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Weng Y.-R.,Shanghai Institute of Digestive Disease | Weng Y.-R.,Shanghai JiaoTong University | Cui Y.,Shanghai Institute of Digestive Disease | Cui Y.,Shanghai JiaoTong University | And 3 more authors.
Molecular Cancer Research | Year: 2012

The structural proteins cytokeratin 18 (CK18) and its coexpressed complementary partner CK8 are expressed in a variety of adult epithelial organs and may play a role in carcinogenesis. In this study, we focused on the biological functions of CK18, which is thought to modulate intracellular signaling and operates in conjunction with various related proteins. CK18 may affect carcinogenesis through several signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, Wnt, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. CK18 acts as an identical target of Akt in the PI3K/Akt pathway and of ERK1/2 in the ERK MAPK pathway, and regulation of CK18 by Wnt is involved in Akt activation. Finally, we discuss the importance of gaining a more complete understanding of the expression of CK18 during carcinogenesis, and suggest potential clinical applications of that understanding. ©2012 AACR.

Wang J.-L.,Shanghai JiaoTong University | Hu Y.,Shanghai JiaoTong University | Kong X.,Shanghai JiaoTong University | Wang Z.-H.,Shanghai JiaoTong University | And 5 more authors.
PLoS ONE | Year: 2013

Gastric cancer (GC) remains a major cause of morbidity and mortality worldwide and there is therefore a clear need to search for more sensitive early diagnostic biomarkers. We performed a systematic review of eight published miRNA profiling studies that compared GC tissues with adjacent noncancerous tissues. A miRNA ranking system was used that took the frequency of comparisons, direction of differential expression and total sample size into consideration. We identified five miRNAs that were most consistently reported to be upregulated (miR-21, miR-106b, miR-17, miR-18a and miR-20a) and two miRNAs that were downregulated (miR-378 and miR-638). Six of these were further validated in 32 paired sets of GC and adjacent noncancerous tissue samples using real-time PCR. MiR-21, miR-106b, miR-17, miR-18a and miR-20a were confirmed to be upregulatedin GC tissues, while the expression of miR-378 was decreased. Moreover, we found a significant association between expression levels of miR-21, miR-106b, miR-17, miR-18a and miR-20a and clinicopathological features of GC. These miRNAs may be used for diagnostic and/or prognostic biomarkers for GC and therefore warrant further investigation. © 2013 Wang et al.

Gao Q.-Y.,Shanghai JiaoTong University | Gao Q.-Y.,State Key Laboratory of Oncogene and Related Genes | Wang Z.-H.,Shanghai JiaoTong University | Wang Z.-H.,State Key Laboratory of Oncogene and Related Genes | And 13 more authors.
BMC Clinical Pathology | Year: 2014

Background: A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance. Methods. Stomach Age was determined by FISH examination of telomere length in stomach biopsies. Δψm was also determined by flow cytometry. Sixty volunteers were used to confirm the linear relationship between telomere length and age while 120 subjects were used to build a mathematical model by a multivariate analysis. Overall, 146 subjects were used to evaluate the validity of the model, and 1,007 subjects were used to evaluate the relationship between prognosis and Δage (calculated from the mathematical model). ROC curves were used to evaluate the relationship between prognosis and Δage and to determine the cut-off point for Δage. Results: We established that a tight linear relationship between the telomere length and the age. The telomere length was obvious different between patients with and without CAG even in the same age. Δψm decreased in individuals whose Stomach Age was greater than real age, especially in younger adults. A mathematical model of Stomach Age (real age + Δage) was successfully constructed which was easy to apply in clinical work. A higher Δage was correlated with a worse outcome. The criterion of Δage >3.11 should be considered as the cut-off to select the subgroup of patients who require endoscopic surveillance. Conclusion: Variation in Stomach Age between individuals of the same biological age was confirmed. Attention should be paid to those with a greater Stomach Age, especially in younger adults. The Δage in the Simple Model can be used as a criterion to select CAG patients for gastric cancer surveillance. © 2014 Gao et al.; licensee BioMed Central Ltd.

Yang W.-S.,State Key Laboratory of Oncogene and Related Genes | Yang W.-S.,Shanghai JiaoTong University | Yang W.-S.,Jiujiang University | Li H.-L.,State Key Laboratory of Oncogene and Related Genes | And 9 more authors.
European Journal of Cancer Prevention | Year: 2016

Coinciding with the increased incidence of non-Hodgkin's lymphoma (NHL) during the past decades, there has been a significant increase in the prevalence of diabetes mellitus in mainland China. We therefore evaluated whether type 2 diabetes (T2D) is associated with the risk of NHL using data from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). The SMHS and SWHS are two on-going, prospective, population-based cohorts of more than 130 000 Chinese adults in urban Shanghai. Self-reported diabetes was recorded on the baseline questionnaire and updated in follow-up surveys. Cox regression models with T2D as a time-varying exposure were used to estimate hazard ratios and 95% confidence intervals, adjusting for covariates. After a median follow-up of 12.9 years for SWHS and 7.4 years for SMHS, 172 NHL cases were identified. Patients with T2D have a higher risk of incident NHL with a hazard ratio of 2.00 (95% confidence interval: 1.32-3.03) compared with those without diabetes. This positive association remained when the analysis was restricted to untreated diabetes or after excluding NHL cases that occurred within 3 years after the onset of diabetes. No interaction effect was found in the development of NHL between T2D and other potential risk factors. A linear inverse association was found between T2D duration and the risk of NHL in both men and women (P for linearity <0.01), with a highest risk of incident NHL in the first 5 years after the diagnosis of diabetes. Our study suggested that T2D might be associated with an increased risk of NHL. © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Pan Q.,Shanghai JiaoTong University | Yang G.-L.,Shanghai JiaoTong University | Yang J.-H.,Shanghai JiaoTong University | Lin S.-L.,Shanghai JiaoTong University | And 10 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2015

Background: Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors. Methods: T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence. Results: Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines. Conclusions: These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors. © 2015 Pan et al.

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