Tiefeng Jin

Ezrin overexpression predicts the poor prognosis of gastric adenocarcinoma

BackgroundEzrin is a cytoskeletal protein that is involved in tumor growth and invasion. It has been suggested that Ezrin expression plays an important role in tumor metastasis. This study is aimed to investigate the clinicopathological significance of Ezrin overexpression in gastric adenocarcinomas.MethodsEzrin protein expression was examined by immunohistochemistry in 26 normal gastric mucosa, 32 dysplasia, and 277 gastric adenocarcinomas. The relationship between Ezrin expression and the clinicopathological features of gastric cancers was analyzed. In addition, a gastric cancer cell line, MKN-1, was also used for immunofluorescence staining to evaluate the distribution of Ezrin protein.ResultsEzrin protein located in the cytoplasm and/or membrane in the migrating gastric cancer cells, and it mainly concentrated at the protrusion site; however, only cytoplasmic distribution was observed in the non-migrating cancer cells by immunofluorescence staining. The positive rate of Ezrin protein expression was significantly higher in gastric adenocarcinoma and dysplasia compared with that in the normal gastric mucosa. Moreover, expression frequency of Ezrin protein increased significantly in lymph node metastasis and late clinical stages. Consistently, strong expression of Ezrin was significantly correlated with poor prognosis of gastric cancer.ConclusionThe detection of Ezrin expression can be used as the marker for early diagnosis and prognosis of gastric adenocarcinoma.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2303598677653946

Prognostic implications of ezrin and phosphorylated ezrin expression in non-small cell lung cancer

BackgroundThe cytoskeletal organizer ezrin is a member of the ezrin-radixin-moesin (ERM) family and plays important roles in not only cell motility, cell adhesion, and apoptosis, but also in various cell signaling pathways. Phosphorylation at Thr-567 and Tyr-353 are key regulatory events in the transition of the dormant to active form of ezrin. This study investigated the prognostic implications of ezrin and phosphorylated ezrin (p-ezrin) expression in non-small cell lung carcinoma (NSCLC).MethodsEzrin and p-ezrin protein expressions were examined by immunohistochemistry in 150 NSCLC and adjacent non-tumor tissues and 14 normal lung tissues. qRT-PCR was used to determine ezrin mRNA expression levels in fresh tissues. The correlations between overexpression of ezrin and p-ezrin and the clinicopathological features of NSCLC were analyzed. The survival rates were calculated by the Kaplan-Meier method for 108 NSCLC cases.ResultsEzrin and ezrinThr-567 proteins showed cytosolic and membranous staining patterns; however, ezrinTyr-353 protein only showed cytosolic staining. Ezrin and p-ezrin were significantly upregulated in NSCLC compared with the normal counterparts. Increased ezrin, ezrinThr-567, and ezrinTyr-353 levels were correlated with the late stage and poor differentiation of NSCLC. However, only ezrinThr-567 was correlated with the presence of lymph node metastasis. In regard to survival, only ezrinThr-567 was related with the overall survival time of patients with NSCLC, and both ezrin and ezrinThr-567 were associated with shortened survival time for patients with early stage NSCLC.ConclusionsEzrin and p-ezrin, especially ezrinThr-567, may prove to be useful as a novel prognostic biomarker of NSCLC.

PI3K/mTOR dual inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A synergistically exert anti-tumor activity in breast cancer

Molecule-targeted therapy has achieved great progress in cancer therapy. Effective drug combinations are one way to enhance the therapeutic efficacy and combat resistance. Here, we determined the effect of the PI3K/mTOR dual inhibitor BEZ235 and the histone deacetylase inhibitor Trichostatin A (TSA) on human breast cancer. We demonstrated that the combination of BEZ235 and TSA results in significant synergistic growth inhibition of multiple breast cancer cell lines. Mechanistic studies revealed that the combined therapy induced apoptosis in a caspase-dependent manner, which might be related to the further depression of the PI3K/Akt/mTOR signalling pathway. Additionally, co-treatment with BEZ235 and TSA enhanced autophagic cell death by up-regulating the expression of LC3B-II and Beclin-1. The vivo tumour modelling studies revealed that BEZ235 combined with TSA blocked tumour growth without noticeable side effects. These data suggest that the combination of BEZ235 and TSA may be a new selective strategy, which may have significant clinical application in the treatment of breast cancer patients.

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.

DEK promoted EMT and angiogenesis through regulating PI3K/AKT/mTOR pathway in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor prognosis. As an oncogene, DEK involves in regulation of various cellular metabolisms and plays an important role in tumor growth and progression. Increasing evidences suggested that abnormal expression of DEK is closely related to multiple malignant tumors. However, the possible involvement of DEK in epithelial to mesenchymal transition (EMT) and angiogenesis in TNBC remains unclear. In the present study, we revealed that the over-expression of DEK was significantly correlated with clinical stage, differentiation, and lymph node (LN) metastasis of TNBC and indicated poor overall survival of TNBC patients. Moreover, we demonstrated that DEK depletion could significantly reduce cell proliferation, migration, invasion and angiogenesis in vitro. We also found that DEK promoted cancer cell angiogenesis and metastasis by activating the PI3K/AKT/mTOR pathway. Furthermore, we revealed the inhibitory effect of DEK depletion on tumor growth and progression in a xenograft tumor model in mice. These data indicated that DEK promotes TNBC cell proliferation, angiogenesis, and metastasis via PI3K/AKT/mTOR signaling pathway, and therefore, it might be a potential target in TNBC therapy.

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.

Upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome

T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, is involved in the tumorigenesis of a number of malignancies. This study was aimed to explore the role of Tiam1 in cervical cancer progression, and evaluate the prognostic values. Tiam1 protein expression levels were detected by immunohistochemical (IHC) staining in 174 cervical cancer tissues, 92 of CINs (cervical intraepithelial neoplasia) and 32 of normal cervical epithelia tissues. Clinicopathological parameters and overall survival data were collected and compared between different Tiam1 statuses. The role of Tiam1 in cervical cancer proliferation, migration and angiogenesis were detected using si-RNA (small interfering RNA) transfection. In results, Tiam1 protein showed a cytoplasmic and nuclear staining pattern in cervical cancer tissues. The strongly positive expression of Tiam1 protein was observed in 51.72% (90/174) of cervical cancers, which was significantly higher than in CINs and normal cervical epithelia tissues (9.38%, 3/32). High Tiam1 protein expression was closely associated with advanced clinical stage, differentiation, lymph node (LN) metastasis, HPV infection and lower overall survival (OS) rates in cervical cancer. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with clinical stage, in patients with cervical cancer. Additionally, Tiam1 depletion by RNAi in cervical cancer cells significantly decreased cell proliferation, migration and angiogenesis. In conclusion, our study demonstrated that upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome.

HBXIP suppression reduces cell proliferation and migration and its overexpression predicts poor prognosis in non-small-cell lung cancer

Emerging evidence has demonstrated that the high expression of HBXIP has been correlated with many cancers. With evaluation of the functional role of HBXIP in non-small-cell lung cancer, the primary aim of this study is to investigate the correlation between HBXIP expression and the prognosis of non-small-cell lung cancer patients. The protein levels of HBXIP were detected using western blotting in non-small-cell lung cancer cells. Cell proliferation and migration assays were measured to evaluate the function of HBXIP in non-small-cell lung cancer cells. A total of 120 non-small-cell lung cancer patients with strict follow-up and 60 adjacent non-tumor lung tissues were selected for immunohistochemical staining of the HBXIP protein. The localization of the HBXIP protein was detected in A549 non-small-cell lung cancer cells using immunofluorescence staining. The correlation between HBXIP expression and the clinicopathological features of non-small-cell lung cancer patients was analyzed by a chi-squared and Fisher’s exact test. The overall survival rates of all of the non-small-cell lung cancer patients were calculated using the Kaplan–Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazards regression model. In function, we showed that suppression of HBXIP decreased A549 cell proliferation and migration. HBXIP protein showed a mainly cytoplasmic staining pattern in non-small-cell lung cancer using immunohistochemical staining in paraffin-embedded non-small-cell lung cancer tissues and immunofluorescence staining in A549 cells. The HBXIP protein had strong positive staining in the non-small-cell lung cancer tissues, which was significantly higher than the percentage of adjacent non-tumor tissues. The overexpression of HBXIP was closely correlated with histological grade, clinical stage, lymph node metastasis, and lower overall survival rates of patients with non-small-cell lung cancer. Moreover, multivariate analysis suggested that HBXIP emerged as a significant independent prognostic factor along with clinical stage in patients with non-small-cell lung cancer. In conclusion, a high level of expression of HBXIP is associated with the progression of non-small-cell lung cancer and may be a useful biomarker for poor prognostic evaluation and a potential molecular therapy target for patients with non-small-cell lung cancer.

Paip1 affects breast cancer cell growth and represents a novel prognostic biomarker

Polyadenylate-binding protein-interacting protein 1 (Paip1) regulates translational initiation. Increasing evidence suggests that Paip1 plays important roles in cancer development and progression. This study explored the role of Paip1 in breast cancer progression and evaluated its prognostic value. The cellular location of Paip1 protein was determined using immunofluorescence. Then, Paip1 protein expression was evaluated by immunohistochemical staining in 119 breast cancers and 40 normal breast tissues. The correlation between Paip1 expression and the clinicopathologic features of breast cancer was evaluated using the χ2 test, and differences in survival curves were analyzed using log-rank tests. The role of Paip1 in breast cancer proliferation and cell cycle progression was identified by siRNA transfection. Paip1 was expressed mainly in the cytoplasm of cancer cells and tissues. Expression was observed in 60.5% of the breast cancers (72/119), which was significantly higher than in normal breast tissues (17.5%; 7/40). High expression of Paip1 protein was associated with high histologic grade, late clinical stage, and a low survival rate. Multivariate analysis indicated that Paip1 was an independent prognostic factor. Additionally, Paip1 depletion by RNAi significantly decreased cell proliferation and induced cell cycle arrest. In conclusion, our study demonstrated that Paip1 promotes the growth of breast cancers and could be a prognostic biomarker and therapeutic target.