NCOA5 low expression correlates with survival in esophageal squamous cell carcinoma.

The nuclear receptor coactivator 5 (NCOA5) was a unique coactivator independent of AF2 that can modulate ERα-mediated transcription. Recent researches have indicated that its downregulation may participate in cancer development and progression. The aims of the present study were to investigate NCOA5 expression in esophageal squamous cell carcinoma (ESCC) and validate its possible influence on patients' prognosis. NCOA5 expression was examined by immunohistochemical staining in 119 ESCC patients' tissues. Ten paired tumor and adjacent normal specimens were examined by Western blot analysis. Statistical analysis was performed to assess its relevance with various clinicopathologic features and its influence on patients' survival. By immunohistochemistry analysis, NCOA5 expression was found to be significantly correlated with differentiation (P = 0.039), T status (P = 0.047) and stage (P = 0.036). Furthermore, we found NCOA5 higher expression in normal tissues than in tumor tissues by Western blot analysis. Univariate analysis showed that poor differentiation (P = 0.035, P = 0.027), lymph node metastasis (P < 0.001, P < 0.001), high T status (P = 0.010, P = 0.012), advanced stage (P < 0.001, P < 0.001) and NCOA5 low expression (P < 0.001, P < 0.001) were significantly correlated with poor prognosis of both disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that NCOA5 low expression (P = 0.019, P = 0.047), high T status (P = 0.015, P = 0.012), lymph node metastasis (P = 0.040, P = 0.021) and advanced stage (P = 0.017, P = 0.046) were independent prognostic factors of poor DFS and OS. Our findings suggest that NCOA5 low expression is associated with ESCC progression and is a potential biomarker in predicting poor prognosis. Further studies of NCOA5 may help develop new therapeutic strategies against ESCC.

Expression of THOP1 and its relationship to prognosis in non-small cell lung cancer.

BACKGROUND: The study was designed to detect the expression level of thimet oligopeptidase (THOP1) protein in non-small cell lung cancer (NSCLC) and investigate its correlation with clinicopathologic features and prognosis. METHODS: Immunohistochemical staining was used to determine the expression of THOP1 protein in 120 NSCLC specimens and 53 distant normal lung tissues. Quantitative real-time PCR and western blotting were employed to measure the expression of THOP1 in 16 pairs of primary NSCLC and corresponding normal tissues. RESULTS: Analysis of immunohistochemical staining suggested low THOP1 expression was found in 71 (59.2%) of the 120 NSCLC specimens and significantly correlated with positive lymph node metastasis (P = 0.048). However, low THOP1 expression was found in 22 (41.5%) of the 53 normal lung tissues. Chi-square test suggested that the expression of THOP1 was significantly higher in the normal lung tissues than that in the NSCLC specimens (P = 0.032). Real-Time PCR and western blotting showed that NSCLC specimens had decreased THOP1 mRNA and protein expression compared to corresponding normal tissues. Univariate analysis demonstrated that low THOP1 expression significantly predicted decreased 5-year disease-free survival (P = 0.038) and overall survival (P = 0.017). In addition, positive lymph node metastasis (P = 0.025) and advanced TNM stage (P = 0.009) significantly predicted decreased 5-year overall survival. However, multivariate Cox regression analysis showed that only low THOP1 expression retained its significance as an independent prognostic factor for unfavorable 5-year disease-free survival (P = 0.046) and overall survival (P = 0.021). CONCLUSIONS: THOP1 may have clinical potentials to be employed as a promising biomarker to identify individuals with better prognosis and a novel antitumor agent for therapy of patients with NSCLC.

Retinoblastoma binding protein 2 (RBP2) promotes HIF-1α-VEGF-induced angiogenesis of non-small cell lung cancer via the Akt pathway.

BACKGROUND: Pathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD34. Two pairs of siRNA sequences and pcDNA3-HA-RBP2 were used to down-regulate and up-regulate RBP2 expression in H1975 and SK-MES-1 cells. An endothelial cell tube formation assay, VEGF enzyme-linked immunosorbent assay, real-time PCR and western blotting were performed to detect the potential mechanisms mediated by RBP2 in tumor angiogenesis. RESULTS: Of the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1α expression (P = 0.028), high VEGF expression (P = 0.048), increased tumor angiogenesis (P = 0.033) and poor prognosis (P = 0.037); high MVD was associated with high HIF-1α expression (P = 0.034), high VEGF expression (P = 0.001) and poor prognosis (P = 0.040). Multivariate analysis indicated that RBP2 had an independent influence on the survival of patients with stage I NSCLC (P = 0.044). By modulating the expression of RBP2, our findings suggested that RBP2 protein depletion decreased HUVECs tube formation by down-regulating VEGF in a conditioned medium. RBP2 stimulated the up-regulation of VEGF, which was dependent on HIF-1α, and activated the HIF-1α via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2. CONCLUSIONS: The RBP2 protein may stimulate HIF-1α expression via the activation of the PI3K/Akt signaling pathway under normoxia and then stimulate VEGF expression. These findings indicate that RBP2 may play a critical role in tumor angiogenesis and serve as an attractive therapeutic target against tumor aggressiveness for early-stage NSCLC patients.

GOLPH3, a good prognostic indicator in early-stage NSCLC related to tumor angiogenesis.

BACKGROUND: Golgi phosphoprotein-3 (GOLPH3) is implicated in cancer development and progression. The aim of this study was to evaluate the prognostic significance of GOLPH3 protein and its association with tumor angiogenesis in patients with early-stage NSCLC. MATERIALS AND METHODS: Immunohistochemistry was performed to determine GOLPH3 protein expression and allow assessment of intratumoral microvessel density (MVD) by counting CD-34 positive immunostained endothelial cells. Correlations of expression with MVD, clinicopathologic features and clinical prognosis were analyzed. RESULTS: A notably higher level of GOLPH3 expression was found in early-stage NSCC tissues at the protein level. However, we do not find any correlation between GOLPH3 expression and clinicopathologic features (p>0.05), although higher MVD was positively associated with GOLPH3 overexpression (p<0.001). Expression of GOLPH3 was found to be an independent prognostic factor in early- stage NSCLC patients, those expressing high levels of GOLPH3 exhibiting a substantially lower 5-year overall survival than GOLPH3-negative patients (adjusted HR =1.899, 95% CI: 1.021-3.532, p=0.043). CONCLUSIONS: High expression of the GOLPH3 protein is common in early-stage NSCC, and is closely associated with tumor progression, increased tumor angiogenesis, and poor survival. We conclude a possibility of its use as a diagnostic and prognostic marker in early-stage NSCC patients.

SIRT1 expression is associated with lymphangiogenesis, lymphovascular invasion and prognosis in pN0 esophageal squamous cell carcinoma.

BACKGROUND: Sirtuin1 (SIRT1) is an NAD(+)-dependent type III histone deacetylase (HDAC). This research investigated the prevalence of SIRT1 protein expression and its prognostic influence with the aim of validating its potential role in lymphangiogenesis and lymphovascular invasion (LVI) in pN0 esophageal squamous cell carcinoma (ESCC). METHODS: A total of 206 patients were enrolled in this retrospective study. SIRT1 and VEGF-C protein expression was detected by immunohistochemical staining. Peritumoral lymphatic microvessel density (LVD) and LVI were evaluated by immunostaining for D2-40. Statistical analysis was then preformed to investigate the relevance of SIRT1 expression and various clinicopathologic features and to examine the effect of SIRT1 on tumor-induced lymphangiogenesis, LVI and prognosis. RESULTS: SIRT1 positive expression was identified in 95 cases in the nucleus and was significantly correlated with T status (P < 0.001), disease stage (P = 0.001), VEGF-C positive expression (P = 0.015), high LVD (P = 0.013) and positive LVI (P = 0.015). Patients with SIRT1 positive expression, high LVD and positive LVI had a significantly unfavorable 5-year disease free survival (P < 0.001, P = 0.030, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.017, and P < 0.001, respectively). However, based on multivariate Cox regression analysis, only SIRT1 positive expression and positive LVI were significant independent prognosticators of poor disease-free survival (P = 0.029 and 0.018, respectively) and overall survival (P = 0.045 and 0.031, respectively). CONCLUSIONS: SIRT1 positive expression was significantly associated with tumor progression, lymphangiogenesis, LVI and poor survival in pN0 ESCC patients. Our research shows a utilization of SIRT1 in prognosing poor survival and providing possible target for ESCC patients through inhibiting its lymphangiogenesis activity.

Metastasis-associated protein 1 nuclear expression is closely associated with tumor progression and angiogenesis in patients with esophageal squamous cell cancer.

BACKGROUND: The purposes of the present study were to detect the expression of metastasis-associated protein 1 (MTA1) in patients with esophageal squamous cell cancer (ESCC), and to evaluate the relevance of MTA1 protein expression to the tumor progression, angiogenesis, and prognosis. METHODS: Both MTA1 protein and intratumoral microvessels were examined by immunohistochemical staining in 131 ESCC patients who successfully underwent subtotal esophagectomy and esophagogastric anastomosis at Qilu Hospital between Jan 2004 and Dec 2005. Intratumoral microvessel density (MVD) was recorded by counting CD-34 positive immunostained endothelial cells. All statistical analyses were performed with SPSS 13.0 statistical software. RESULTS: High expression of MTA1 protein was detected in 57 cases and significantly correlated with tumor invasion depth (P = 0.041), lymph node metastasis (P = 0.021), pathologic stage (P = 0.003), and MVD (P = 0.044). Survival analysis showed that patients with MTA1 protein high expression had significantly poor overall 5-year survival (P = 0.002), and the factor found on multivariate analysis to significantly affect overall survival was only pathologic stage (P = 0.040). Further stratified survival analysis split by pathologic stage demonstrated that MTA1 protein high expression significantly predicted unfavorable prognosis among patients with pathologic stage II disease (P = 0.006). CONCLUSIONS: High expression of the MTA1 protein is common in ESCC, and is closely associated with tumor progression, increased tumor angiogenesis, and poor survival. These findings indicate that MTA1 protein has clinical potentials as a useful indicator of progressive phenotype, a promising prognostic predictor to identify patients with poor prognosis, and a potential novel therapeutic target of antiangiogenesis for patients with ESCC.

Overexpression of metastasis-associated protein 1 is significantly correlated with tumor angiogenesis and poor survival in patients with early-stage non-small cell lung cancer.

BACKGROUND: The aims of this work are to detect the expression levels of metastasis-associated protein 1 (MTA1) in patients with early-stage non-small cell lung cancer (NSCLC), and to investigate the relationship of MTA1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. METHODS: One hundred and two patients with pathologic stage I NSCLC who successfully underwent curative surgical resection were enrolled in this study. Immunohistochemical staining for MTA1 and CD34 was performed using the streptavidin-peroxidase method, and intratumoral microvessel density (MVD) was recorded by counting CD34-positive immunostained endothelial cells. All statistical analyses were performed with SPSS statistical software to determine the effects of MTA1 protein on clinicopathologic factors, tumor angiogenesis, and prognosis. RESULTS: MTA1 protein overexpression was detected in 41 cases and was significantly associated with MVD (P = 0.008). MTA1 protein overexpression and high MVD were significantly associated with tumor relapse (P = 0.004 and 0.007) and poor 5-year disease-free survival (P = 0.001 and 0.004). Patients with MTA1 protein overexpression and high MVD had significantly poor overall survival (P = 0.005 and 0.043) and disease-specific survival (P = 0.006 and 0.031) at 5 years after operation. Multivariate analysis demonstrated that MTA1 protein overexpression was an independent prognosticator for unfavorable disease-free, overall, and disease-specific survival (P = 0.011, 0.024, and 0.046). CONCLUSIONS: MTA1 protein overexpression is common in early-stage NSCLC and is significantly associated with tumor angiogenesis and poor survival. These findings suggest that MTA1 may have clinical potential as a promising predictor to identify individuals with poor prognostic potential and as a possible novel target molecule of antiangiogenic therapy for patients with early-stage NSCLC.

Metastasis-associated protein 1 (MTA1) overexpression is closely associated with shorter disease-free interval after complete resection of histologically node-negative esophageal cancer.

BACKGROUND: The purpose of the present study was to investigate the expression of metastasis-associated protein 1 (MTA1) and its relationship to the disease-free interval after resection of pathologic N0 (pN0) esophageal squamous cell cancer (ESCC). METHODS: The subjects were 90 patients who successfully underwent complete resection of pN0 ESCC between May 2001 and May 2003. Immunohistochemical staining for MTA1 protein was performed using the avidin-biotin peroxidase complex method. Log-rank test was performed to compare the disease-free interval, and Cox regression multivariate analysis was performed to judge independent prognostic factors. RESULTS: Metastasis-associated protein 1 overexpression was detected in 40 esophageal cancer tissues. Disease-free interval was significantly associated with MTA1 protein overexpression (p = 0.015). The overall 5-year survival rate was 45.6%, the 5-year survival rate of patients with MTA1 protein overexpression was significantly lower than that of those without overexpression (25.0 versus 62.0%; p < 0.001). The results of multivariate analysis confirmed that T status and MTA1 protein overexpression were independent prognostic factors. CONCLUSIONS: Metastasis-associated protein 1 overexpression was detected in pN0 ESCC and was significantly correlated with shorter disease-free interval. T status and MTA1 protein overexpression were both independent prognostic factors. These findings suggested MTA1 might be a predictor of relapsing phenotype and a prognostic factor in esophageal cancer.

Gene diagnosis and prognostic significance of lymph node micrometastasis after complete resection of histologically node-negative non-small cell lung cancer.

BACKGROUND: The purpose of the present study was to investigate the prevalence of lymph node micrometastasis (LNMM) based on the detection of MUC1 mRNA, and assess the impact of these micrometastases on prognosis after resection of pathologic N0 (pN0) non-small cell lung cancer (NSCLC). METHODS: The subjects were 89 patients who underwent complete resection of pN0 NSCLC at our department between January 2000 and January 2002. All lymph nodes (402 stations) obtained from these patients were re-evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) to detect MUC1 mRNA. The diagnosis of LNMM was based on the detection of MUC1 mRNA. The Kaplan-Meier method was used to calculate the survival rate, and Cox regression multivariate analysis was performed to determine independent prognostic factors. RESULTS: Micrometastases were detected in 36 lymph node stations (9.0%) from 21 patients (23.6%). The TNM staging of these 21 patients was upregulated from stage IA-IIB to stage IIIA. The 5-year survival rate of patients with LNMM was significantly lower than that of patients without LNMM (23.8% versus 44.1%; p < 0.05). The results of multivariate analysis confirmed that T status, histology, and LNMM were independent prognostic factors. CONCLUSIONS: The prevalence of LNMM in patients with pN0 NSCLC was 23.6% (21/89). T status, histology, and LNMM were independent prognostic factors.

Lymph node micrometastasis: a predictor of early tumor relapse after complete resection of histologically node-negative esophageal cancer.

PURPOSE: To investigate the prevalence of lymph node micrometastasis (LNMM) on the basis of the detection of MUC1 mRNA, and assess the impact of these micrometastases on disease-free interval after resection of pathologic N0 (pN0) esophageal squamous cell cancer (ESCC). METHODS: The subjects were 93 patients who underwent complete resection of pN0 ESCC at our department between January 1999 and January 2001. All lymph nodes (426 stations) obtained from these patients were reevaluated by reverse transcription-polymerase chain reaction to detect MUC1 mRNA. The diagnosis of LNMM was based on the detection of MUC1 mRNA. A log-rank test was performed to compare the disease-free interval, and Cox regression multivariate analysis was performed to determine the independent prognostic factors. RESULTS: Micrometastasis was detected in 40 lymph node stations (9.4%) from 32 patients (34.4%). Disease-free interval was significantly associated with LNMM (P = 0.0138). The 5-year survival rate of patients with LNMM was significantly lower than that of those without LNMM (P = 0.004). The results of multivariate analysis confirmed that T status and LNMM were independent prognostic factors. CONCLUSIONS: The prevalence of LNMM in patients with pN0 ESCC was 34.4% (32/93). Thus, LNMM was significantly associated with the disease-free interval. T status and LNMM were both independent prognostic factors.