Down-regulation of microRNA152 is associated with the diagnosis and prognosis of patients with osteosarcoma

Potential values of microRNA152 (miR-152) as a serum diagnostic and prognostic biomarker have not been determined in human osteosarcoma. By detecting the expression of miR-152 among 80 osteosarcoma patients, 20 periostitis patients and 20 healthy individuals using qRT-PCR, we aimed to explore the clinical significance of miR-152 in osteosarcoma patients. The expression of miR-152 was significantly decreased in patients with osteosarcoma compared to patients with periostitis (P<0.01) and healthy controls (P<0.01). The relationship between clinicopathologic characteristics and miR-152 was analyzed by chi-square test. The outcome indicated that miR-152 might be linked with the development of osteosarcoma. Moreover, the receiver operating characteristic (ROC) curve was performed to estimate the diagnostic value of miR-152. The result demonstrated that miR-152 might be a promising diagnostic marker of osteosarcoma with an AUC of 0.956, combing with 92.5% specificity and 96.2% sensitivity. The relationship between miR-152 and overall survival of osteosarcoma patients was analyzed by Kaplan-Meier curve and log rank test. As a result, the survival time of patients with low miR-152 expression was significantly shorter than those with high miR-152 expression (P<0.001). Then Cox regression analysis was used to estimate the prognostic value of miR-152 in osteosarcoma. The outcomes showed that low miR-152 expression (P=0.004) might be a potential independent prognostic marker for osteosarcoma patients. These findings suggested that down-regulation of miR-152 could be considered as a predictor for diagnosis and prognosis of osteosarcoma patients.     

Increased MT2-MMP expression in gastric cancer patients is associated with poor prognosis

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that contribute to tumorigenesis and metastasis due to their ability to degrade the extracellular matrix (ECM) and basement membrane. In despite of many reports in other solid tumors, the role of membrane type-2 MMP (MT2-MMP) in gastric cancer (GC) remains to be elucidated. The aim of this study was to investigate MT2-MMP expression in human GC tissue microarray (TMA) samples using immunohistochemistry (IHC). We found that MT2-MMP expression in tumor tissues was significantly higher compared to peritumoral tissues (P < 0.01). However, there were no statistically significant differences between MT2-MMP expression and clinicopathological parameters. In addition, univariate and multivariate Cox regression analysis showed GC patients with high MT2-MMP expression have poor overall survival (OS) compared to patients with low MT2-MMP expression (P = 0.013, P = 0.040, respectively). In conclusion, MT2-MMP is involved in GC invasion and metastasis and may serve as an independent prognostic factor for GC patients.     

Interleukin-17A gene polymorphism is associated with susceptibility to gastric cancer

We conducted a study to investigate the role of three common SNPs in the IL-17A and IL-17F genes (rs2275913G>A, rs3748067C>T and rs763780T>C) in the development of gastric cancer, and their interaction with H.pylori infection. A total of 326 patients with gastric cancer and 326 control subjects were consecutively recruited between May 2012 and May 2014. Genotyping of IL-17A rs2275913G>A and rs3748067C>T and IL-17F rs763780T>C was performed in a 384-well plate format on the Sequenom MassARRAY platform. By logistic regression analysis, individuals carrying the GA and AA genotypes of IL-17 rs2275913G>A were significantly associated with an increased risk of gastric cancer when compared with GG genotype, and the adjusted Ors (95% CI) were 1.46 (1.03-2.06) for GA genotype and 2.57 (1.51-4.43) for AA genotype. We observed that the GA+AA genotype of rs2275913 was associated with an increased risk of gastric cancer among H.pylori infection subjects (OR=2.21, 95% CI=1.29-3.79). In conclusion, we found that there was a significant association between L-17A rs2275913G>A polymorphism and increased gastric cancer risk, especially in H.pylori infection subjects.     

Down-regulation of PAX6 by promoter methylation is associated with poor prognosis in non small cell lung cancer

Background: Promoter methylation is an alternative mechanism of gene silencing in human tumorigenesis. Although a number of methylated genes have been found in non small cell lung cancer (NSCLC), useful methylation markers for early prognostic evaluation of NSCLC remain largely unknown. Methods: Using methylation-specific PCR (MSP), we examined promoter methylation status of PAX6 gene, and explored their association with clinical features in NSCLC via chi-square test. NSCLC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses. Results: The methylation level of PAX6 gene was higher in tumor tissues than that in normal tissues. In addition, PAX6 promoter methylation showed a very significant correlation with differentiation (P = 0.002), distant metastasis (P = 0.024), and TNM stage (P = 0.002). PAX6 gene promoter hyper-methylation was found to be significantly associated with poor overall survival (P = 0.018) and to serve as an independent marker for prognosis using multivariate Cox regression analysis (HR: 2.254, 95% CI: 1.088-4.667, P = 0.029). Conclusion: We found that PAX6 gene was specifically methylated in NSCLC, and demonstrated the effect of promoter methylation of PAX6 gene on clinical outcome in NSCLC, indicating the methylated PAX6 may be useful biomarkers for prognostic evaluation in NSCLC.     

Overexpression of HLA-DR is associated with prognosis of glioma patients

Aims: Since the poor prognosis of glioma, our study was aimed to find out the role of HLA-DR in the prognosis of glioma patients that may contribute to the timely post-operative treatment on the glioma patients. Methods: 60 glioma patients were enrolled in the prospective cohort study. Western blotting was used to detect the content of HLA-DR. Kaplan-Meier curve was adopted to evaluate the effects of HLA-DR on the survival time of glioma patients. Cox regression analysis was used to evaluate the roles of clinical features and HLA-DR in the pathogenesis of glioma. Results: The expression level of HLA-DR was higher in tumor tissue, compared with normal tissues (P < 0.05). Moreover, expression levels of HLA-DR were correlated with the factors of pathological degree, Enneking staging and KPS score. The survival rate of patients with high content of HLA-DR was lower than those of patients with low content of HLA-DR. Cox regression analysis indicated that Enneking staging and HLA-DR were all associated with the prognosis of glioma (HR=14.43, 95% CI=1.05-199.16; HR=21.39, 95% CI=2.07-220.76). Conclusion: HLA-DR may serve as a biomarker for the prognosis of glioma patients.     

Low CA II expression is associated with tumor aggressiveness and poor prognosis in gastric cancer patients

Background: Carbonic anhydrase II is present in normal gastric mucosa; thus, this study aimed to investigate whether its expression persisted in neoplastic gastric tissues, as well as its prognostic value for gastric cancer patients. Methods: The protein CA II expression pattern was retrospectively analyzed by immunohistochemistry in 181 gastric cancer patients who had undergone gastrectomy. The relationship between the CA II expression level and clinicopathological parameters was investigated. Survival analysis according to CA II expression was measured by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of CA II expression. Results: CA II expression was significantly decreased in gastric cancer tissues compared with normal stomach mucosa. Low expression was significantly associated with tumor size, depth of invasion, lymph node involvement, distant metastasis and TNM stage, and it predicted poor survival in gastric cancer patients. Moreover, CA II was an independent prognosis indicator for the overall survival of gastric cancer patients. Conclusions: The down-regulation of CA II expression was observed in gastric cancer and may serve as an independent prognostic factor for the overall survival of gastric cancer patients.     

Overexpression of CD39 and high tumoral CD39+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer

CD39/ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) is a cell surface-located, rate-limiting enzyme in the generation of adenosine, and plays a crucial role in tumor development. We examined co-expression of CD39 and CD8in gastric cancer (GC) and showed that the expression of CD39 and CD8 increased significantly in tumor tissues compared to paired peritumor tissues. The expression of tumoral CD39 (tCD39), but not tumoral CD8 (tCD8), was related to overall survival. Furthermore, the CD39⁺/CD8⁺ ratio was associated with poor prognosis in resected GC patients. Taken together, our data indicate that highCD39 expression and high tCD39⁺/CD8⁺ ratio in GC is a predictor of poor prognosis for GC patients after radical resection. Moreover, CD39 could serve as a potential target for cancer immunotherapy.     

Identification of long noncoding RNA TC0101441 as a novel biomarker for diagnosis and prognosis of gastric cancer

The present work aimed to explore the prognostic values of lncRNA TC0101441 (TC0101441) in patients with gastric cancer (GC). The expression of TC0101441 in a total of 159 GC specimens and matched normal specimens was detected by quantitative RT-PCR. ROC assays were conducted to determine the diagnostic value of TC0101441 expression in GC patients. The association of TC0101441 expression with clinical characteristics of 159 patients was analyzed using chi-square test. Kaplan-Meier methods were employed to determine the prognostic value of TC0101441 expression in the survival rate of GC patients. Multivariate Cox regression assays were used to identify whether TC0101441 could be a prognostic biomarker for GC patients. We found that TC0101441 expression was significantly increased in GC specimens compared to that in the normal specimens (P < 0.01). High TC0101441 expression was correlated with lymphatic metastasis (P = 0.027) and TNM stage (P = 0.015). TC0101441 could distinguish GC specimens from adjacent normal gastric specimens with an area under the receiver operating characteristic curve (AUC) of 0.8082. Survival data revealed that patients with high TC0101441 expression had worse overall survival (P = 0.0009) and disease-free survival (P < 0.0001) rates than those with low TC0101441 expression. Multivariate assays showed that TC0101441 expression was an independent biomarker for GC patients. The present study suggested that TC0101441 expression was increased in GC and may be aprognostic and diagnostic biomarker for GC.     

Long non-coding RNA CCAT2 is up-regulated in gastric cancer and associated with poor prognosis

Introduction: Dysregulation of long non-coding RNAs (lncRNAs) play important roles in tumor progression. The aim of our study was to explore the clinicopathologic and prognostic significance of lncRNA CCAT2 expression in human gastric cancer. Methods: Expression levels of lncRNA CCAT2 in 85 pairs of gastric cancer and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: Expression levels of lncRNA CCAT2 in gastric cancer tissues were significantly higher than those in adjacent non-tumor tissues. By statistical analyses, high lncRNA CCAT2 expression was observed to be closely correlated with higher incidence of lymph node metastasis and distance metastasis. Moreover, patients with high lncRNA CCAT2 expression had shorter overall survival and progression-free survival compared with the low lncRNA CCAT2 group. Multivariate analyses indicated that high lncRNA CCAT2 expression was an independent poor prognostic factor for gastric cancer patients. Conclusions: Our results suggested that up-regulation of lncRNA CCAT2 was correlated with gastric cancer progression, and lncRNA CCAT2 might be a potential molecular biomarker for predicting the prognosis of patients.     

Decreased expression of SEMA3A is associated with poor prognosis in gastric carcinoma

Background/purpose: SEMA3A (semaphorin-3A), is a secreted protein that belongs to the semaphorin family and can function as both a chemoattractive agent or a chemorepulsive agent. SEMA3A has been shown to be a tumor suppressor in various cancers. This study investigated the expression of SEMA3A in gastric cancer and its prognostic value for gastric cancer patients. Methods: We examined the expression of SEMA3A in paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. In vitro, we evaluate the effects of SEMA3A on gastric cancer cell proliferation and migration by MTT, transwell and wound-healing assays. Furthermore, we analyzed SEMA3A expression in 128 patients who underwent resection procedures using immunohistochemistry. The relationships between the SEMA3A expression levels, the clinicopathological factors, and patient survival were investigated. Results: Our results revealed decreased SEMA3A mRNA (P = 0.0037) and protein (P = 0.033) expression in tumor tissue samples compared with matched adjacent non-tumorous tissue samples. Overexpression of SEMA3A inhibits gastric cancer cell proliferation and migration in vitro. Immunohistochemical staining data showed that SEMA3A expression was significantly decreased in 54.68% of gastric cancer cases. In addition, the chi-square test revealed that low SEMA3A expression was significantly correlated with poor differentiation (P = 0.015), Vascular invasion (P = 0.001), depth of invasion (P < 0.001), lymph node metastasis (P = 0.029), distant metastasis (P = 0.002) and advanced TNM stage (P = 0.003). SEMA3A expression was positively correlated with clinical TNM stage, that suggested the more advanced clinical TNM stage corresponding to the lower expression level of SEMA3A (r_s = -0.322, P < 0.001) by Spearman rank correlation analysis. Kaplan-Meier survival analysis demonstrated that low expression of SEMA3A was significantly correlated with a poor prognosis for gastric cancer patients (P < 0.001). The multivariate analysis revealed that SEMA3A expression was an independent prognostic factor of the overall survival rate of patients with gastric cancer. Conclusion: SEMA3A expression decreased significantly as gastric cancer progressed and metastasized, suggesting that SEMA3A might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.     

早期胃癌规范化诊治流程及预后因素

胃癌依然是世界范围内最常见的癌症之一。近些年,在日本,早期胃癌(early gastric cancer,EGC)约占胃癌治疗患者的57%,而在中国,该比例却不足10%。包括内镜粘膜下剥离术(endoscopic submucosal dissection,ESD)和内镜下粘膜切除术(endoscopic mucosal resection,EMR)在内的微创手术,对于EGC患者而言是治愈性的治疗,而且患者会获得很好的预后。对于EGC而言,规范化诊治流程非常重要。首先,内镜、超声内镜及组织学检查是筛选微创手术患者的关键步骤。第二,仔细评估微创手术标本可以为将来可能的外科干预提供重要信息,这些信息包括脉管瘤栓、肿瘤体积、组织学类型、浸润深度。此外,淋巴细胞浸润情况,淋巴管侵犯、HER2/neu、Mucin-4、VEGF C、VEGF D过表达是EGC的预后因素。     

Immunohistochemical analysis of colorectal cancer with gastric phenotype: Claudin‐18 is associated with poor prognosis

Claudin‐18 plays a key role in constructing tight junctions, and altered claudin‐18 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin‐18 in colorectal cancer (CRC). The aim of this study is to investigate the significance of claudin‐18 expression in CRC and its association with clinicopathological factors. We performed clinicopathological analysis of claudin‐18 expression in a total of 569 CRCs by immunohistochemistry. Moreover, we investigated the association between claudin‐18 and various markers including gastric/intestinal phenotype (MUC5AC, MUC6, MUC2 and CD10), CDX2, claudin‐3, claudin‐4, p53 and Ki‐67. Claudin‐18 expression was detected in 21 of the 569 CRCs (4%) and was seen exclusively on the cell membrane. Positive expression of claudin‐18 showed a significant correlation with positive expression of MUC5AC (P < 0.0001) and negative expression of CDX2 (P= 0.0013). The prognosis of patients with positive claudin‐18 expression was significantly poorer than in negative cases (P= 0.0106). Multivariate analysis revealed that T grade, M grade and claudin‐18 expression were independent predictors of survival in patients with CRC. We revealed that claudin‐18 expression correlates with poor survival in patients with CRC and is associated with the gastric phenotype.     

HOXD13 methylation status is a prognostic indicator in breast cancer

Homeobox protein Hox-D13 is encoded by HOXD13 gene which is frequently methylated in cancer and has been recognized as a tumor suppressor in pancreatic cancer. In this study, we examined HOXD13 mRNA expression in 40 pairs of breast cancers and corresponding normal breast tissues. Bisulfite sequencing of HOXD13 promoter was performed in 6 pairs of breast tumors and corresponding normal breast tissues to examine the potential HOXD13 CpG methylated sites. HOXD13 DNA methylation frequency analysis was performed using MethyLight in 196 pairs of breast cancers and corresponding normal breast samples. DNA methylation status and clinico-pathological features were investigated. Kaplan-Meier survival analysis and Cox proportional hazards models were utilized to assess the effect of methylation status on overall survival. We found that 60% (24/40) of breast cancers showed low HOXD13 mRNA expression when compared with corresponding normal breast tissue. The predicted CpG island was located in the -1325 bp to +675 bp region. Next, the -332 bp site in HOXD13 gene promoter was further examined and in 57.7% (113/196) samples methylation was detected at this site. HOXD13 methylation was correlated with larger tumor size (P = 0.004), but not with other clinico-pathological parameters. In addition, patients with methylated -HOXD13 promoter had worse overall survival (OS) (P = 0.005). Based on our results we conclude that HOXD13 methylation is a common event in primary breast cancer and is associated with poor survival of breast cancer patients. HOXD13 methylation could therefore potentially be used as a prognostic factor for breast cancer.     

Up-regulation of ROR2 is associated with unfavorable prognosis and tumor progression in cervical cancer

Aims: To investigate the clinical significance of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in cervical cancer. Methods: We examined ROR2 levels in 8 pairs of surgically resected cervical cancer and adjacent normal cervical tissues by real-time PCR. Moreover, we performed immunohistochemistry to examine ROR2 expression in 94 paraffin-embedded cervical cancer samples and analyzed the association between ROR2 expression, clinicopathologic factors and prognosis. Results: ROR2 expression was up-regulated in cervical cancer tissues compared with adjacent normal cervix. In paraffin-embedded cervical cancer samples, high expression of ROR2 was shown in 40 (42.6%) of 94 cases, also, it was significantly associated with tumor stage (P = 0.018) and lymph nodes metastasis (P = 0.013). Moreover, survival analysis showed that ROR2 expression was an independent prognostic factor of poor overall and recurrent free survival (P = 0.045 and 0.001, respectively). Conclusion: These results indicate that ROR2 is significantly correlated with cancer progression and poor prognosis in cervical cancer.     

MOK overexpression is associated with promoter hypomethylation in patients with acute myeloid leukemia

Overexpression of MAPK/MAK/MRK overlapping kinase (MOK) has been found in various tumors. However, the mechanism underlying MOK upregulation remains unclear. A CpG island was identified in MOK promoter. In this study, we evaluated the expression and methylation status of MOK gene in acute myeloid leukemia (AML). Hypomethylation of MOK promoter was detected in 31.0% (45/145) of AML patients. The degree of MOK hypomethylation was significantly correlated with MOK expression in AML patients. MOK-hypomethylated patients had a trend towards lower WBCs. Receiver operating characteristic curve (ROC) analysis showed a good performance in distinguishing AML patients from controls with an area under the ROC curve (AUC) of 0.820 (P < 0.001). In summary, our results suggest MOK promoter hypomethylation is a common event and contributes to MOK overexpression in AML.     

FHIT gene in gastric cancer: association with tumour progression and prognosis

The FHIT (fragile histidine triad) gene has been recently identified and cloned at chromosome 3p14.2 including FRA3B, the most common fragile site in the human genome. FHIT is suggested to be a candidate tumour suppressor gene in gastrointestinal tract tumours. To elucidate the role of the FHIT gene in gastric cancer, a total of 133 curatively R0-resected gastric carcinomas were investigated for loss of heterozygosity (LOH) at 3p14.2, using four polymorphic microsatellite loci (D3S1300, D3S1313, D3S1481, and D3S1234). LOH of the FHIT gene affecting at least one of the investigated loci was observed in 20 of 123 informative tumours (16·3 per cent). The presence of LOH was correlated neither with major prognostic factors such as pT category, pN category or vascular invasion, nor with histological type or grade of differentiation of the tumours. In addition, there were no differences in the prognosis between patients with gastric carcinomas showing LOH at the FHIT gene and patients with tumours lacking LOH at the FHIT gene. These findings suggest that LOH of the FHIT gene represents an event in the tumourigenesis of only a small subset of gastric carcinomas and does not correlate with tumour progression or prognosis. Copyright © 1999 John Wiley & Sons, Ltd.     

Decreased SARI expression predicts poor prognosis of Chinese patients with non-small cell lung cancer

SARI is associated with the risk for several cancers, and loss of SARI expression is frequently found in aggressive and metastatic cancer. Limited evidence shows that SARI is a tumor suppressor gene, but the role of SARI in non-small cell lung cancer (NSCLC) has not been previously reported. This study was to investigate the SARI expression profile in surgically resected lung cancer tissues of Chinese patients by immunohistochemistry and evaluate the relationship between SARI expression and prognosis of lung cancer patients. Furthermore, SARI gene was transfected into lung cancer cells (A549), and the growth curve and cell healing of lung cancer cells were determined, aiming to investigate the influence of SARI on the growth and migration of lung cancer cells in vitro. Results showed that 103 of 195 (52.82%) tissues were positive for SARI. When compared with normal tissues, SARI expression significantly reduced in 50.26% of NSCLC tissues. Patients with negative or reduced SARI expression were more likely to have advanced lung cancer and lymph node metastasis. In squamous carcinoma and adenocarcinoma patients, the SARI expression had no relation with the survival time; However in one-on-one analysis SARI expression in tumor cells and adjacent tissues, patients which tumor cells SARI express reduced than adjacent tissues, survival time was significantly shorter than those without reduction in SARI expression (Log Rank test, p = 0.001). After transfection by SARI gene, the proliferation and migration of A549 cells were obviously inhibited (p < 0.001). These results demonstrate that decreased SARI expression may predict a poor prognosis in NSCLC patients, and SARI may serve as a prognostic biomarker and potential therapeutic target for lung cancer.