surgical resection is the major way to cure pancreatic ductal adenocarcinoma (PDAC). However, this operation is complex, and the peri-operative risk is high, making patients more likely to be admitted to the intensive care unit (ICU). Therefore, establishing a risk model that predicts admission to ICU is meaningful in preventing patients from post-operation deterioration and potentially reducing socio-economic burden.

Methods: We retrospectively collected 120 clinical features from 1242 PDAC patients, including demographic data, pre-operative and intra-operative blood tests, in-hospital duration, and ICU status. Machine learning pipelines, including Supporting Vector Machine (SVM), Logistic Regression, and Lasso Regression, were employed to choose an optimal model in predicting ICU admission. Ordinary least-squares regression (OLS) and Lasso Regression were adopted in the correlation analysis of post-operative bleeding, total in-hospital duration, and discharge costs.

Results: SVM model achieved higher performance than the other two models, resulted in an AU-ROC of 0.80. The features, such as age, duration of operation, monocyte count, and intra-operative partial arterial pressure of oxygen (PaO), are risk factors in the ICU admission. The protective factors include RBC count, analgesic pump dexmedetomidine (DEX), and intra-operative maintenance of DEX. Basophil percentage, duration of the operation, and total infusion volume were risk variables for staying in ICU. The bilirubin, CA125, and pre-operative albumin were associated with the post-operative bleeding volume. The operation duration was the most important factor for discharge costs, while pre-lymphocyte percentage and the absolute count are responsible for less cost.

Conclusions: We observed that several new indicators such as DEX, monocyte count, basophil percentage, and intra-operative PaO showed a good predictive effect on the possibility of admission to ICU and duration of stay in ICU. This work provided an essential reference for indication in advance to PDAC operation.
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http://dx.doi.org/10.1186/s12885-020-07626-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694304PMC
November 2020

Changes in plasma bile acids are associated with gallbladder stones and polyps.

BMC Gastroenterol 2020 Oct 31;20(1):363. Epub 2020 Oct 31.

Department of General Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Background: The development of gallbladder disease (GBD) is related to bile acid (BA) metabolism, and the rate of BA circulation increases the risk of biliary cancer. However, it is unclear whether patterns of circulating bile acids (BAs) change in patients with benign GBDs such as gallbladder stones and polyps. Herein, we compared and characterised plasma BA profiles in patients with cholecystolithiasis and non-neoplastic polyps with healthy controls, and explored relationships between plasma BA profiles, demographics, and laboratory test indices.

Methods: A total of 330 subjects (13 healthy controls, 292 cholecystolithiasis and 25 non-neoplastic polyps) were recruited and plasma BA profiles including 14 metabolites from patients with pathologically confirmed cholecystolithiasis and non-neoplastic polyps were compared with controls. BAs were quantitated by liquid chromatography and mass spectrometry, and statistical and regression analyses of demographics and laboratory test indices were performed.

Results: Females displayed a higher burden of GBD than males (63.36% cholecystolithiasis, 60% non-neoplastic polyps). Cholecystolithiasis and non-neoplastic polyps were associated with increased plasma total secondary BAs, while levels of primary BAs were lower than in healthy controls. Plasma ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycyurdeoxycholic acid (GUDCA), taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) were decreased significantly in GBDs, and ursodeoxycholic acid (UDCA) was negatively correlated with white blood cell count and neutrophil percentage.

Conclusions: Secondary BA levels were higher in patients with cholecystolithiasis and non-neoplastic polyps. White blood cell count and percentage of neutrophil in peripheral blood were negatively correlated with UDCA, indicating an anti-inflammation effect of UDCA.
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http://dx.doi.org/10.1186/s12876-020-01512-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603702PMC
October 2020

Lifestyle, multi-omics features, and preclinical dementia among Chinese: The Taizhou Imaging Study.

Alzheimers Dement 2021 01 10;17(1):18-28. Epub 2020 Aug 10.

State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China.

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.
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http://dx.doi.org/10.1002/alz.12171DOI Listing
January 2021

Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche.

Cell Biosci 2020 28;10:89. Epub 2020 Jul 28.

School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438 China.

For decades, cancer metastasis has been a heated topic for its high mortality. Previous research has shown that pre-metastatic niche and metastatic niche are the 2 crucial steps in cancer metastasis, assisting cancerous cells' infiltration, survival, and colonization at target sites. More recent studies have unraveled details about the specific mechanisms related to the modification of pro-invasion environments. Here, we will review literatures on extracellular matrix (ECM) alterations, general cancer metastasis, organ specificity, pre-metastatic niche, metastatic niche, colony formation and impact on the course of metastasis. Respectively, the metastatic mechanisms like effect of hypoxia or inflammation on pre-metastatic niche construction, as well as the interaction between cancer cells and local milieu will be discussed. Based on the evidences of metastatic niches, we revisit and discussed the "Seed and Soil" hypothesis by Paget. This review will seek to provide insight into the mechanism of metastatic organ specificity which pre-metastatic niche and metastatic niche might suggest from an evolutionary aspect.
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http://dx.doi.org/10.1186/s13578-020-00453-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388444PMC
July 2020

Transcriptomic analysis of the mechanisms of alleviating renal interstitial fibrosis using the traditional Chinese medicine Kangxianling in a rat model.

Sci Rep 2020 06 30;10(1):10682. Epub 2020 Jun 30.

School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, People's Republic of China.

Renal interstitial fibrosis (RIF) is currently recognized as a crucial mechanism of the pathogenesis of chronic kidney disease (CKD). Kangxianling (KXL, anti-fibrin) is a traditional Chinese medicine that has been proven to significantly reduce the levels of ECM deposition and inhibit renal fibrosis. To characterize the mechanisms and drug targets of KXL, we established a RIF rat model and treated the rats with KXL and losartan. Histological analyses validated the establishment of the RIF model and the treatment effect of KXL. Multiple levels of transcriptomic datasets were generated using lncRNA, mRNA and microRNA sequencing of kidney tissues. Functional annotations and pathway analyses were performed to unravel the therapeutic mechanisms. A multi-level transcriptomic regulatory network was built to illustrate the core factors in fibrosis pathogenesis and therapeutic regulation. KXL and losartan significantly reduced the progression of RIF, and a better therapeutic effect was shown with higher concentrations of KXL. According to the cluster analysis results of the RNA-seq data, the normal control (NC) and high concentration of KXL (HK) treatment groups were the closest in terms of differentially expressed genes. The WNT, TGF-β and MAPK pathways were enriched and dominated the pathogenesis and therapy of RIF. miR-15b, miR-21, and miR-6216 were upregulated and miR-107 was downregulated in the fibrosis model. These small RNAs were shown to play critical roles in the regulation of the above fibrosis-related genes and could be inhibited by KXL treatment. Finally, based on the lncRNA datasets, we constructed a mRNA-lncRNA-miRNA coexpression ceRNA network, which identified key regulatory factors in the pathogenesis of kidney fibrosis and therapeutic mechanisms of KXL. Our work revealed the potential mechanism of the Chinese medicine Kangxianling in inhibiting renal interstitial fibrosis and supported the clinical use of KXL in the treatment of kidney fibrosis.
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http://dx.doi.org/10.1038/s41598-020-67690-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327068PMC
June 2020

The progress of gut microbiome research related to brain disorders.

J Neuroinflammation 2020 Jan 17;17(1):25. Epub 2020 Jan 17.

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

There is increasing evidence showing that the dynamic changes in the gut microbiota can alter brain physiology and behavior. Cognition was originally thought to be regulated only by the central nervous system. However, it is now becoming clear that many non-nervous system factors, including the gut-resident bacteria of the gastrointestinal tract, regulate and influence cognitive dysfunction as well as the process of neurodegeneration and cerebrovascular diseases. Extrinsic and intrinsic factors including dietary habits can regulate the composition of the microbiota. Microbes release metabolites and microbiota-derived molecules to further trigger host-derived cytokines and inflammation in the central nervous system, which contribute greatly to the pathogenesis of host brain disorders such as pain, depression, anxiety, autism, Alzheimer's diseases, Parkinson's disease, and stroke. Change of blood-brain barrier permeability, brain vascular physiology, and brain structure are among the most critical causes of the development of downstream neurological dysfunction. In this review, we will discuss the following parts: Overview of technical approaches used in gut microbiome studiesMicrobiota and immunityGut microbiota and metabolitesMicrobiota-induced blood-brain barrier dysfunctionNeuropsychiatric diseases ■ Stress and depression■ Pain and migraine■ Autism spectrum disordersNeurodegenerative diseases ■ Parkinson's disease■ Alzheimer's disease■ Amyotrophic lateral sclerosis■ Multiple sclerosisCerebrovascular disease ■ Atherosclerosis■ Stroke■ Arteriovenous malformationConclusions and perspectives.
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http://dx.doi.org/10.1186/s12974-020-1705-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969442PMC
January 2020

Transcriptome Sequencing to Detect the Potential Role of Long Noncoding RNAs in Salt-Sensitive Hypertensive Rats.

Biomed Res Int 2019 6;2019:2816959. Epub 2019 Dec 6.

Department of Nephrology, Jing'an District Central Hospital of Shanghai Affiliated to Fudan University, No. 259, Xikang Road, Jing'an District, Shanghai 200000, China.

Backgrounds: Long noncoding RNAs (lncRNAs) play an important role in various biological processes. However, their functions in salt-sensitive hypertension are largely unknown. In this study, the lncRNA-seq technique was employed to compare the expression profiles of lncRNAs and mRNAs in salt-sensitive hypertensive rats.

Methods: Blood pressure, serum sodium, and urinary creatinine were texted in salt-sensitive and salt-insensitive rats fed with different salt concentrations. High-throughput sequencing was used to detect the expression of lncRNAs and mRNA in the renal medulla of the two groups.

Results: Blood pressure and urinary sodium/creatinine of high-salt diets of the sensitive group were significantly higher than that in the control group. Serum sodium has no significant difference between the two groups in high-salt diets. NONRATG007131.2 and NONRATG012674.2 were the most different lncRNAs in the high salt-sensitive group. Correlation analysis reveals that Matn1, Serpinb12, Anxa8, and Hspa5 may play an important role in salt-sensitive hypertension.

Conclusion: This study analyzed the difference in lncRNA and mRNA between salt-sensitive and salt-insensitive rats with different salt diets by high-throughput sequencing. Salt sensitivity and salt concentration were two key factors for the induction of hypertension. We found some potential genes that play an important role in salt-sensitive hypertension.
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http://dx.doi.org/10.1155/2019/2816959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925802PMC
May 2020

Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis.

Sci Adv 2019 06 19;5(6):eaav4275. Epub 2019 Jun 19.

Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.

Carcinoma cells undergo epithelial-mesenchymal transition (EMT); however, contributions of EMT heterogeneity to disease progression remain a matter of debate. Here, we addressed the EMT status of ex vivo cultured circulating and disseminated tumor cells (CTCs/DTCs) in a syngeneic mouse model of metastatic breast cancer (MBC). Epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation ability, whereas mesenchymal-type CTCs showed limited metastatic ability. EpCAM expression served as a surrogate marker to evaluate the EMT heterogeneity of clinical samples from MBC, including metastases, CTCs, and DTCs. The proportion of epithelial-type CTCs, and especially DTCs, correlated with distant metastases and poorer outcome of patients with MBC. This study fosters our understanding of EMT in metastasis and underpins heterogeneous EMT phenotypes as important parameters for tumor prognosis and treatment. We further suggest that EpCAM-dependent CTC isolation systems will underestimate CTC numbers but will quantify clinically relevant metastatic cells.
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http://dx.doi.org/10.1126/sciadv.aav4275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584608PMC
June 2019

Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia.

Hematology 2019 Dec;24(1):487-491

c School of Life Sciences, Fudan University , Shanghai , People's Republic of China.

Objectives: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied.

Methods: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets.

Results: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network.

Conclusion: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.
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http://dx.doi.org/10.1080/16078454.2019.1631506DOI Listing
December 2019

AMPK alleviates high uric acid-induced Na-K-ATPase signaling impairment and cell injury in renal tubules.

Exp Mol Med 2019 05 22;51(5):1-14. Epub 2019 May 22.

Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, People's Republic of China.

One of the mechanisms in hyperuricemia (HUA)-induced renal tubular injury is the impairment of Na-K-ATPase (NKA) signaling, which further triggers inflammation, autophagy, and mitochondrial dysfunction and leads to cell injury. Here, we used RNA sequencing to screen the most likely regulators of NKA signaling and found that the liver kinase B1(LKB1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway was the most abundantly enriched pathway in HUA. AMPK is a key regulator of cell energy metabolism; hence, we examined the effect of AMPK on HUA-induced dysregulation of NKA signaling and cell injury. We first detected AMPK activation in high uric acid (UA)-stimulated proximal tubular epithelial cells (PTECs). We further found that sustained treatment with the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), but not the AMPK inhibitor Compound C, significantly alleviated UA-induced reductions in NKA activity and NKA α1 subunit expression on the cell membrane by reducing NKA degradation in lysosomes; sustained AICAR treatment also significantly alleviated activation of the NKA downstream molecules Src and interleukin-1β (IL-1β) in PTECs. AICAR further alleviated high UA-induced apoptosis, autophagy, and mitochondrial dysfunction. Although AMPK activation by metformin did not reduce serum UA levels in hyperuricemic rats, it significantly alleviated HUA-induced renal tubular injury and NKA signaling impairment in vivo with effects similar to those of febuxostat. Our study suggests that AMPK activation may temporarily compensate for HUA-induced renal injury. Sustained AMPK activation could reduce lysosomal NKA degradation and maintain NKA function, thus alleviating NKA downstream inflammation and protecting tubular cells from high UA-induced renal tubular injury.
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http://dx.doi.org/10.1038/s12276-019-0254-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531502PMC
May 2019

Specific zinc finger-induced methylation of PD-L1 promoter inhibits its expression.

FEBS Open Bio 2019 06 14;9(6):1063-1070. Epub 2019 May 14.

Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, Shanghai, China.

DNA methylation of promoter regions is often associated with epigenetic silencing of gene expression, and DNA methyltransferase (DNMTs) has been used to suppress gene expression. In order to explore the synergistic roles of two methyltransferase members Dnmt3a and Dnmt1, we constructed expression plasmid that could express a recombinant DNMTs consisting of the C-terminal domains of both Dnmt3a and Dnmt1 fused to a zinc finger domain which binds to the PD-L1 promoter of human prostate cancer cells (DU145). Programmed death ligand 1 (PD-L1, B7-H1, CD-274) is a transmembrane protein widely expressed on antigen-presenting and other immune cells. The interaction of PD-L1 with its receptor PD-1 is considered an 'immune checkpoint' for possible cancer therapy. DU145 cells treated with the Dnmt3aC-1C plasmid showed significantly reduced expression of PD-L1 as compared to Dnmt3aC or Dnmt1C alone. Our results show that the fusion of Dnmt1 improves the methylation activity of Dnmt3a and enhances its biological functions. This combinatorial strategy can be used to better control PD-L1 expression to support cytotoxic T lymphocytes (CTL) response against tumors.
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http://dx.doi.org/10.1002/2211-5463.12568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551500PMC
June 2019

Comparison and development of machine learning tools in the prediction of chronic kidney disease progression.

J Transl Med 2019 04 11;17(1):119. Epub 2019 Apr 11.

Department of Nephrology, Huadong Hospital Affiliated To Fudan University, Shanghai, 200040, China.

Background: Urinary protein quantification is critical for assessing the severity of chronic kidney disease (CKD). However, the current procedure for determining the severity of CKD is completed through evaluating 24-h urinary protein, which is inconvenient during follow-up.

Objective: To quickly predict the severity of CKD using more easily available demographic and blood biochemical features during follow-up, we developed and compared several predictive models using statistical, machine learning and neural network approaches.

Methods: The clinical and blood biochemical results from 551 patients with proteinuria were collected. Thirteen blood-derived tests and 5 demographic features were used as non-urinary clinical variables to predict the 24-h urinary protein outcome response. Nine predictive models were established and compared, including logistic regression, Elastic Net, lasso regression, ridge regression, support vector machine, random forest, XGBoost, neural network and k-nearest neighbor. The AU-ROC, sensitivity (recall), specificity, accuracy, log-loss and precision of each of the models were evaluated. The effect sizes of each variable were analysed and ranked.

Results: The linear models including Elastic Net, lasso regression, ridge regression and logistic regression showed the highest overall predictive power, with an average AUC and a precision above 0.87 and 0.8, respectively. Logistic regression ranked first, reaching an AUC of 0.873, with a sensitivity and specificity of 0.83 and 0.82, respectively. The model with the highest sensitivity was Elastic Net (0.85), while XGBoost showed the highest specificity (0.83). In the effect size analyses, we identified that ALB, Scr, TG, LDL and EGFR had important impacts on the predictability of the models, while other predictors such as CRP, HDL and SNA were less important.

Conclusions: Blood-derived tests could be applied as non-urinary predictors during outpatient follow-up. Features in routine blood tests, including ALB, Scr, TG, LDL and EGFR levels, showed predictive ability for CKD severity. The developed online tool can facilitate the prediction of proteinuria progress during follow-up in clinical practice.
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http://dx.doi.org/10.1186/s12967-019-1860-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458616PMC
April 2019

RNA-seq analyses the effect of high-salt diet in hypertension.

Gene 2018 Nov 27;677:245-250. Epub 2018 Jul 27.

Department of Cardiology, Tongji Hospital of Tongji University, Shanghai, China. Electronic address:

Objectives: High-salt diet is one of the major risk factors in the development of hypertension. Previous studies have observed a relationship between high-salt induced blood pressure levels and cardiac-cerebral disease. However, the molecular mechanism of high-salt diet induced hypertension and the serious complications in cardiovascular system still remain unknown.

Materials And Methods: We built high-salt diet induced hypertension rat models, and investigated the transcriptomic alteration in four hypertension affected tissues, i.e. ventricle and atrium in heart as well as cortex and medulla in kidney. Differential expression gene (DEG) analysis and further functional annotation including Ingenuity Pathway Analysis (IPA) was performed to reveal the molecular mechanism of high-salt induced hypertension and organ injury.

Results: We observed that several genes associated with cardiovascular development and organ injury were significantly dysregulated rat fed with high-salt diet, such as Mmp-15, Igfbp7, Rgs18 and Hras. We demonstrated that differential expressed genes were functionally related to the increased levels of alkaline phosphatase (ALP).

Conclusion: Our study provided new insight about molecular mechanism of high-salt induced hypertension and heart and kidney damage.
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http://dx.doi.org/10.1016/j.gene.2018.07.069DOI Listing
November 2018

A Comprehensive Analysis of Gene Expression of Xenobiotic and Endogenous Metabolizing Enzymes and Transporters in Rat Multiple Organs.

Curr Pharm Biotechnol 2018 ;19(3):240-249

Center for Pharmacogenomics, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai 200438, China.

Background: Drug metabolizing enzymes and transporters (DMETs) play crucial roles in drug absorption and disposition. Species differences in the interaction of compounds with DMETs may contribute to the accuracy of animal models in predicting human responses in clinical studies. Thus it is important to clarify the expression heterogeneity of DMETs between human and rat, that is commonly used as a model for evaluating drug efficacy and drug safety.

Methods: We compared the expression patterns of DMETs based on a rat RNA-seq dataset and the human Genotype-Tissue Expression (GTEx) datasets. A relatively high correlation of expression of DMETs between rat and human was observed in most organs, while a lower correlation was detected in the liver and kidney; however, a greater number of genes were variably expressed in the latter two organs. We characterized the basal expression traits of DMETs in rat in terms of organ, sex, and developmental differences.

Results: Co-expressed modules across organs of DMETs were identified to include potential functionally- related genes. Interestingly, most of these modules showed liver- and/or kidney-specific expression. Moreover, we identified DMETs modules that were highly correlated to sex or developmental stages. Finally, we created networks containing sex and/or developmentally-related drugs and diseases with their related DMETs to display the clinical significance of sexually dimorphic and/or developmentally- specific DMET genes.

Conclusion: Our study provides a deeper understanding of species differences in not only DMETs but specific susceptibility to adverse drug reactions (ADRs).
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http://dx.doi.org/10.2174/1389201019666180525113727DOI Listing
October 2018

Advances in single-cell RNA sequencing and its applications in cancer research.

Oncotarget 2017 Aug 16;8(32):53763-53779. Epub 2017 May 16.

Center for Pharmacogenomics, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, 200438, China.

Unlike population-level approaches, single-cell RNA sequencing enables transcriptomic analysis of an individual cell. Through the combination of high-throughput sequencing and bioinformatic tools, single-cell RNA-seq can detect more than 10,000 transcripts in one cell to distinguish cell subsets and dynamic cellular changes. After several years' development, single-cell RNA-seq can now achieve massively parallel, full-length mRNA sequencing as well as sequencing and even has potential for multi-omic detection. One appealing area of single-cell RNA-seq is cancer research, and it is regarded as a promising way to enhance prognosis and provide more precise target therapy by identifying druggable subclones. Indeed, progresses have been made regarding solid tumor analysis to reveal intratumoral heterogeneity, correlations between signaling pathways, stemness, drug resistance, and tumor architecture shaping the microenvironment. Furthermore, through investigation into circulating tumor cells, many genes have been shown to promote a propensity toward stemness and the epithelial-mesenchymal transition, to enhance anchoring and adhesion, and to be involved in mechanisms of anoikis resistance and drug resistance. This review focuses on advances and progresses of single-cell RNA-seq with regard to the following aspects: 1. Methodologies of single-cell RNA-seq 2. Single-cell isolation techniques 3. Single-cell RNA-seq in solid tumor research 4. Single-cell RNA-seq in circulating tumor cell research 5.

Perspectives:
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http://dx.doi.org/10.18632/oncotarget.17893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581148PMC
August 2017

Lactobacillus plantarum LP‑Onlly alters the gut flora and attenuates colitis by inducing microbiome alteration in interleukin‑10 knockout mice.

Mol Med Rep 2017 Nov 24;16(5):5979-5985. Epub 2017 Aug 24.

Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China.

The association between inflammatory bowel disease (IBD) and gut microbes has been widely investigated. Our previous study demonstrated that Lactobacillus plantarum LP‑Onlly (LP) applied as a probiotic altered the gut flora and attenuated colitis in interleukin (IL)‑10 knockout (IL‑10‑/‑) mice. In the present study, metagenome sequencing was performed to investigate the gut microbiome in IL‑10‑/‑mice and the influence of oral administration of LP on microbial composition. Metagenomics sequencing was performed to investigate the influence of IBD on the gut microbiome with and without LP treatment. The alteration of the abundances of various taxonomic and functional groups were investigated across these gut microbiomes. The present study demonstrates that Akkermansia muciniphila was significantly enriched in IL‑10‑/‑ mice, and bacteroides were significantly increased following LP administration. In addition, the phylum Bacteroidetes and Firmicutes were significantly influenced by LP administration. Further characterization of functional capacity revealed that in the gut metagenomes of IL‑10‑/‑mice, genes encoding cell cycle control, replication, recombination, repair and cell envelope biogenesis were decreased, but intracellular trafficking, secretion, and vesicular transport were increased. The present findings indicate that the gut metagenome is associated with IBD, and oral administration of LP contributes to prevention of gut inflammation, providing insight into the treatment of IBD.
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http://dx.doi.org/10.3892/mmr.2017.7351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865777PMC
November 2017

Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients.

Sci Rep 2017 07 10;7(1):4951. Epub 2017 Jul 10.

Center for Pharmacogenomics, School of Pharmacy and Shanghai Cancer Center, Fudan University, Shanghai, China.

Recent genome-sequencing studies have revealed dozens of genes frequently mutated in esophageal squamous cell carcinoma, but few genes are associated with patients' clinical outcomes. Novel prognostic biomarkers are urgently needed in the clinic. We collected both somatic mutations and clinical information of 442 Chinese esophageal squamous cell carcinoma patients from four published studies. Survival analysis was performed to reveal the clinical significance of the mutated genes. Dysregulation of the mutated genes was observed from public gene-expression data sets and its effects on cell migration and invasion were investigated with siRNA-mediated silencing. Our integrated analysis revealed 26 genes significantly and frequently mutated in esophageal squamous cell carcinoma. Importantly, mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor survival. In addition, ZFHX4 was overexpressed in tumor tissues compared to normal controls, and knockdown of ZFHX4 in vitro significantly inhibited cell migration and invasion. Mutations in ZFHX4 were strongly associated with poor prognosis and the down-regulation of ZFHX4 inhibits the progression of esophageal squamous cell carcinoma. Further investigation is warranted to confirm the prognostic values of ZFHX4 in a prospective study.
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http://dx.doi.org/10.1038/s41598-017-04221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504002PMC
July 2017

Expression profiling and functional annotation of noncoding genes across 11 distinct organs in rat development.

Sci Rep 2016 12 9;6:38575. Epub 2016 Dec 9.

College of Chemistry, Sichuan University, Chengdu 610064, China.

Accumulating evidence suggests that noncoding RNAs (ncRNAs) have important regulatory functions. However, lacking of functional annotations for ncRNAs hampered us from carrying out the subsequent functional or predictive research. Here we dissected the expression profiles of 3,458 rat noncoding genes using rat bodymap RNA-sequencing data consisting of 11 solid organs over four developmental stages (juvenile, adolescent, adult and aged) from both sexes, and conducted a comprehensive analysis of differentially expressed noncoding genes (DEnGs) between various conditions. We then constructed a co-expression network between protein-coding and noncoding genes to infer biological functions of noncoding genes. Modules of interest were linked to online databases including DAVID for functional annotation and pathway analysis. Our results indicated that noncoding genes are functionally enriched through pathways similar to those of protein-coding genes. Terms about development of the immune system were enriched with genes from age-related modules, whereas terms about sexual reproduction were enriched with genes in sex-related modules. We also built connection networks on some significant modules to visualize the interactions and regulatory relationship between protein-coding and noncoding genes. Our study could improve our understanding and facilitate a deeper investigation on organ/age/sex-related regulatory events of noncoding genes, which may lead to a superior preclinical model for drug development and translational medicine.
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http://dx.doi.org/10.1038/srep38575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146941PMC
December 2016

Identification of Tissue-Specific Protein-Coding and Noncoding Transcripts across 14 Human Tissues Using RNA-seq.

Sci Rep 2016 06 22;6:28400. Epub 2016 Jun 22.

Center for Pharmacogenomics, School of Pharmacy, and State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 201203, China.

Many diseases and adverse drug reactions exhibit tissue specificity. To better understand the tissue-specific expression characteristics of transcripts in different human tissues, we deeply sequenced RNA samples from 14 different human tissues. After filtering many lowly expressed transcripts, 24,729 protein-coding transcripts and 1,653 noncoding transcripts were identified. By analyzing highly expressed tissue-specific protein-coding transcripts (TSCTs) and noncoding transcripts (TSNTs), we found that testis expressed the highest numbers of TSCTs and TSNTs. Brain, monocytes, ovary, and heart expressed more TSCTs than the rest tissues, whereas brain, placenta, heart, and monocytes expressed more TSNTs than other tissues. Co-expression network constructed based on the TSCTs and TSNTs showed that each hub TSNT was co-expressed with several TSCTs, allowing functional annotation of TSNTs. Important biological processes and KEGG pathways highly related to the specific functions or diseases of each tissue were enriched with the corresponding TSCTs. These TSCTs and TSNTs may participate in the tissue-specific physiological or pathological processes. Our study provided a unique data set and systematic analysis of expression characteristics and functions of both TSCTs and TSNTs based on 14 distinct human tissues, and could facilitate future investigation of the mechanisms behind tissue-specific diseases and adverse drug reactions.
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http://dx.doi.org/10.1038/srep28400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916594PMC
June 2016
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