Junjie Piao

DEK over expression as an independent biomarker for poor prognosis in colorectal cancer.

BackgroundThe DEK protein is related to chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. High expression levels of the human DEK gene have been correlated with numerous human malignancies. This study explores the roles of DEK in tumor progression and as a prognostic determinant of colorectal cancer.MethodsColorectal cancer specimens from 109 patients with strict follow-up, and colorectal adenomas from 52 patients were selected for analysis of DEK protein by immunohistochemistry. The correlations between DEK over expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher’s exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models.ResultsDEK protein showed a nuclear immunohistochemical staining pattern in colorectal cancers. The strongly positive rate of DEK protein was 48.62% (53/109) in colorectal cancers, which was significantly higher than that in either adjacent normal colon mucosa (9.17%, 10/109) or colorectal adenomas (13.46%, 7/52). DEK over expression in colorectal cancers was positively correlated with tumor size, grade, lymph node metastasis, serosal invasion, late stage, and disease-free survival- and 5-year survival rates. Further analysis showed that patients with late stage colorectal cancer and high DEK expression had worse survival rates than those with low DEK expression. Moreover, multivariate analysis showed high DEK expression, serosal invasion, and late stage are significant independent risk factors for mortality in colorectal cancer.ConclusionsDEK plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor of colorectal cancers.

Ezrin protein overexpression predicts the poor prognosis of pancreatic ductal adenocarcinomas

Ezrin, a member of the ezrin/radixin/moesin (ERM) protein family, plays an important role in tumor metastasis. Accumulating studies demonstrated that a high expression level of human ezrin has been correlated with numerous human malignancies. This study was aimed to explore the clinicopathological significance of ezrin protein expression in pancreatic ductal adenocarcinomas (PDAC), and to further identify its role as a potential biomarker and therapeutic target of PDAC. Immunohistochemical (IHC) staining of ezrin protein was performed on 106 PDAC tissue samples and 37 adjacent and 21 normal pancreatic tissue samples. Additionally, localization of ezrin protein in Panc-1 PDAC cell line was observed using immunofluorescence (IF) staining. The correlation between ezrin overexpression and the clinicopathological features of PDAC was evaluated using Chi-square test, and differences in survival curves were analyzed using log-rank tests. In results, ezrin protein is widely distributed in the cytoplasm and membrane of PDAC cells by IHC and IF staining, but some cases showed a cell membrane staining pattern. The positive rate of ezrin protein expression was 82.1% (87/106) in PDAC, which was significantly higher than it in either adjacent pancreatic tissues (37.8%, 14/37) or normal pancreatic tissues (19.0%, 4/21). Overexpression of ezrin was closely related with larger tumor size, positive lymph node metastasis and advanced clinical stage. However, it was not correlated with patient age, gender, differentiation, Ki-67 expression index, and pancreas calcification point. Survival analysis showed that patients with ezrin high expression level had significantly lower overall survival rate than that with ezrin low expression level. Importantly, further analysis using a Cox proportional hazard regression model revealed that high ezrin expression emerged as a significant independent hazard factor for overall survival rates of patients with PDAC along with lymph node metastasis and TNM stage. In conclusion, ezrin protein played an important role in the progression of PDAC, and the overexpression of ezrin protein might be a useful prognostic marker of PDAC.

Mechanisms underlying cancer growth and apoptosis by DEK overexpression in colorectal cancer.

Our previous study indicated that DEK protein was overexpressed in colorectal carcinoma (CRC) compared with the normal colorectal mucosa. DEK was also significantly correlated with the prognostic characteristics of patients with CRC, demonstrating that DEK played an important role in CRC progression. In this work, we evaluate the effects of DEK on biological behaviors in CRC and explore the related molecular mechanisms. The results showed that DEK was overexpressed in human CRC tissues, and was correlated with the Ki-67 index and the apoptotic index. DEK depletion by RNAi in SW-620 and HCT116 cells significantly decreased cell proliferation, but increased cell apoptosis. Upregulation of DEK was involved in the p53/MDM, Bcl-2 family, and caspase pathways. Our study demonstrates that DEK promotes the growth of CRC, and could be a therapeutic target in CRC.

High expression of DEK predicts poor prognosis of gastric adenocarcinoma

BackgroundDEK, as an oncoprotein, plays an important role in cancer development and progression. This study aimed to investigate the clinicopathological significance of DEK overexpression in patients with gastric cancer.Materials and methodsThe expression of DEK protein was evaluated by immunohistochemical (IHC) staining of 172 gastric cancer samples with complete clinicopathological features, and the correlation between DEK expression and clinicopathological features was examined. Survival rates were also calculated using the Kaplan-Meier method in gastric cancer patients with complete survival data.ResultsDEK protein showed a strictly nuclear staining pattern in gastric cancers with IHC and immunofluorescence. The strongly positive rate of DEK protein was 60.5% (104/172) in gastric cancers, which was significantly higher than that in either gastric dysplasia (19.4%, 7/36) or adjacent normal mucosa (0%, 0/27). DEK expression in gastric cancer correlated to tumor size, differentiation, clinical stage, disease-free survival, and overall survival rates. Further analysis showed that patients with early-stage gastric cancer and high DEK expression had shorter disease-free survival and overall survival duration than those with low DEK expression.ConclusionHigh level of DEK protein expression predicts the poor prognosis of patients with gastric cancer. DEK expression might be potentially used as an independent effective biomarker for prognostic evaluation of gastric cancers.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5050145571193097

Ezrin contributes to cervical cancer progression through induction of epithelial-mesenchymal transition

Cervical cancer is the third most common cancer in females worldwide. The treatment options for advanced cervical cancer are limited, leading to high mortality. Ezrin is a membrane-cytoskeleton-binding protein recently reported to act as a tumor promoter, and we previously indicated that the aberrant localization and overexpression of Ezrin could be an independent effective biomarker for prognostic evaluation of cervical cancers. In this study, we identified Ezrin as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in cervical cancer. Ezrin knock-down inhibited anchorage-independent growth, cell migration, and invasion of cervical cancer cell lines in vitro and in vivo. EMT was inhibited in Ezrin-depleted cells, with up-regulation of E-cadherin and Cytokeratin-18 (CK-18) and down-regulation of mesenchymal markers. Ezrin knock-down also induced Akt phosphorylation. These results implicate Ezrin as an EMT regulator and tumor promoter in cervical cancer, and down-regulation of Ezrin suppressed cervical cancer progression, possibly via the phosphoinositide 3-kinase/Akt pathway. Furthermore, the expression pattern of Ezrin protein was closely related with the lymphovascular invasion status of cervical cancer by immunohistochemistry, and the survival analysis revealed that the cervical cancer patients with the perinuclear Ezrin expression pattern had longer survival time than those with the cytoplasmic Ezrin expression pattern. Ezrin thus represents a promising target for the development of novel and effective strategies aimed at preventing the progression of cervical cancer.

Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC.

β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers

NQO1 is a FAD-binding protein that can form homodimers and reduce quinones to hydroquinones, and a growing body of evidence currently suggests that NQO1 is dramatically elevated in solid cancers. Here, we demonstrated that NQO1 was elevated in breast cancer and that its expression level was positively correlated with invasion and reduced disease free survival (DFS) and overall survival (OS) rates. Next, we found that β-lapachone exerted significant anti-proliferation and anti-metastasis effects in breast cancer cell lines due to its effects on NQO1 expression. Moreover, we revealed that the anti-cancer effects of β-lapachone were mediated by the inactivation of the Akt/mTOR pathway. In conclusion, these results demonstrated that NQO1 could be a useful prognostic biomarker for patients with breast cancer, and its bioactivatable drug, β-lapachone represented a promising new development and an effective strategy for indicating the progression of NQO1-positive breast cancers.

Target gene screening and evaluation of prognostic values in non-small cell lung cancers by bioinformatics analysis

BACKGROUND Non-small cell lung cancer (NSCLC) is the major leading cause of cancer-related deaths worldwide. This study aims to explore molecular mechanism of NSCLC. METHODS Microarray dataset was obtained from the Gene Expression Omnibus (GEO) database, and analyzed by using GEO2R. Functional and pathway enrichment analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then, STRING, Cytoscape and MCODE were applied to construct the Protein-protein interaction (PPI) network and screen hub genes. Following, overall survival (OS) analysis of hub genes was performed by using the Kaplan-Meier plotter online tool. Moreover, miRecords was also applied to predict the targets of the differentially expressed microRNAs (DEMs). RESULTS A total of 228 DEGs were identified, and they were mainly enriched in the terms of cell adhesion molecules, leukocyte transendothelial migration and ECM-receptor interaction. A PPI network was constructed, and 16 hub genes were identified, including TEK, ANGPT1, MMP9, VWF, CDH5, EDN1, ESAM, CCNE1, CDC45, PRC1, CCNB2, AURKA, MELK, CDC20, TOP2A and PTTG1. Among the genes, expressions of 14 hub genes were associated with prognosis of NSCLC patients. Additionally, a total of 11 DEMs were also identified. CONCLUSION Our results provide some potential underlying biomarkers for NSCLC. Further studies are required to elucidate the pathogenesis of NSCLC.

Mortalin overexpression predicts poor prognosis in early stage of non–small cell lung cancer

Mortalin is a member of the heat shock protein 70 family, which is involved in multiple cellular processes and may play key roles in promoting carcinogenesis. This study attempted to identify the clinical consequences of Mortalin overexpression and its roles in the prognostic evaluation of non–small cell lung cancer. A total of 120 non–small cell lung cancer samples paired with the adjacent non-tumor tissue samples and 10 normal lung tissues were selected for immunohistochemical staining for Mortalin. The localization of Mortalin was detected in A549 non–small cell lung cancer cells using immunofluorescence staining. The correlations between Mortalin overexpression and the clinical features of non–small cell lung cancers were evaluated using the chi-square test. The survival analysis was calculated via the Kaplan–Meier method and the Cox proportional hazard models. Our studies suggested that Mortalin exhibited a primarily cytoplasmic staining pattern in the non–small cell lung cancers. The rate of strongly positive Mortalin expression was higher in the non–small cell lung cancer samples than in the adjacent non-tumor samples or in normal lung tissues. Mortalin overexpression was significantly correlated with high histological grades, advanced stages, lymph node metastases, and lower disease-free survival and overall survival rates of the patients with non–small cell lung cancer. The survival analysis demonstrated that Mortalin overexpression was a significant independent prognostic factor in non–small cell lung cancer, especially for patients with early stage of non–small cell lung cancer. In conclusion, Mortalin is up-regulated in non–small cell lung cancer, and it may be a potential biomarker of prognostic evaluation and a molecular therapeutic target for patients with early stage of non–small cell lung cancer.

Mortalin expression in pancreatic cancer and its clinical and prognostic significance

Mortalin, an essential mitochondrial chaperone protein, is involved in the tumorigenesis of a number of malignancies. This study aimed to investigate the expression of Mortalin in pancreatic ductal adenocarcinoma (PDAC) cells and to determine its clinicopathological and prognostic significance. The localization of Mortalin protein was detected in BXPC-3 PDAC cells using immunofluorescence. Immunohistochemistry was also used to detect Mortalin expression in well-defined tissues obtained from 106 PDAC patients and 46 corresponding nontumor pancreatic tissues. Clinicopathological parameters and overall survival data were collected and compared between different Mortalin statuses. The results of immunohistochemistry and immunofluorescence showed that Mortalin was primarily present in the cytoplasm of PDAC cells. The ratio of strong positive staining for Mortalin was higher in PDAC tissues (55.66%; 59/106) than in normal adjacent tissues (23.91%; 11/46). Positive relationships between Mortalin expression and clinical stage, perineural invasion, lymph node metastasis, and lower overall survival were observed. Multivariate Cox regression analysis identified Mortalin as a significant independent prognostic factor, in addition to location, clinical stage, and perineural invasion, for survival of PDAC patients. Therefore, we present strong evidence that Mortalin may function as a practical marker to predict prognosis and as a potential therapeutic target in PDAC treatment.