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Hu Z.,Nanjing Medical University | Dong J.,Nanjing Medical University | Wang L.-E.,University of Texas M. D. Anderson Cancer Center | Ma H.,Nanjing Medical University | And 8 more authors.
Carcinogenesis | Year: 2012

It has been demonstrated that there are abundant stable microRNAs (miRNAs) in plasma/serum, which can be detected and are potentially disease specific. However, the lack of suitable endogenous controls for serum miRNA detection is the restriction for the widely usage of this kind of biomarkers and for the between-laboratory comparison of the findings. We first systematically screened for endogenous control miRNAs (ECMs) by testing 10 pooling samples (using both Solexa sequencing and TaqMan low density array) and 50 individual samples (using quantitative reverse transcription-PCR) of different cancer traits and healthy controls. Then we assessed serum miRNAs used as potential biomarkers for breast cancer risk prediction based on a two-stage case-control analysis, including 48 breast cancer patients and 48 controls for the discovery stage and 76 breast cancer patients and 76 controls for validation. We identified two candidate ECMs (miRNA-191 and miRNA-484). Normalized by the two ECMs, we found four miRNAs (miR-16, miR-25, miR-222 and miR-324-3p) that were consistently differentially expressed between breast cancer cases and controls. The area under the receiver operating characteristic curve is 0.954 for the four-miRNA signature in the discovery stage (sensitivity = 0.917 and specificity = 0.896) and 0.928 in the validation stage (sensitivity = 0.921 and specificity = 0.934). In conclusion, the four-miRNA signature from serum may serve as a non-invasive prediction biomarker for breast cancer. Furthermore, we proposed the combination of miRNA-484 and miRNA-191 as endogenous control for serum miRNA detection, at least for most common cancers. © The Author 2012. Published by Oxford University Press. All rights reserved.


Dong Z.Z.,Nantong University | Yao D.-F.,Nantong University | Wu W.,Nantong University | Yao M.,Nantong University | And 6 more authors.
Hepatobiliary and Pancreatic Diseases International | Year: 2010

BACKGROUND: The active form of nuclear factor-kappa B (NFκB) is involved in the initiation, generation, and development of hepatocellular carcinoma (HCC), and is up-regulated in inflammation-associated malignancies. We investigated the dynamic expression of NF-κB and its influences on the occurrence of HCC through antiangiogenic (thalidomide) intervention in NF-κB activation. METHODS: Hepatoma models were induced with 2-fluorenylacetamide (2-FAA, 0.05%) in male Sprague-Dawley rats, and thalidomide (100 mg/kg body weight) was administered intragastrically to intervene in NF-κB activation. The pathological changes in the liver of sacrificed rats were assessed after hematoxylin and eosin staining. NF-κB mRNA was amplified by RT-nested PCR. The alterations of NF-κB and vascular endothelial growth factor (VEGF) expression were analyzed by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting. RESULTS: Rat hepatocytes showed denatured, precancerous, and cancerous stages in hepatocarcinogenesis, with an increasing tendency of hepatic NF-κB, NF-κB mRNA, and VEGF expression, and their values in the HCC group were higher than those in controls (P<0.001). In the thalidomidetreated group, the morphologic changes generated only punctiform denaturation and necrosis at the early or middle stages, and nodular hyperplasia or a little atypical hyperplasia at the final stages, with the expression of NF-κB (x2=9.93, P<0.001) and VEGF (x2=8.024, P<0.001) lower than that in the 2-FAA group. CONCLUSION: NF-κB is overexpressed in hepatocarcinogenesis and antiangiogenic treatment down-regulates the expression of NF-κB and VEGF, and delays the occurrence of HCC. Copyright © 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.


Chen Y.,Nanjing Medical University | Xia X.,Nanjing Medical University | Wang S.,Nanjing Medical University | Wu X.,Nanjing Medical University | And 8 more authors.
Journal of Gastroenterology | Year: 2013

Background: The multifunctional protein JWA was previously identified as a novel regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. Methods: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry. Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. Results: Compared with adjacent non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil- leucovorin-cisplatin (FLP) therapy did not show these effects. Conclusion: FAK plus JWA may serve as a more prognostic and predictive biomarker for GC than each separately with a potential clinical application. © 2012 Springer Japan.


Xu W.,Nanjing Medical University | Xu W.,Cancer Center | Wang S.,Nanjing Medical University | Wang S.,Cancer Center | And 15 more authors.
Cell Death and Disease | Year: 2014

Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis- diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitinproteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer. © 2014 Macmillan Publishers Limited.


Huang Y.,Nanjing Medical University | Wang W.,Yixing Peoples Hospital | Chen Y.,Nanjing Medical University | Zhang J.,Nanjing Medical University | And 8 more authors.
Journal of Gastroenterology | Year: 2014

Background Protein p21Cip1/Waf1 is a cyclin-dependent kinase inhibitor, which plays important roles in cell cycle arrest, senescence, and apoptosis. Interestingly, the nuclear and cytoplasmic p21 executes various functions in the cell. In this study, we investigated the prognostic impact of subcellular p21 expression in gastric cancer (GC). Methods Expressions of subcellular p21 was assessed by immunohistochemistry using a tissue microarray in a training cohort and it went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of subcellular p21 expression status was evaluated. We also studied the roles of subcellular p21 in GC cell migration and invasion. Results Nuclear and cytoplasmic p21 protein levels were significantly reduced and increased in GC lesions compared with adjacent non-cancerous tissues, respectively. Low nuclear p21 or high cytoplasmic p21 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients. Multivariate regression analysis showed that low nuclear and high cytoplasmic p21 expression, separately and together, were independent negative markers of OS. Finally, we found that nuclear p21 inhibits but cytoplasmic p21 promotes cell migration and invasion abilities. Conclusions These findings suggest that nuclear and cytoplasmic p21 protein expression in tumor are novel candidate prognostic markers in resectable human gastric carcinoma, and they exert distinct roles in cell migration and invasion. © 2013, Springer Japan.

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