Overexpression of ASAP1 is associated with poor prognosis in epithelial ovarian cancer

Aims: This study was conducted to analyze the clinical significance of ASAP1 in epithelial ovarian cancer (EOC). Methods: A total of 95 patients with EOC were included in the study. The expression profile of ASAP1 in 10 pairs of ovarian cancer and normal ovary tissues were detected by Real-time PCR. The expression level of ASAP1 in 95 paraffin-embedded EOC specimens was measured by immunohistochemistry staining. Statistical analysis was performed to evaluate the clinicopathologic significance of ASAP1. Results: Levels of ASAP1 mRNA were higher in EOC than in normal ovary tissues. Patients with higher ASAP1 expression had shorter overall (P=0.019) and recurrence-free (P=0.030) survival time, whereas those with lower ASAP1 expression survived longer. In addition, high expression of ASAP1 was correlated with poor overall (P=0.044) and recurrence-free (P=0.006) survival in patients with advanced carcinomas. Moreover, statistical analysis displayed a signifi cant correlation in ASAP1 expression with pelvic metastasis (P=0.015). Multivariate analysis revealed that an elevated ASAP1 expression was a significant independent prognostic factor for the overall (P=0.039) and recurrence-free (P=0.028) survival of EOC patients. Conclusion: These results indicated that elevated expression of ASAP1 plays an important role in the progression and metastasis of ovarian cancer, and that ASAP1 may be used as a biomarker in predicting patient outcome in EOC patients.     

Preoperative CA125 as a prognostic factor in stage I epithelial ovarian cancer

The purpose of the present study was to evaluate preoperative CA125 as a prognostic factor in stage I epithelial ovarian cancer (EOC). Preoperative serum CA125 levels from 118 women with FIGO (International Federation of Gynaecology and Obstetrics) stage I EOC were analysed and the prognostic value was evaluated and compared with other prognostic factors (age, grade, substages, histologic type). By the Kaplan-Meier estimate we demonstrated that patients with stage I EOC and preoperative serum CA125 levels <65 U/mL had a significantly longer survival compared to stage I EOC patients with preoperative serum CA125 > or = 65 U/mL (p=0.01). The results from the present study may be useful for decision making respecting postoperative chemotherapy in stage I EOC patients. Serum CA125 levels might therefore be included as a prognostic factor in future clinical trials of stage I EOC.     

Loss of BMP-10 is correlated with poor survival in ovarian cancer

Introduction

The expression of bone morphogenetic protein-10 (BMP-10) is downregulated in some cancer types, but its function and mechanism in ovarian cancer remains unclear.

FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer

Here, we show that overexpression of fer tyrosine kinase (FER), a non-receptor tyrosine kinase, predicts poor postoperative outcome and might be involved in cancer-cell survival in non-small cell lung cancer (NSCLC). Systematic screening using in silico analyses and quantitative RT-PCR revealed that FER was overexpressed in about 10% of NSCLC patients. Evaluation of FER expression using immunohistochemistry (IHC) on tissue microarrays was consistent with the mRNA level detected using quantitative RT-PCR. In analyses of 135 NSCLC patients who had undergone potential curative resection, we found that FER overexpression detected using IHC had no association with clinicopathological features such as age, sex, smoking history, histological type, disease stage, T factor, N factor, adjuvant chemotherapy history, or EGFR mutation, but was correlated with poor postoperative survival periods. A multivariate Cox regression analysis showed that this prognostic impact was independent of other clinicopathological features. In functional analyses of FER in vitro, FER exhibited a transforming activity, suggesting that it possesses oncogenic functions. We also found that human lung cancer NCI-H661 cells, which exhibited FER-outlier expression, were led to apoptosis by the knockdown of FER using RNA interference. FER overexpression might serve as a prognostic biomarker and be involved in cancer-cell survival in NSCLC.     

Low levels of ADAM23 expression in epithelial ovarian cancer are associated with poor survival

Background

ADAM23, a member of the disintegrin and metalloprotease (ADAM) family, has been reported to be expressed in several types of tumours. Nevertheless, the exact role of ADAM23 in epithelial ovarian cancer (EOC) remains unclear. The aim of this study was to investigate ADAM23 expression in EOC and evaluate its clinicopathological and prognostic significance.

The AgNORs count in predicting long-term survival in serous ovarian cancer

Introduction

The value of argyrophilic nucleolar organizer regions (AgNORs) to predict survival in patients with ovarian cancer has not been clearly explained yet. The aim of study was to assess the value of analysis of the mean number of AgNORs per nucleus (mAgNOR) and mean percentage of nuclei with five or more AgNORs per nucleus (pAgNOR) in the prediction of disease-free survival (DFS) and overall survival (OS) in patients with serous ovarian cancer.

Material and methods

The study examined 52 patients treated for serous ovarian cancer with a follow-up period of 2-143 months. After silver staining paraffin specimens from primary surgery, mAgNOR and pAgNOR in cancer cells were counted and analyzed. Age, grading, radicality of surgery and FIGO staging were analyzed as covariates.

Results

Mean mAgNOR equaled 4.4 ±0.9 and pAgNOR equaled 42.2 ±20.8%. Both mAgNOR and pAgNOR were the lowest in G1 tumors. The mAgNOR and pAgNOR were lower in stage I than stage IV cancers. The DFS and OS rates were respectively 15.4% and 21.2%. In univariate analysis FIGO staging, grading, and pAgNOR were associated with worse prognosis, while radicality of surgery remained a significant protective factor in terms of DFS. Higher FIGO staging and older age worsened OS. In multivariate analysis FIGO staging remained significantly associated with both DFS (HR 1.98; 95% CI 1.05-3.71) and OS (HR 1.76; 95% CI 1.00-3.10), while age affected OS rates (HR 1.78; 95% CI 1.04-2.95).

Conclusions

mAgNOR and pAgNOR are useful markers of cellular kinetics. Prospective studies in larger populations are needed to confirm these results in terms of AgNORs’ effects on survival.     

Prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) in Danish patients with recurrent epithelial ovarian cancer (REOC)

The level of the soluble urokinase plasminogen activator receptor (suPAR) is elevated in tumour tissue from several types of cancer. This is the first study aiming to predict the prognosis for survival by the use of a pre-chemotherapeutic plasma suPAR value in 71 patients with recurrent epithelial ovarian cancer (REOC). For determination of suPAR, pre-chemotherapeutic blood samples from the patients with REOC were processed into plasma (EDTA) within one working day from venipuncture. The plasma suPAR level is not correlated with performance status (p=0.41), FIGO stage (p=0.09), treatment-free interval (TFI) of 12 months (p=0.26), site of recurrence (peritoneum, p=0.50 or pelvis, p=0.44), age (p=0.43), or serum CA125 (p=0.09). Univariate as well as multivariate analyses cannot demonstrate that high pre-chemotherapeutic levels of plasma suPAR (p=0.22, p=0.80) are associated with shorter survival of REOC patients. Multivariate analysis showed that only TFI of 12 months (p=0.001) and performance score status of 2 (p=0.02) were independent prognostic factors. Our study indicates that pre-chemotherapeutic measurement of plasma suPAR level in REOC patients may not be useful to identify a subgroup of patients with poor prognosis.     

Overexpression of trophoblast cell surface antigen 2 as an independent marker for a poor prognosis and as a potential therapeutic target in epithelial ovarian carcinoma

Most patients with epithelial ovarian cancer (EOC) are diagnosed at an advanced stage, and therapeutic options for these patients are limited. The identification of suitable biomarkers could be helpful for patients with EOC, who might benefit from targeted therapies even in advanced stages of the disease. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in various human malignant tumours; however, this has not been demonstrated clearly in EOC. In this study, we further evaluated whether TROP2 is a promising marker for EOC, and thus also a potential target for EOC immunotherapy. Quantitative real‐time polymerase chain reaction (qPCR) and fluorescence‐activated cell sorting (FACS) analysis were employed to determine TROP2 mRNA and protein expression in both human EOC and normal ovarian cell lines. Additionally, TROP2 protein expression was measured by immunohistochemistry in 128 EOC tissue samples, 21 normal ovarian tissues and 18 normal fallopian tubes. The correlations between TROP2 protein expression and patients' clinicopathological features were investigated, and survival outcomes were analysed. TROP2 mRNA and protein levels were upregulated significantly in EOC cell lines compared with normal cell lines. The protein of TROP2 was expressed in the majority of EOC tissue samples (90.6%) and overexpressed in 75 (58.6%) of the 128 tumour samples. TROP2 overexpression was correlated with relevant clinicopathological characteristics and was associated with significantly shortened overall survival and disease‐free survival. Furthermore, TROP2 was an independent prognostic marker for EOCs as analysed by Cox regression. TROP2 was a potential biomarker for targeted therapy in patients with TROP2‐overexpressing EOC.     

Overexpression of UQCRC2 is correlated with tumor progression and poor prognosis in colorectal cancer

Ubiquinol-cytochrome c reductase complex core protein 2 (UQCRC2) is an important subunit of mitochondrial respiratory complex III. However, its role in tumorigenesis and tumor progression remains unknown, especially with regards to colorectal cancer (CRC). In this research, we measured the expression of UQCRC2 protein by immunohistochemistry assay in 89 paired paraffin-embedded tumor tissues and corresponding adjacent normal tissues from patients with colorectal adenocarcinoma and investigated possible correlations of UQCRC2 expression with clinicopathological parameters and prognosis. We found that UQCRC2 was significantly upregulated in CRC tissues compared with adjacent normal tissues, and immunohistochemical UQCRC2 status was correlated to the depth of invasion (T), lymph node metastasis (N), advanced TNM stage. Multivariate analysis indicated that UQCRC2 remained an independent prognostic factor for poorer overall survival. Furthermore, we determined the role of UQCRC2-knockdown in CRC cells (RKO and HCT116) using lentivirus-mediated small hairpin RNAs (shRNAs). The effects of UQCRC2 knockdown on CRC cells (RKO and HCT116) proliferation were analyzed by cell proliferation and colony formation assay, and cell cycle and apoptosis were assessed by flow cytometry. We found that silencing UQCRC2 suppressed cell proliferation and colony formation in RKO and HCT116 cells, led to a cell cycle arrest and induced cell apoptosis in vitro. These results provided novel insights into the potential role of UQCRC2 in the tumorigenesis and progression of CRC, and revealed that UQCRC2 may serve as a new prognostic and therapeutic target in CRC.     

Overexpression of FZD7 is associated with poor survival in patients with colon cancer

BackgroundOverexpression of Frizzled-7 (FZD7) has been associated with tumor invasion and distant metastases, but little is known about the relationship between FZD7 expression and prognosis in colon cancer.Patients and methodsA total of 114 patients with colon cancer between June 2010 and December 2010 were enrolled in this study. The expression of FZD7 in cancerous and adjacent non-cancerous tissues was determined by immunohistochemistry, and the association between FZD7 expression and patient’s clinicopathological characteristics was explored. The correlation between FZD7 expression and prognosis of colon cancer patients was analyzed using the Oncomine database and R2.ResultsFZD7 expression levels were significantly higher in colon cancer tissues compared with adjacent non-cancerous tissues (P < 0.001). High expression of FZD7 was significantly associated with metastatic or recurrent disease in colon cancer (P = 0.010). Kaplan-Meier survival analysis demonstrated that colon cancer patients with high expression of FZD7 had a significantly poorer OS (P = 0.013) and DFS (P = 0.010). Cox regression demonstrated that the expression of FZD7 was an independent prognostic factor for DFS (HR = 6.647, P = 0.023). A meta-analysis from the Oncomine database demonstrated that FZD7 mRNA levels were significantly higher in colorectal cancer tissues than in normal colorectal tissues, and FZD7 high expression was associated with a significantly poorer event and relapse-free survival time by analyzing the data from the R2: Genomics Analysis and Visualization Platform.ConclusionsOverexpression of FZD7 was associated with poor survival in patients with colon cancer. Our data suggest that FZD7 expression could be an effective prognostic biomarker for colon cancer.     

WAVEs亚家族在卵巢癌中的表达及临床意义

目的 探讨WAVEs亚家族在卵巢癌(oc)中的表达及其与临床病理特征的关系.方法 用免疫组化法检测60例OC、25例卵巢交界性肿瘤、30例卵巢良性肿瘤和21例正常卵巢组织中WAVEs蛋白的表达,结合临床病理资料进行分析;反转录聚合酶链反应法(RT-PCR)和Western blot分别检测WAVEs mRNA和蛋白表达.结果 1)WAVE1在OC中的表达显著高于正常卵巢组织、卵巢良性组织和卵巢交界性组织(P＜0.01).2)WAVE1在OC中的表达与临床分期、病理分化程度及Ca-125水平密切相关(.P＜0.05),而与年龄、肿瘤大小及腹水量无关.3)WAVE1在OC中mRNA、蛋白水平显著高于正常卵巢组织、卵巢良性肿瘤和交界性肿瘤(P＜0.01).而WAVE2、WAVE3在各组表达均低.结论 WAVE1在OC中高表达,可能与其发生发展及侵袭转移有关,可望成为卵巢癌治疗的靶标.     

The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer

Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation‐induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule‐associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression‐free (p = 0.0232), disease‐specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease‐specific [hazard ratio (HR): 2.55 (95% CI 1.21–5.37); p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00–3.77); p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia‐related proteins carbonic anhydrase‐IX and HIF‐1α. The functional link between hypoxia and autophagy was demonstrated using clear cell and high‐grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high‐grade serous lines. Together, our findings indicate that hypoxia‐induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High expression of MAGE-A9 in tumor and stromal cells of non-small cell lung cancer was correlated with patient poor survival

Melanoma associated antigen-A (MAGE-A) is an oncogene and correlated with tumor initiation and development. However the roles of MAGE-A9 in non-small cell lung cancer (NSCLC) are still unknown. We investigated MAGE-A9 mRNA expression in 18 tumor tissues of NSCLC by qRT-PCR and MAGE-A9 protein expression in 213 NSCLC samples of tissue arrays by immunohistochemical staining. We assessed the relationship between MAGE-A9 expression and clinical parameters. The results showed that the high expression of MAGE-A9 protein in NSCLC tumor cells were commonly present in squamous cell carcinomas (P = 0.030). It was also related to larger tumor diameter, lymph node metastasis and later stage grouping with TNM classification (all P < 0.05). Whereas the expression of MAGE-A9 in stromal cells was higher in squamous cell carcinomas as well. Cox regression univariate and multivariable analysis revealed that MAGE-A9 expression in tumor cells of NSCLC (P < 0.001) is an independent prognostic factor in five-year overall survival rate. We concluded that the molecular assessment of MAGEA9 could be considered to improve prognostic evaluation and to identify eligible patients for potential target therapy.     

Overexpression of histone demethylase JMJD5 promotes metastasis and indicates a poor prognosis in breast cancer

In this study, we showed the expression of JMJD5 was increased in breast cancer tissues and breast adenocarcinoma cell lines MCF-7 as well as triple negative breast cancer cell lines MDA-MB-231 compared with paired adjacent normal mammary tissues and normal mammary epithelial cell lines MCF-10A. The higher expression of JMJD5 was significantly corresponded with clinical stage, histological grade and lymph node metastasis. Overexpression of JMJD5 promoted cell invasion and induce EMT, while JMJD5 siRNA inhibits MDA-MB-231 cells invasion in vitro. Moreover, qChIP analysis revealed the Snail family proteins Snai1 was the direct target of JMJD5 in breast cancer cells. Luciferase reporter assays suggested that the overexpression of JMJD5 resulted in the activation of Snail1 promoter-driven luciferase reporter. The changes in the level of RNA and protein implied that the activation of Snail was the important mechanisms by which JMJD5 triggers metastasis. We also detected the higher expression of JMJD5 protein was an independent unfavorable biomarker for worse overall survival in breast cancer patients. Therefore, our results identified an important role for JMJD5 in breast cancer through the regulation of snail1.     

Association of pancreatic adenocarcinoma up-regulated factor expression in ovarian mucinous adenocarcinoma with poor prognosis

Pancreatic adenocarcinoma up-regulated factor (PAUF) expression is elevated in both ovarian tumors and pancreatic adenocarcinoma. However, PAUF expression in ovarian tumors according to histologic subtype and grade has not been investigated. In this study, we examined various clinicopathologic features of 24 patients with mucinous cystadenoma (MCA), 36 with mucinous borderline tumors (MBTs), and 46 with mucinous adenocarcinomas (MACs) according to PAUF expression status assessed using immunohistochemistry. We found that MACs more frequently stained positive for PAUF than did MCAs and MBTs (P < 0.0001). Although there was no significant differences with respect to other clinicopathologic characteristics of MACs according to PAUF expression status, patients with PAUF-weakly positive and PAUF-strongly positive MACs tended to have a shorter overall survival (OS) than those with PAUF-negative MAC, determined using a Kaplan–Meier analysis (P = 0.1885). After adjusting for various clinicopathologic parameters, PAUF positivity of MACs was a significant predictive factor for disease-free survival (DFS) (negative vs. weakly positive: P = 0.045, hazard ratio [HR] = 57.406, 95% confidence interval [CI]: 1.090-3022.596; and negative vs. strongly positive: P = 0.034, HR = 97.890, 95% CI: 1.412-6785.925). In conclusion, PAUF was more frequently expressed in MAC than in its benign and borderline counterparts, and was associated with a poor OS and DFS in MAC patients. Therefore, we suggest that PAUF may be a practical biomarker for histopathological categorization and a prognostic marker for patients with an ovarian mucinous tumor.     

Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype

Multiple fibroblast growth factor (FGF) axis alterations are known to occur in prostate cancer. Here we simultaneously profiled key components of this axis to determine their relevance in disease progression. An optimized immunohistochemistry protocol was used in expression analysis of FGF2, FGF8, FGFR1, FGFR4, and Sef (similar expression to FGF) in a single TMA of prostate cancer. FGF ligands and receptors were overexpressed in cancers compared to benign samples (p < 0.0001), while Sef expression was reduced (p < 0.0001). There was a positive association between higher grades and increased FGFR4 (p = 0.02), FGF2, and FGF8 (p = 0.002 and p < 0.0001). Sef expression was progressively lower with increasing grade (p = 0.005). Clinical stage was positively associated with FGF2, FGF8, and FGFR4 expression (p = 0.005, 0.03, and 0.012) but not with FGFR1 or Sef expression. Only reduced Sef was associated with bone metastasis (p = 0.02) and was also predictive of subsequent metastasis in initially localized tumours (p = 0.004). Down‐regulation of Sef and increased FGFR4 were also the only independent variables associated with disease‐specific survival (HR 1.73, p = 0.04 and HR 0.56, p = 0.01). In in vitro studies, silencing Sef enhanced the cell response to FGFs (p < 0.001) and substantially mitigated the effectiveness of an FGFR1 inhibitor. Conversely, increased Sef blocked the response to FGFs and had a comparable suppressive effect to the inhibitor. This study demonstrates that increased FGFR4 and reduced Sef may be critical FGF alterations associated with prostate cancer progression. Sef may also have a role in the tumour response to FGFR inhibition and warrants further investigation in this context. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.