Publications by authors named "Chun-Kui Shao"

68 Publications

EBV-Induced CXCL8 Upregulation Promotes Vasculogenic Mimicry in Gastric Carcinoma NF-κB Signaling.

Front Cell Infect Microbiol 2022 7;12:780416. Epub 2022 Mar 7.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2022.780416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936189PMC
April 2022

ebv-circRPMS1 promotes the progression of EBV-associated gastric carcinoma via Sam68-dependent activation of METTL3.

Cancer Lett 2022 06 15;535:215646. Epub 2022 Mar 15.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China. Electronic address:

Epstein-Barr virus (EBV) is a tumor virus that is associated with a variety of neoplasms, including EBV-associated gastric carcinoma (EBVaGC). Recently, EBV was reported to generate various circular RNAs (circRNAs). CircRNAs are important regulators of tumorigenesis by modulating the malignant behaviors of tumor cells. However, to date, the functions of ebv-circRNAs in EBVaGC remain poorly understood. In the present study, we observed high ebv-circRPMS1 expression in EBVaGC and showed that ebv-circRPMS1 promoted the proliferation, migration, and invasion and inhibited the apoptosis of EBVaGC cells. In addition, METTL3 was upregulated in GC cells overexpressing ebv-circRPMS1. Mechanistically, ebv-circRPMS1 bound to Sam68 to facilitate its physical interaction with the METTL3 promotor, resulting in the transactivation of METTL3 and cancer progression. In clinical EBVaGC samples, ebv-circRPMS1 was associated with distant metastasis and a poor prognosis. Based on these findings, ebv-circRPMS1 contributed to EBVaGC progression by recruiting Sam68 to the METTL3 promoter to induce METTL3 expression. ebv-circRPMS1, Sam68, and METTL3 might serve as therapeutic targets for EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2022.215646DOI Listing
June 2022

Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway.

Cancer Lett 2022 02 2;526:259-272. Epub 2021 Dec 2.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.11.031DOI Listing
February 2022

Liver involvement in patients with erythropoietic protoporphyria: retrospective analysis of clinicopathological features of 5 cases.

Ann Diagn Pathol 2022 Feb 17;56:151859. Epub 2021 Nov 17.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China. Electronic address:

Erythropoietic protoporphyria (EPP) is a rare inherited disease whose morbidity is about 1:75,000 to 1:200,000. It is caused by the deficiency of porphyrin ferrochelatase (FECH). Liver involvement in EPP is even rarer. The diagnosis of EPP with liver involvement mainly relies on clinical manifestations, laboratory examinations, histopathological examinations and genetic testing, which is still a huge challenge for both clinicians and pathologists. Here, 5 cases of EPP with liver injury were collected, and the clinicopathological features of these patients were analyzed. The clinical manifestations and laboratory examinations varied from person to person, whereas the liver biopsies showed that there were dark brown deposits within the hepatocytes, Kupffer cells, bile canaliculi and the lumen of bile ducts, which was a constant finding by histopathological examination. Gene tests were conducted in two of the five cases, and the results confirmed the diagnosis. Fully understanding of the diseases can help us reduce the rate of missed diagnosis and provide proper treatment as early as possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2021.151859DOI Listing
February 2022

Comparative Transcriptome Provides a Systematic Perspective on Epstein-Barr Virus-Associated Gastric Carcinoma Cell Lines.

Onco Targets Ther 2021 23;14:5169-5182. Epub 2021 Oct 23.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

Purpose: Epstein-Barr virus (EBV) is widely recognised to cause various tumours, and EBV-associated gastric carcinoma (EBVaGC) is a special type of GC. It has obviously different clinical features and pathological manifestations from EBV-negative gastric carcinoma, but its progression remains elusive. The underlying cancer progression of viral infection detected by genome-wide transcriptome analysis has been demonstrated in numerous diseases.

Methods: We performed comparative RNA sequencing to identify gene expression signatures between GC and EBVaGC cell lines. The differentially expressed (DE) genes were analysed using gene ontology and pathway enrichment.

Results: A total of 4438 DE mRNAs, 3650 DE long non-coding RNAs (lncRNAs), and 248 DE circular RNAs (circRNAs) were detected in GC cells after EBV infection, most of which were highly related to oncogenesis. Likewise, EBV-coding RNA and non-coding RNA were also well-supplemented in EBVaGC. According to bioinformatics, DE mRNAs may contribute to the completion of EBV-infected host cells and modulate mitosis. Binding to actin and participating in adherens junctions to promote contact between the virus and cells are a potential function of DE lncRNAs. The roles of DE circRNAs were enriched in DNA repair and protein modification, and a typical example of this is acting as an miRNA sponge. The establishment of a circRNA-miRNA-mRNA network helps to determine the key elements in the progression of EBVaGC.

Conclusion: This study is the first to systematically reveal the transcriptome landscape of EBVaGC, which will provide an essential resource for genomic, genetic, and molecular mechanisms in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S332513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550799PMC
October 2021

A urine extracellular vesicle circRNA classifier for detection of high-grade prostate cancer in patients with prostate-specific antigen 2-10 ng/mL at initial biopsy.

Mol Cancer 2021 07 23;20(1):96. Epub 2021 Jul 23.

Department of Urology, The Third Affiliated Hospital, Sun Yat-Sen University, Tianhe Road 600, Guangzhou, 510630, China.

The aim of this study was to identify a urine extracellular vesicle circular RNA (circRNA) classifier that could detect high-grade prostate cancer (PCa) of Grade Group (GG) 2 or greater. For this purpose, we used RNA sequencing to identify candidate circRNAs from urinary extracellular vesicles from 11 patients with high-grade PCa and 11 case-matched patients with benign prostatic hyperplasia. Using ddPCR in a training cohort (n = 263), we built a urine extracellular vesicle circRNA classifier (Ccirc, containing circPDLIM5, circSCAF8, circPLXDC2, circSCAMP1, and circCCNT2), which was evaluated in two independent cohorts (n = 497, n = 505). Ccirc showed higher accuracy than two standard of care risk calculators (RCs) (PCPT-RC 2.0 and ERSPC-RC) in both the training cohort and the validation cohorts. In all three cohorts, this novel urine extracellular vesicle circRNA classifier plus RCs was statistically more predictive than RCs alone for predicting ≥ GG2 PCa. This assay, which does not require precollection digital rectal examination nor special handling, is repeatable, noninvasive, and can be easily implemented as part of the basic clinical workflow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-021-01388-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299620PMC
July 2021

α-Fetoprotein mRNA in situ hybridisation is a highly specific marker of hepatocellular carcinoma: a multi-centre study.

Br J Cancer 2021 06 6;124(12):1988-1996. Epub 2021 Apr 6.

Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC.

Methods: Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC.

Results: AFP RNAscope improved the HCC detection sensitivity by 24.7-32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions.

Conclusions: AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01363-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184895PMC
June 2021

Preoperative identification of microvascular invasion in hepatocellular carcinoma by XGBoost and deep learning.

J Cancer Res Clin Oncol 2021 Mar 27;147(3):821-833. Epub 2020 Aug 27.

Organ Transplantation Research Center of Guangdong Province, Guangzhou, 510630, Guangdong, China.

Purpose: Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively.

Methods: In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models.

Results: Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923-0.973) and 0.980 (95% CI 0.959-0.993), respectively (p = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797-0.947) and 0.906 (95% CI 0.821-0.960), respectively (p = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p = 0.027).

Conclusion: The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-020-03366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873117PMC
March 2021

Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer.

EMBO Rep 2020 10 12;21(10):e49689. Epub 2020 Aug 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Cancer stem cells (CSCs) are cancer-initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44 CD24 cells. In SNU-4th cells, an EBV-encoded circRNA, ebv-circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.201949689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534631PMC
October 2020

EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway.

Cell Oncol (Dordr) 2020 Oct 12;43(5):901-913. Epub 2020 Jun 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China.

Purpose: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBV-associated tumors worldwide. To date, 44 mature EBV-encoded microRNAs (EBV miRNAs) have been identified, but their roles in EBVaGC development are still poorly understood. In this study, we aimed to investigate the roles and targets of ebv-miR-BART10-3p (BART10-3p) and ebv-miR-BART22 (BART22) in EBVaGC.

Methods: EBV miRNA expression in EBVaGCs was evaluated by deep sequencing and qRT-PCR, and relationships between BART10-3p or BART22 expression and clinicolpathological characteristics and survival rates of patients with EBVaGC were analyzed. The roles of BART10-3p and BART22 and their underlying mechanisms were further investigated through exogenous overexpression or silencing in EBVaGC cells, and validated in clinical EBVaGC tissue samples.

Results: BART10-3p and BART22 were found to be highly expressed in the EBVaGC cell lines SNU719 and YCCEL1. Higher expression of BART10-3p or BART22 in primary EBVaGC samples was significantly associated with lymph node metastasis and a worse 5-year overall survival. BART10-3p and BART22 promoted cell migration and invasion by targeting adenomatous polyposis coli (APC) and Dickkopf 1 (DKK1), thereby activating the Wnt signaling pathway and, consequently, upregulating downstream Twist and downregulating downstream E-cadherin. In 874 primary gastric carcinoma samples, APC and DKK1 were found to be lower expressed in EBVaGC than in EBV-negative samples, and their expression levels were inversely correlated with those of BART10-3p and BART22 in 71 EBVaGC samples.

Conclusions: From our data we conclude that BART10-3p and BART22 play vital roles in promoting EBVaGC metastasis by targeting APC and DKK1 and, subsequently, activating the Wnt signaling pathway, thereby providing novel prognostic biomarkers and potential therapeutic targets for EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13402-020-00538-0DOI Listing
October 2020

A CpG Methylation Classifier to Predict Relapse in Adults with T-Cell Lymphoblastic Lymphoma.

Clin Cancer Res 2020 07 31;26(14):3760-3770. Epub 2020 Mar 31.

Department of Hematology, Jiangxi Provincial Cancer Hospital, Nanchang, P.R. China.

Purpose: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens.

Experimental Design: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort ( = 160). The four-CpG classifier was validated in the internal testing cohort ( = 68) and independent validation cohort ( = 321).

Results: The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk ( < 0.001). This classifier also showed good predictive value in the internal testing cohort ( < 0.001) and the independent validation cohort ( < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and / status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation.

Conclusions: Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-4207DOI Listing
July 2020

A gene-expression-based signature predicts survival in adults with T-cell lymphoblastic lymphoma: a multicenter study.

Leukemia 2020 09 20;34(9):2392-2404. Epub 2020 Feb 20.

Department of Hematology, Jiangxi Provincial Cancer Hospital, Nanchang, PR China.

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565-6.628; p < 0.001), disease-free survival (DFS: HR 3.148, 95% CI 1.857-5.339; p < 0.001), and overall survival (OS: HR 3.790, 95% CI 2.237-6.423; p < 0.001) compared with low-risk patients. The prognostic accuracy of the classifier was validated in the internal testing (n = 84) and independent validation cohorts (n = 360). A prognostic nomogram consisting of five independent variables including the classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement, and NOTCH1/FBXW7 status showed significantly greater prognostic accuracy than each single variable alone. The addition of a five-miRNA-based signature further enhanced the accuracy of this nomogram. Furthermore, patients with a nomogram score ≥154.2 significantly benefited from the BFM protocol. In conclusion, our nomogram comprising the 11-gene-based classifier may make contributions to individual prognosis prediction and treatment decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0757-5DOI Listing
September 2020

Improving pathological early diagnosis and differential biomarker value for hepatocellular carcinoma via RNAscope technology.

Hepatol Int 2020 Jan 12;14(1):96-104. Epub 2019 Dec 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, People's Republic of China.

Background: The diagnostic and prognostic values of glypican3 (GPC3) and glutamine synthetase (GS) proteins in hepatocellular carcinoma (HCC) have been reported, but their specificity and sensitivity remain low. Here, we applied RNAscope to improve HCC early pathological and differential diagnosis by estimating GPC3 and GS mRNAs.

Methods: We performed RNAscope and immunohistochemistry (IHC) to detect GPC3 and GS biomarkers on the tissue sections of 194 cases, including high- and low-grade liver dysplastic nodules; highly, moderately, and poorly differentiated HCCs; intrahepatic cholangiocarcinomas (ICCs); metastatic HCC; and carcinomas from other organs.

Results: The results showed that all the cases that were negative for GPC3 by RNAscope were also negative for this protein by IHC. The use of RNAscope assay improved the GPC3 and GS specificity and sensitivity by 20-30%. Hence, HCC shows early recognition and upgrades the metastatic HCC differentiation by 23% compared with IHC (p = 0.0001, 0.0064). Meanwhile, all liver cirrhosis, cholangiocytes and non-HCC samples were negative for GPC3 and GS except lymphocytes in lymphomas, and 2 (8.3%) out of the 24 ICC samples but not in the cancer cells.

Conclusion: RNAscope for GPC3 and GS panel was highly specific and sensitive for the pathological identification of dysplastic nodules, early stages of HCCs, and would differentiate them from HCCs and metastatic tumors compared with IHC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12072-019-10006-zDOI Listing
January 2020

Differential expression of HER2 and downstream proteins in prediction of advanced tumor phenotypes and overall survival of patients with Epstein-Barr virus-positive vs. negative gastric cancers.

Pathol Res Pract 2019 Nov 27;215(11):152675. Epub 2019 Sep 27.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. Electronic address:

This study evaluated the associations of HER2 protein, HER2 gene amplification, and positivity for p-AKT, p-ERK, and p-PLCγ proteins with clinicopathological status and overall survival (OS) of patients who had Epstein-Barr virus-associated gastric cancer (EBVaGC; n = 58) or EBV-negative GC (EBVnGC; n = 329). Tissue samples were subjected to immunohistochemistry and fluorescence in situ hybridization (FISH). Results showed that EBVaGC less expressed HER2 and amplified HER2 gene. p-AKT (p =  0.035) and p-ERK (p =  0.001) were inhibited in EBVaGC than in EBVnGC, while p-PLCγ (p =  0.034) was upregulated. Among EBVaGC patients, p-ERK positivity was associated with Lauren classification (p = 0.023), and p-PLCγ positivity was inversely associated with TNM stage (p = 0.041) and lymph node metastasis (p = 0.041). In contrast, among EBVnGC patients, HER2 expression was associated with distant metastasis (p = 0.043) and p-AKT positivity was associated with intestinal subtype (p < 0.004), lymph node metastasis (p = 0.031), distant metastasis (p < 0.001), and elder age (>60y, p < 0.004). Overall analysis showed that EBVaGC patients presented better OS than EBVnGC patients (p = 0.044). Among EBVaGC patients, p-AKT positivity (p = 0.008) was associated with worse OS; as well as, HER2 high expression (p < 0.001), p-AKT positivity (p = 0.010), and p-PLCγ (p <  0.001) were associated with worse OS in EBVnGC patients. Multivariate analysis showed that distant metastasis (95% CI: 1.559 to 4.028, p <  0.001), HER2 high expression (95% CI: 1.058 to 2.454, p =  0.026), and p-PLCγ positivity (95% CI: 1.056 to 2.435, p = 0.027) were independent prognostic predictors of OS in EBVnGC patients. Our results indicated that p-AKT positive patients presented worse OS than p-AKT negative ones in EBVaGC, as well as, HER2, p-AKT, and p-PLCγ are prognostic biomarkers for OS in EBVnGC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2019.152675DOI Listing
November 2019

Prognostic and predictive value of a microRNA signature in adults with T-cell lymphoblastic lymphoma.

Leukemia 2019 10 5;33(10):2454-2465. Epub 2019 Apr 5.

Department of Hematology, Shunde Hospital of Southern Medical University, Shunde, China.

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0466-0DOI Listing
October 2019

The roles of EBV-encoded microRNAs in EBV-associated tumors.

Crit Rev Oncol Hematol 2019 Mar 25;135:30-38. Epub 2019 Jan 25.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China. Electronic address:

Epstein-Barr virus (EBV) is believed to be a pathogen causing a number of human cancers, but the pathogenic mechanisms remain unclear. An increasing number of studies have indicated that EBV-encoded microRNAs (EBV miRNAs) are expressed in a latency type- and tumor type-dependent manner, playing important roles in the development and progression of EBV-associated tumors. By targeting one or more genes of the virus and the host, EBV miRNAs are responsible for the deregulation of a variety of viral and host cell biological processes, including viral replication, latency maintenance, immune evasion, cell apoptosis and metabolism, and tumor proliferation and metastasis. In addition, some EBV miRNAs can be used as excellent diagnostic, prognostic and treatment efficacy predictive biomarkers for EBV-associated tumors. More importantly, EBV miRNA-targeting therapeutics have emerged and have been developing rapidly, which may open a new era in the treatment of EBV-associated tumors in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2019.01.014DOI Listing
March 2019

Identification of virus-encoded circular RNA.

Virology 2019 03 16;529:144-151. Epub 2019 Jan 16.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

Circular RNAs (circRNAs) are a novel class of non-coding RNA molecules in eukaryotic organisms that have potentially important roles in gene regulation. Nevertheless, whether viruses can encode circRNA is still uncertain. To examine whether large genome DNA viruses can generate circRNA during the infection of human cells, we performed RNA sequencing of ribosomal RNA-depleted total RNA from Epstein-Barr virus (EBV)-infected cell lines, including SNU-719, AGS-EBV, C666-1 and Akata. We identified an EBV-encoded circRNA, ebv_circ_RPMS1, that consists of the head-to-tail splicing of exons 2-4 from the RPMS1 gene. Furthermore, we demonstrated that ebv_circ_RPMS1 was localized in both cytoplasm and nuclei. Given that circRNAs shape gene expression by titrating microRNAs, regulating transcription and/or interfering with splicing, we identified a novel viral regulator of host and/or viral gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2019.01.014DOI Listing
March 2019

The implication of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric carcinoma.

Hum Pathol 2019 03 15;85:82-91. Epub 2018 Nov 15.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity that has conspicuously inflammatory infiltration compared with EBV-negative gastric carcinoma. To date, the local immune status in EBVaGC and its relationship with patient prognosis and apoptosis of tumor cells are largely unknown. In this study, we evaluated the density of different types of tumor-infiltrating lymphocytes (TILs) in 53 EBVaGCs and 67 EBV-negative gastric carcinomas and analyzed its relationship with patient outcomes and apoptosis of tumor cells in EBVaGC. The average number of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, CD56+ natural killer cells, Fascin+ dendritic cells (DCs), and FoxP3+ Tregs and the average proportions of Ki-67, interleukin 1β, granzyme B, interferon γ, and interleukin 10 in TILs were higher in EBVaGC, and CD8+ T cells were the predominant constituent cells of TILs in EBVaGC. Patients with higher numbers of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs survived longer in EBVaGC, and CD8+ T cells and Fascin+ DCs were independent prognostic factors for patient survival. Besides, CD8+ T cells were positively correlated with apoptotic index of tumor cells. However, the apoptosis of tumor cells was lower, and the expression of survivin and NF-κBp65 in tumor cells was up-regulated in EBVaGC. These findings suggested that CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs predict a better prognosis in EBVaGC; CD8+ T cells might through a nonapoptotic pathway eliminate tumor cells, thereby improving the patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.11.002DOI Listing
March 2019

Determination and genome-wide analysis of Epstein-Barr virus (EBV) sequences in EBV-associated gastric carcinoma from Guangdong, an endemic area of nasopharyngeal carcinoma.

J Med Microbiol 2018 Nov 21;67(11):1614-1627. Epub 2018 Sep 21.

1​Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No.600 Tianhe Road, Guangzhou 510630, PR China.

About 10 % of gastric carcinoma worldwide is associated with EBV, which is defined as EBV-associated gastric carcinoma (EBVaGC). To date, EBV sequence data from EBVaGC in Guangdong, China, an endemic area of nasopharyngeal carcinoma (NPC), are not available. In the present study, two EBV genomes from EBVaGC specimens from Guangdong (designated as GDGC1 and GDGC2) were determined by next-generation sequencing, de novo assembly and joining of contigs by Sanger sequencing. In addition, we sequenced EBV from two Korean EBVaGC cell lines, YCCEL1 and SNU-719. Genomic diversity, including single nucleotide polymorphisms (SNPs) and insertions and deletions (indels), phylogenetic analysis and rates of protein evolution, was performed using bioinformatics software. The four gastric carcinoma-derived EBV (GC-EBV) were all type I. Compared with the reference EBV genome, a total of 1815 SNPs (146 indels), 1519 SNPs (106 indels), 1812 SNPs (126 indels) and 1484 SNPs (106 indels) were found in GDGC1, GDGC2, YCCEL1 and SNU-719, respectively. These variations were distributed across the entire genome, especially in latent genes. In contrast, the sequences of promoters and non-coding RNAs were strictly conserved. Phylogenetic analyses suggested the presence of at least two parental lineages of EBV among the GC-EBV genomes. Rates of protein evolution analyses showed that lytic genes were under purifying selection; in contrast, latency genes were under positive selection. In conclusion, this study determined the EBV genomes in EBVaGC from Guangdong and performed a detailed genome-wide analysis of GC-EBV, which would be helpful for further understanding of the relationship between EBV genomic variation and EBVaGC carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1099/jmm.0.000839DOI Listing
November 2018

Expression of CCL21 by EBV-associated gastric carcinoma cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway.

Pathology 2018 Oct 24;50(6):613-621. Epub 2018 Aug 24.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

About 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV), which are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are usually accompanied by massive lymphocytes infiltration, among which CD8 T cells are predominant. To date, the apoptosis of the infiltrating CD8 T cells in EBVaGC has not been investigated. In the present study, we assessed the immunophenotype and apoptosis of tumour infiltrating lymphocytes (TILs) in both EBVaGC and EBV-negative gastric carcinoma (EBVnGC). We found that CD8CCR7 T lymphocytes were increased in EBVaGC compared to EBVnGC [60.53 ± 28.41/high power fields (HPF) vs 19.63 ± 15.97/HPF; p < 0.001]. Moreover, the apoptosis index of TILs was lower in EBVaGC than that in EBVnGC (1.34 ± 0.90 vs 5.94 ± 3.77; p < 0.001). Given that the CCL21-CCR7 axis is reported to be potentially involved in apoptosis, we examined the expression of CCL21 in both EBVaGC and EBVnGC. We found that CCL21 expression was higher in EBVaGC than in EBVnGC (p < 0.001). We also showed that the expression of CCL21 by EBVaGC cells protected CD8CCR7 T lymphocytes from apoptosis. Furthermore, the up-regulation of Bcl-2 contributed to the inhibition of apoptosis in CD8CCR7 T cells. Collectively, these findings suggest that expression of CCL21 by EBVaGC cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway. To our best knowledge, this is the first study to investigate the apoptosis of CD8 T cells in EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pathol.2018.05.004DOI Listing
October 2018

Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis.

J Clin Invest 2018 08 9;128(8):3425-3438. Epub 2018 Jul 9.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Cancer progression is associated with alterations of intra- and extramedullary hematopoiesis to support a systemic tumor-promoting myeloid response. However, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. Here, we showed that the heightened splenic myelopoiesis in tumor-bearing hosts was not only characterized by the accumulation of myeloid precursors, but also associated with profound functional alterations of splenic early hematopoietic stem/progenitor cells (HSPCs). With the distinct capability to produce and respond to granulocyte-macrophage CSF (GM-CSF), these splenic HSPCs were "primed" and committed to generating immunosuppressive myeloid cells. Mechanistically, the CCL2/CCR2 axis-dependent recruitment and the subsequent local education by the splenic stroma were critical for eliciting this splenic HSPC response. Selective abrogation of this splenic EMH was sufficient to synergistically enhance the therapeutic efficacy of immune checkpoint blockade. Clinically, patients with different types of solid tumors exhibited increased splenic HSPC levels associated with poor survival. These findings reveal a unique and important role of splenic hematopoiesis in tumor-associated myelopoiesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI97973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063469PMC
August 2018

Collapsin response mediator protein 4 promotor methylation level as a potential predictor for diagnosing primary malignant lymphoma of the prostate.

Cancer Cell Int 2018 4;18. Epub 2018 Jan 4.

Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630 China.

Background: Primary malignant lymphoma of the prostate (PMLP) is prone to occur in the elderly, and it has no significant correlation with lactate dehydrogenase (LDH) and prostate specific antigen (PSA). Clinical symptoms and imaging data of PMLP remain unspecific, and its prognosis is poor. A previous result showed that collapsin response mediator protein 4 (CRMP4) promotor methylation can be used as a predictor for lymph node metastases in prostate biopsies. However, the relationship between CRMP4 promotor methylation and PMLP has not been studied.

Methods: We investigated the clinicopathological features of PMLP and the significance of CRMP4 methylation in PMLP. The clinical data and diagnosis information of 10 patients with PMLP were retrospectively analyzed. The CRMP4 promotor methylation level in paraffin-embedded tissues of the 10 patients with PMLP were determined and then compared to limited prostate cancer (LPCa) and its negative lymph node tissue [LPCa-LN (-) (10 cases)] and also to metastatic prostate adenocarcinoma (mPCa) and its positive lymph node tissue [mPCa-LN (+) (10 cases)]. Methylation of the CRMP4 promotor in each group was analyzed statistically. A receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of CRMP4 methylation in PMLP.

Results: The average methylation value of CRMP4 in 10 PMLP patients, 20 cases of prostate adenocarcinoma tissue, 10 cases LPCa-LN (-) and 10 cases mPCa-LN (+) were 42.3, 30.6, 6.7 and 20.3%, respectively. A Kruskal-Wallis test showed that the difference of CRMP4 methylation was significant (X = 38.0, P < 0.001). An ROC curve analysis found that CRMP4 methylation > 40.9% could diagnose PMLP. This method had 90% sensitivity and 95% specificity under conditions of CRMP4 methylation > 40.9%. The area under the curve (AUC) was 0.957.

Conclusions: Methylation of the CRMP4 gene was significantly increased in PMLP, and it is expected to become a new predictor for PMLP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-017-0484-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753574PMC
January 2018

Expression pattern of cancer-associated fibroblast and its clinical relevance in intrahepatic cholangiocarcinoma.

Hum Pathol 2017 07 27;65:92-100. Epub 2017 Apr 27.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. Electronic address:

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and lack of effective treatment, characterized by dense desmoplastic stroma rich in cancer-associated fibroblasts (CAFs), which have been indicated to facilitate tumor progression in several types of human cancer. However, the clinical relevance of CAFs in ICC has not been fully characterized. Here, we evaluated the histological phenotype of CAFs and immunohistochemical expressions of α-SMA, FSP-1, and PDGFRβ in 71 ICC cases, and found that immature CAF phenotype was significantly associated with lymph node metastasis (P=.045), advanced TNM stage (P=.025) and poor 5-year overall survival (OS) (38.5% versus 78.6%, P=.015). In addition, α-SMA, FSP-1, and PDGFRβ were positively expressed in stromal fibroblasts in 63.4% (45/71), 84.5% (60/71), and 78.9% (56/71) of patients, respectively. Positive expression of α-SMA was correlated with poor differentiation (P=.032); FSP-1 expression in stromal fibroblasts was linked with lymph node metastasis (P=.022) and immature phenotype (P=.048). What's more, positive expression of FSP-1 in cancer cells was observed in 22.5% (16/71) of cases and was correlated with worse 5-year OS (36.4% versus 76.7%, P=.014). Importantly, in multivariate analysis, histological CAF phenotype was an independent prognostic factor for OS in ICC. Our findings demonstrated histological categorization of CAFs was a useful predictor for prognosis, providing new evidence that CAFs play a crucial role in tumor progression and can serve as potential therapeutic targets in ICC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2017.04.014DOI Listing
July 2017

Clinical significance of spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia in Epstein-Barr virus-associated and Epstein-Barr virus-negative gastric cancer.

Hum Pathol 2017 05 12;63:128-138. Epub 2017 Mar 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2017.02.016DOI Listing
May 2017

Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases.

J Natl Cancer Inst 2017 01 25;109(6). Epub 2017 Jan 25.

Affiliations of authors: Department of Urology (XG, LYL, JP, MKC, ZC, JGQ), Department of Pathology (DH, CKS, ZLS), and Department of Radiology (JW), The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Urology, St. Elisabeth Hospital, University of Leipzig, Leipzig, Germany (JR); Department of Urology, The First Affiliated Hospital, Nanchang University, Nanchang, China (WPL); Department of Urology, Changhai Hospital, The Second Military Medical University, Shanghai, China (SCR); Department of Urology, Cancer Center, Sun Yat-sen University, Guangzhou, China (FJZ); Department of Urology, Guangzhou First Municipal People's Hospital, Guangzhou Medical University, Guangzhou, China (KJX); Department of Urology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (XZ); Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China (HJQ); Department of Urology, Cancer Hospital, Guangxi Medical University, Nanning, China (XZB); Department of Urology, Guangdong General Hospital, Guangzhou, China (JML); Department of Urology, Shenzhen People's Hospital, Shenzhen, China (JGY); Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China (LL).

Background: For patients with prostate cancer (PCa), the presence of pelvic lymph node metastasis (LNM) is a strong predictor of poor outcome. However, the approaches with promising sensitivity and specificity to detect LNM are still lacking. We investigated the value of collapsin response mediator protein 4 (CRMP4) promoter methylation in biopsies as a predictor for LNM.

Methods: CRMP4 promoter methylation at two previously identified CpG sites was determined in 80 case-matched biopsy samples (the training set) using bisulfite pyrosequencing. The predictive cutoff value was independently validated using cohort I of 339 PCa patients (Southern China) and cohort II of 328 case patients (Germany, across China). Mann-Whitney U test, the receiver operating characteristic curve, McNemar's test, and logistic regression were used to assess data. All statistical tests were two-sided.

Results: In the training set, CRMP4 promoter methylation (≥15.0% methylated) was statistically significantly associated with LNM (P < 001). Successful validations were achieved in both cohorts I and II (sensitivity = 92.3%, 95% confidence interval [CI] = 79.3 to 97.9, and sensitivity = 92.2%, 95% CI = 81.1 to 97.8, respectively; specificity = 92.7%, 95% CI = 80.2 to 99.1, and specificity = 91.3%, 95% CI = 87.4 to 94.4, respectively). The sensitivity of CRMP4 promoter methylation is superior to conventional MRI (cohort I: 92.3% vs 26.2%, P < 001; cohort II: 92.2% vs 33.3%, P < 001). CRMP4 promoter methylation is an independent predictor of LNM (cohort I: hazard ratio [HR] = 8.35, 95% CI = 5.64 to 12.35, P < 001; cohort II: HR = 12.46, 95% CI = 5.82 to 26.70, P < 001) in a multivariable analysis model.

Conclusion: CRMP4 promoter methylation in diagnostic biopsies could be a robust biomarker for LNM in PCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djw282DOI Listing
January 2017

Inflammatory Molecule, , Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFκB Signaling.

Mol Cancer Res 2017 04 20;15(4):467-477. Epub 2017 Jan 20.

Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.

P-selectin glycoprotein ligand 1 (SELPLG/) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of in tumor development remains unknown. Therefore, this study investigates the mechanistic role of in the development of intestinal tumors in colorectal cancer. Apc mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a Apc; genotype. The incidence and pathologic features of the intestinal tumors were compared between the Apc mice and Apc; mice. Importantly, -deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1γ) was found in the -deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies demonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of the signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of Apc; mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of -positive cells was associated with a favorable tumor-node-metastasis staging and decreased lymph node metastasis. deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1γ/NFκB signaling axis. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-16-0309DOI Listing
April 2017

Comparative analysis of 22 Epstein-Barr virus genomes from diseased and healthy individuals.

J Gen Virol 2017 Jan 22;98(1):96-107. Epub 2017 Feb 22.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, PR China.

Epstein-Barr virus (EBV) infects most of the world's population and is causally associated with several human cancers, but little is known about how EBV genetic variations might influence EBV-associated diseases and their geographical patterns. In the present study, 22 EBV whole-genome sequences from diseased and healthy individuals were analysed to explore EBV sequence variations at the whole-genome level. We found that the 22 EBV genomes were generally highly similar to each other at the genome level. However, varying degrees of genetic diversity were detected across the entire genome, especially in the latent genes. In contrast, the sequences of promoters and non-coding RNAs were strictly conserved. These findings suggested that both latent genes and non-coding RNAs play important roles in the EBV life cycle. When we investigated changes in known T-cell epitopes in some latent and lytic proteins, we observed that some T-cell epitopes were changed, while others were conserved. These findings indicate that the effect of EBV variations in protein sequences that seem to have been selected by the host immune system should be considered when conducting EBV-targeted immunotherapy. Taken together, our results provide a global view of EBV genome sequence variation, which not only is important for designing vaccines and immunotherapy for EBV but also adds to the understanding of EBV biology and the relationships between viral sequence variation and EBV-associated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1099/jgv.0.000699DOI Listing
January 2017

A new prognostic histopathologic classification of nasopharyngeal carcinoma.

Chin J Cancer 2016 May 5;35:41. Epub 2016 May 5.

State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, #651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.

Background: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response.

Methods: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS).

Results: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28).

Conclusions: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40880-016-0103-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857443PMC
May 2016

Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma.

Hum Pathol 2016 07 4;53:25-34. Epub 2016 Mar 4.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

As a special subtype of gastric carcinoma, Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. The Cancer Genome Atlas Research Network revealed that EBVaGC also has distinct molecular features: PIK3CA mutations, DNA hypermethylation, and JAK2, PD-L1, and PD-L2 amplification. Here, we evaluated PIK3CA, JAK2, PD-L1, and PD-L2 expression in 59 EBVaGC and 796 EBV-negative gastric carcinoma (EBVnGC) cases using immunohistochemistry and found that PIK3CA, JAK2, PD-L1, and PD-L2 were highly expressed in 75.9% and 48.8% (P<.001), 81.8% and 71.1% (P=.091), 92.5% and 84.8% (P=.132), and 98.1% and 89.7% (P=.049) of the EBVaGC and EBVnGC cases, respectively. However, the expression of PIK3CA, JAK2, PD-L1, or PD-L2 was not significantly associated with clinicopathological features or patient outcomes in EBVaGC. In contrast, in EBVnGC, high PIK3CA expression was significantly associated with indolent clinicopathological features and independently predicted better 5-year overall survival (57.8% versus 33.4%, P<.001). Our study indicated that the protein expression of the 4 characteristic molecules of EBVaGC was basically consistent with their genetic alterations, making them potential characteristic protein biomarkers and therapeutic targets of EBVaGC. The favorable impact of PIK3CA overexpression on survival found in this study gives us new insight into the clinical significance of PIK3CA in EBVnGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2016.02.007DOI Listing
July 2016

Accumulation Mechanisms of CD4(+)CD25(+)FOXP3(+) Regulatory T Cells in EBV-associated Gastric Carcinoma.

Sci Rep 2015 Dec 17;5:18057. Epub 2015 Dec 17.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, China.

Approximately 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV) and are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are known to be accompanied by massive CD8(+) cytotoxic T cell (CTL) infiltration; however, adoptive cellular immunotherapy based on EBV-specific CD8(+) CTLs has been explored with limited success. Because regulatory T cells (Tregs) are regarded as a critical hurdle in anti-tumour immunity, we assessed the distribution of Tregs in 45 cases of EBVaGC and 45 cases of EBV-negative gastric carcinoma (EBVnGC) with matched clinicopathological parameters by immunohistochemistry. We showed that Tregs were significantly increased in EBVaGC compared to EBVnGC (15.92 ± 11.45/HPF vs. 8.45 ± 6.16/HPF, p = 0.001). In addition, we explored the accumulation mechanisms of Tregs in EBVaGC by using EBV (+) gastric carcinoma cell lines SNU719 and GT39 as ex vivo models. When peripheral blood mononuclear cells (PBMCs) were co-cultured with EBV (+) gastric carcinoma cell lines, the Treg frequency increased, and they underwent phenotypic and functional changes. The enhanced recruitment by CCL22 produced by EBVaGC cells, the decreased emigration due to CCR7 downregulation on the Treg surface, the higher proliferation rate, and the lower apoptosis rate of Tregs at tumour sites may promote the accumulation of Tregs in EBVaGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep18057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682180PMC
December 2015
-->