Prognosis Of Pancreatic Carcinoma Research Articles

ROLE OF CARBOHYDRATE ANTIGEN (CA19-9) AND CARCINOEMBRYONIC ANTIGEN (CEA) AS A PROGNOSTIC FACTORS IN PANCREATIC CARCINOMA

Objective:To investigate the potential utility of pre-treatment carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) as prognostic indicators to assess prognosis in pancreatic carcinoma. MaterialsandMethods:This retrospective observational study was carried out at the Department of General Surgery Hayatabad Medical Complex Peshawar from July 2017 to June 2022. A total of 70 patients with the diagnosis of pancreaticcarcinoma were enrolled.Allpatientswerehistologicallydiagnosedwithpancreaticcarcinoma. ThelevelsofCA19-9andCEAwereevaluatedbeforetreatment.Allpatientsreceivedeitheranoperation,chemotherapy or chemoradiotherapy (CRT), and patientswho only received supportive care, palliative surgery or othertreatmentswerenotincludedinthestudy.Patients with a history of other malignancies were excluded. Results:A total of 70 patients were included in this study. Age ranged between 25-75 years, with a mean age of 50 years. Included patients were stratified into 2 groups (35 each) in regard to their preoperative CEA & CA 19-9 level. Group 1: (Normal serum level group, CEA level value <5ng/ml & CA19-9 <37 U/ml), Group 2: (Elevated level group ≥5ng/ml & ≥37 U/ml)There were 19(54.3%) males and 16(45.7%) females in group 1 with male to female ratio of 1.18:1 and 18(51.4%) male & 17(48.6%) females in group 2 with male to female ratio 1.05:1. CA 19-9 and CEA were evaluated at initial diagnosis,andthemedianlevelswere37U/mL(range,0.1-20000U/mL) and 3.4 ng/mL (range, 0.04-8566 ng/mL), respectively. Conclusion:Patientswithelevated serum CEA levels at diagnosis demonstrated poor overall survival. Pre-treatment CEA level may predict the prognosis of patients with pancreatic adenocarcinoma.

TCF12 activates MAGT1 expression to regulate the malignant progression of pancreatic carcinoma cells.

As a highly malignant gastrointestinal tumor, pancreatic carcinoma (PC) has poor prognosis due to its low early diagnosis rate, advanced tumor resection and chemotherapy resistance. Magnesium transporter 1 (MAGT1) is a magnesium ion transporter located on the cell membrane, which shows promotive effects on biological behaviors of multiple tumor cells. The aim of the present study was to investigate the role of MAGT1 in the progression of PC and its potential molecular mechanism. Based on the Gene Expression Profiling Interactive Analysis website, MAGT1 was highly expressed in tissues from patients with PC and was associated with poor prognosis. In functional experiments, MAGT1 was highly expressed in PC cell lines. The Cell Counting Kit-8, gap closure and Transwell assays, and western blot analysis, were used to investigate the effects of MAGT1 overexpression or knockdown on the biological behaviors of PC cells. It was found that MAGT1 promoted the proliferation, migration and invasion of PC cells in vitro. According to the Encyclopedia of RNA Interactomes website, transcription factor 12 (TCF12) mRNA expression level was positively correlated with MAGT1 expression level in the tissues from patients with PC. Positive targeting regulation of MAGT1 by TCF12 was also confirmed using a dual-luciferase gene reporter assay and chromatin immunoprecipitation. In addition, knockdown of TCF12 expression inhibited the proliferation and migration of PC cells, but overexpression of MAGT1 expression partly reversed this. These results suggested that TCF12 could promote the proliferation, migration and invasion of PC cells by activating MAGT1 expression, which was associated with poor prognosis. These findings suggest that MAGT1 could be a promising biomarker for the occurrence, progression and prognosis of PC.

Identification of Acute Pancreatitis-Related Genes and Pathways by Integrated Bioinformatics Analysis.

The present study aimed to identify the differential expressed genes that are related to acute pancreatitis. Microarray datasets GSE109227 and GSE3644 were downloaded from the public database and analyzed to screen the genes. Afterward, integrated analysis of these genes were performed, including gene ontology and pathway enrichment analysis, protein-protein interaction network construction, expression level evaluation in human organs, relevant miRNAs and TFs prediction, and prognosis values of hub genes in pancreatic carcinoma. A total number of 93 differential expressed genes were screened from the datasets, and EGFR, CDH1, ACTB, CD44, and VCL were identified as hub DEGs. Functional enrichment analysis demonstrated that these genes were mostly enriched in biological processes such as cell adhesion, platelet aggregation, glycoprotein binding, and also involved in multiple pathways included adherent junction, proteoglycans in cancer, bacterial invasion of epithelial cells, focal adhesion, Rap1 signaling pathway, regulation of actin cytoskeleton, and pathways in cancers. The five hub genes were all expressed in human pancreas organs with various levels. Hub gene-related network investigation predicted core miRNAs including hsa-mir-16-5p and main TFs like SOX9 with close interactions with these hub genes. Survival analysis also indicated that the high expression of EGFR, CDH1, ACTB, CD44, and VCL were significantly associated with poor prognosis in pancreatic carcinoma. The study suggested that hub genes EGFR, CDH1, ACTB, CD44, and VCL may play vital role in the pathogenesis of acute pancreatitis and may serve as potential biomarkers to facilitate future acute pancreatitis diagnosis and treatment.

Gene signature associated with neuro-endocrine activity predicting prognosis of pancreatic carcinoma.

BackgroundGenomic analysis is the promising tool to clear understanding of the tumorigenesis and guide molecular classification for pancreatic cancer. Our purpose was to develop a critical predictive model for prognosis in pancreatic carcinoma, based on the genomic data.MethodsThe online The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets were queried as training and validation cohorts for comprehensive bioinformatic analysis. We applied Lasso and multivariate Cox regression to shrink genes and construct predictive model.ResultsA four genes model (DNAH10: HR = 0.71, 95% CI = 0.57–0.88, HSBP1L1: HR = 1.51, 95% CI = 1.18–1.92, KIAA0513: HR = 0.69, 95% CI = 0.50–0.96, and MRPL3: HR = 3.73, 95% CI = 2.03–6.86), was proposed and validated. The C‐index was 0.73 (95% CI: 0.7–0.77). Patients in high‐risk and low‐risk group, stratified by model, suffered significantly different overall survival time (15.1 vs. 49.3 months, p < 0.0001 in TCGA; 423 vs. 618 days, p = 0.038 in ICGC). Taken clinical parameters into consideration, the risk‐score was independent marker in clinical subpopulation. To explore the molecular mechanisms, 579 differential expression genes (DEG) in two groups were identified by edgeR. Functional enrichment of DEG indicated neuro‐endocrine activity was the potential mechanism for the discrepant prognosis.ConclusionA specific four genes signature with the ability to predicted survival of pancreatic carcinoma was generated, which may indicate the connection between neuro‐endocrine activity and patients’ prognosis.

Identification of candidate diagnostic and prognostic biomarkers for pancreatic carcinoma.

BackgroundPancreatic carcinoma (PC) is one of the most aggressive cancers affecting human health. It is essential to identify candidate biomarkers for the diagnosis and prognosis of PC. The present study aimed to investigate the diagnosis and prognosis biomarkers of PC.MethodsDifferentially expressed genes (DEGs) were identified from the mRNA expression profiles of GSE62452, GSE28735 and GSE16515. Functional analysis and the protein-protein interaction network analysis was performed to explore the biological function of the identified DEGs. Diagnosis markers for PC were identified using ROC curve analysis. Prognosis markers were identified via survival analysis of TCGA data. The protein expression pattern of the identified genes was verified in clinical tissue samples. A retrospective clinical study was performed to evaluate the correlation between the expression of candidate proteins and survival time of patients. Moreover, comprehensive analysis of the combination of multiple genes/proteins for the prognosis prediction of PC was performed using both TCGA data and clinical data. In vitro studies were undertaken to elaborate the potential roles of these biomarkers in clonability and invasion of PC cells.FindingsIn total, 389 DEGs were identified. These genes were mainly associated with pancreatic secretion, protein digestion and absorption, cytochrome P450 drug metabolism, and energy metabolism pathway. The top 10 genes were filtered out following Fisher's exact test. ROC curve analysis demonstrated that TMPRSS4, SERPINB5, SLC6A14, SCEL, and TNS4 could be used as biomarkers for the diagnosis of PC. Survival analysis of TCGA data and clinical data suggested that TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can be potential biomarkers for the prognosis of PC. Comprehensive analysis show that a combination of identified genes/proteins can predict the prognosis of PC. Mechanistically, the identified genes attributes to clonability and invasiveness of PC cells.InterpretationWe synthesized several sets of public data and preliminarily clarified pathways and functions of PC. Candidate molecular markers were identified for diagnosis and prognosis prediction of PC including a novel gene, TMC7. Moreover, we found that the combination of TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can serve as a promising indicator of the prognosis of PC patients. The candidate proteins may attribute to clonability and invasiveness of PC cells. This research provides a novel insight into molecular mechanisms as well as diagnostic and prognostic markers of PC.FundNational Natural Science Foundation of China [No. 81602646 & 81802339], Natural Science Foundation of Guangdong Province [No. 2016A030310254] and China Postdoctoral Science Foundation [No. 2016M600648].

Clinical significance of expression of DPC4 protein in prognosis of pancreatic carcinoma

目的 观察DPC4蛋白表达与胰腺癌患者预后的关系。 方法 对山西省人民医院2007年1月至2012年12月81例胰腺癌术后患者，采用免疫组织化学方法检测DPC4蛋白表达情况，并采用Kaplan-Meier法进行生存分析。 结果 81例胰腺患者中DPC4蛋白阳性表达率为53%（43/81）。DPC4阳性组胰腺癌患者术后中位生存期长于DPC4阴性组（40个月比33个月，P=0.029），DPC4阳性组患者生存风险比是DPC4阴性组的1.826倍（HR=1.826，95% CI 1.063~3.134）。 结论 DPC4蛋白阳性表达的胰腺癌患者术后预后好于DPC4阴性者。

Comparison of prognostic prediction between nomogram based on lymph node ratio and AJCC 8th staging system for patients with resected pancreatic head carcinoma: a SEER analysis.

BackgroundThe prognosis of pancreatic carcinoma (PC) remains poor and the American Joint Committee on Cancer (AJCC) 8th staging system for survival prediction in PC patients after curative resection is still limited. Thus, the aim of this study is to refine a valuable prognostic model and novel staging system for PC with curative resection.MethodsThe data of 3,458 patients used in this study were retrieved from the Surveillance, Epidemiology, and End Results database registry of National Cancer Institute. The prognostic value of lymph node ratio (LNR) was analyzed in the primary cohort and prognostic nomogram based on the LNR was established to create a novel staging system. Then, analyses were conducted to evaluate the application of the formulated nomogram staging system and the AJCC 8th staging system. The predictive performance of model was further validated in the internal validation cohort.ResultsSignificant positive correlations were found between LNR and all factors except for surgical procedures. The results of univariate and multivariate analyses showed that LNR was identified as an independent prognostic indicator for overall survival (OS) in both primary and validation cohorts (all P < 0.001). A prognostic nomogram based on the LNR was formulated to obtain superior discriminatory abilities. Compared with the AJCC 8th staging system, the formulated nomogram staging system showed higher hazard ratios of stage II, III, and IV disease (reference to stage I disease) that were 1.637, 2.300, and 3.521, respectively, by univariate analyses in the primary cohort and the distinction between stage I, II, and III disease at the beginning or end of the survival curves was more apparent. All these results were further verified in the validation cohort.ConclusionLNR can be considered as a useful independent prognostic indicator for PC patients after curative resection regardless of the surgical procedures. Compared with the AJCC 8th staging system, the formulated nomogram showed superior predictive accuracy for OS and its novel staging system revealed better risk stratification.

Latent Transforming Growth Factor β Binding Protein 2 (LTBP2) as a Novel Biomarker for the Diagnosis and Prognosis of Pancreatic Carcinoma.

BackgroundLatent transforming growth factor β binding protein 2 (LTBP2) is proven to be associated with ECM and involved in the advancement of several kinds of cancer. The present study evaluated the diagnosis and prognosis of pancreatic carcinoma (PC) using LTBP2 as a biomarker.Material/MethodsProtein levels of LTBP2 were evaluated in 111 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent nontumor tissues via immunohistochemistry. ELISA method was used to quantify the serum concentration of LTBP2. The subjects in this study included 141 PDAC patients, 20 patients with benign pancreatic disease, and 20 healthy volunteers.ResultsIHC results showed that LTBP2 levels were significantly elevated in the PDAC tissues as compared with the adjacent nontumor tissues (P<0.05). Sixty-one of the 111 (54.9%) PDAC tissues showed high expression of the protein. LTBP2 overexpression was significantly correlated with poor differentiation (P=0.018) and advanced TNM stage (P=0.036). Moreover, Kaplan-Meier analysis showed that high levels of LTBP2 predicted worse overall survival (P=0.001) and disease-free survival (P=0.001). Multivariate Cox regression analysis indicated that high expression of LTBP2 was an autonomous prognostic factor for poor overall and disease-free survival (P=0.001; P=0.002). Receiver operating characteristic (ROC) curve analyses of showed that LTBP-2 had an area under the curve (AUC) of 0.846 (95% confidence intervals: 0.757–0.934) and cut-off value of 19.12.ConclusionsLTBP2 is a novel biomarker for the diagnosis of PC and may be a potential target for PDAC clinical therapy.

Role of ca 19-9 as a tumor marker in diagnosis and prognosis of pancreatic carcinoma and cholangiocarcinoma (A study of 46 cases)

Introduction: Ca19-9 is currently the single most useful tumor marker for diagnosis and prognosis of pancreatic cancer and cholangiocarcinoma. Aim: The aim is to elucidate the importance of tumor marker ca 19-9 as a diagnostic and prognostic tool in pancreatic carcinoma and cholangio-carcinoma. Material and Methods: The time period of the study was from september-2012 to september- 2014. The patients were investigated pre-operatively and post operatively for ca 19-9 levels in their serum with the use of ELISA (enzyme linked immunosorbant assay) test. Results: Total 28 cases of pancreatic lesions were considered which included 24 cases of pancreatic ductal adenocarcinoma, It was observed that when preoperative serum CA 19-9 level was less than 37 u/ml median survival was 28 months. However when CA 19-9 level was more than 200 u/ml, median survival was 6 months. Out of 18 cases studied in gallbladder tumors, 15 cases were of cholangiocarcinoma. Patients with pre-therapy serum CA 19-9 level was between 37 -200 u/ml median survival was 23.25 months. When CA 19-9 level was more than 200 u/ml, median survival was 10.25 months. Conclusion: Elevated level of ca 19-9 in pancreatic carcinoma and cholangiocarcinoma are associated with higher age group, male sex, higher histological grade, higher TNM staging and metastasis. Post operative ca 19-9 value has definitive prognostic value to detect any metastasis or recurrence in pancreatic carcinoma and cholangio- carcinoma. Therefore it can be concluded that ca 19-9 is an important tumor marker for pancreatic carcninoma and cholangio-carcinoma.

Prognostic significance of HMGA1 and HMGA2 proteins expressions in pancreatic carcinoma

Objective To study the expressions and prognostic significance of high mobility group protein A1 (HMGA1) and high mobility group protein A2 (HMGA2) in pancreatic carcinoma. Methods The expressions of HMGA1 and HMGA2 were examined by immunohistochemical SP method in 60 cases of pancrea-tic carcinoma and 30 cases of normal pancreatic tissues. The relationship between the expression and prognosis was also analyzed. Results The expressions of HMGA1 and HMGA2 in pancreatic carcinoma were significantly higher than those in normal tissues, and the positive expression rates were 70.0% vs. 6.7% (χ2=32.105, P=0.000) and 73.3% vs. 3.3%(χ2=39.200, P=0.000). The expression of HMGA1 in pancreatic carcinoma was correlated with histological grade (χ2=6.774, P=0.034), TNM stage (χ2=4.776, P=0.029) and lymphatic metastasis (χ2=12.614, P=0.000). The expression of HMGA2 in pancreatic carcinoma was correlated with histological grade (χ2=8.200, P=0.017) and TNM stage (χ2=7.253, P=0.007). The expression of HMGA1 was positively associated with HMGA2 expression(r=0.393, P=0.001). Kaplan-Meier analysis showed that the median survival time of HMGA1 and HMGA2 positive patients were shorter than those patients with HMGA1 negative and HMGA2 negative (14.0 months vs. 24.0 months, χ2=14.568, P=0.000; 15.0 months vs. 21.0 months, χ2=7.270, P=0.007). Conclusion HMGA1 and HMGA2 are highly expressed in pancreatic carcinoma, and play synergistic roles in the generation and progress of pancreatic carcinoma. There is certain value of combined detection of HMGA1 and HMGA2 to predict the prognosis of pancreatic carcinoma. Key words: Pancreatic neoplasms; HMGA proteins

Overexpressed HSPA2 correlates with tumor angiogenesis and unfavorable prognosis in pancreatic carcinoma

Heat shock-related 70-kDa protein 2 (HSPA2) is known to correlate with tumor development and progression. This work aimed to determine the expression and prognostic roles of HSPA2 in pancreatic carcinoma. Tumor and their corresponding non-tumor tissues were obtained from 80 patients with pancreatic carcinoma. HSPA2 expression in tumor and non-tumor tissues was evaluated by immunohistochemistry. Expression of vascular endothelial growth factor (VEGF) and CD31 in tumor tissues were also evaluated by immunostaining. The relationships of HSPA2 with clinicopathological data, tumor angiogenesis and prognosis were analyzed. The results showed that HSPA2 expression was significantly elevated in tumor tissues compared with adjacent non-tumor tissues (P < 0.05). High HSPA2 expression was significantly associated with aggressive clinicopathological characteristics. HSPA2 staining was positively correlated with VEGF (r = 0.466, P < 0.001) and microvessel density (MVD) (r = 0.366, P = 0.001) in tumor tissues. Patients with high HSPA2 expression showed worse relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001) than those with low HSPA2 expression. Multivariate analysis indicated that high HSPA2 expression was an independent predictor for poor RFS (P < 0.001) and OS (P = 0.001). Taken together, overexpressed HSPA2 is correlated with tumor angiogenesis and poor prognosis in pancreatic carcinoma. HSPA2 may play an important role in tumor progression, and serve as a potential biomarker for the prediction of adverse prognosis in pancreatic carcinoma.

Concept renovation and technical progress in surgical treatment of pancreatic cancer

Pancreatic carcinoma has the poorest prognosis in all the digestive cancers, and the management is still challenging. In recent years, the rapid development of surgical technique has led to the increase in the resection rate and the significant decrease in perioperative mortality and morbidity. However, the prognosis of pancreatic carcinoma has not been improved. Nowadays, the treatment strategy of pancreatic carcinoma has been changed from first into the mode of multidisciplinary team. If 1 mm rule was used as the standard protocol for assessment of resection margins, most of the pancreatic resection were therefore R1 resections. Neoadjuvant therapy is advocated for patients who meet specific characteristics. Under the guidance of the concept of precision medicine, surgical treatment of pancreatic carcinoma should be changed from the modes of morphology and surgery to the modes biology and oncology. Key words: Pancreatic neoplasms; Surgical procedures, operative; Multidisciplinary team

Overexpression and clinical significance of MYC-associated zinc finger protein in pancreatic carcinoma.

This study aimed to investigate the expression and clinical significance of MYC-associated zinc finger protein (MAZ) in pancreatic carcinoma (PC), and the biological functions of MAZ in PC cells. MAZ expression was detected in 57 PC tissues and 41 paired adjacent nontumor tissues by immunohistochemistry. Compared to the expression in adjacent nontumor tissues, MAZ was significantly higher expressed in PC tissues (P<0.0001). In addition, MAZ expression had a significant correlation with certain clinical characteristics of PC patients, such as age, tumor diameter, tumor number, and the serum level of CA199 (P<0.05). The survival analysis showed that the survival time of PC patients with high expression of MAZ was significantly lower than patients with low expression of MAZ (P=0.0365). After MAZ was knocked down in PANC-1 cells by RNA interference, the cells’ ability to proliferate, invade, and migrate was decreased significantly (P<0.01). Moreover, MAZ expression was found to be associated with Ki-67, a cell proliferation marker, in PC tissues, further supporting the idea that MAZ promotes PC cell proliferation. Our study clarifies an oncogenic role of MAZ in pathogenesis of PC and provides MAZ as a biomarker in the treatment and prognosis of PC.

The value of combined detection with MMP-9 and uPA in prognosis of pancreatic carcinoma

Objective To explore the value of combined detection with MMP-9 and uPA in the prognosis of pancreatic carcinoma. Methods By immunohistochemistry PV methods, the expression of MMP-9 and uPA was respectively studied in 63 surgical specimens of primary pancreatic carcinoma and the survival time of patients with pancreatic carcinoma was analysed. Results The expressions of MMP-9 and uPA were positively related (r=0.573, P=0.000). The expression of MMP-9 and uPA significantly correlated with differentiation(r=-0.271, P=0.032; r=-0.333, P=0.008), TNM stages(r=-0.449, P=0.000; r=-0.430, P=0.000)and lymph node metastasis(r=0.329, P=0.009; r=0.400, P=0.001), separately. The expression of MMP-9 had also a significant correlation with tumer size(r=-0.297, P=0.018)and distant metastasis(r=0.320, P=0.011). Univariate analysis identified that tumor size(χ2=8.766, P=0.012), differentiation(χ2=29.050, P=0.000), clinical stage(χ2=24.940, P=0.000), distant metastasis(χ2=12.846, P=0.000), lymph node metastasis(χ2=15.457, P=0.000), MMP-9(χ2=32.700, P=0.000)and uPA(χ2=41.495, P=0.000)were significantly associated with prognosis. Kaplan-Meier survival analysis showed that 1-year survival rate of patients with MMP-9 (-), uPA (-)were significantly longer than that of the patients with MMP-9 (+ ), uPA (+ ), respectively(χ2=32.700, P=0.000; χ2=41.495, P=0.000); 1-year survival rate of patients with MMP-9 (-)/uPA(-)was significantly longer than the others(Log-rank test, χ2= 54.892, P=0.000). COX regression revealed that differentiation (RR=2.315, P=0.004), clinical stage(RR=1.694, P=0.002), MMP-9(RR=0.165, P=0.000) and uPA(RR=0.244, P=0.007)was independent prognostic factors in pancreatic carcinoma. Conclusion They may have a synergistic function in the the process of growth and invasion in pancreatic cancer between MMP-9 and uPA, and the posssible mechanism is that uPA activate degradation of MMP-9, which is not favorable to prognosis.Combined analysis of MMP-9 and uPA may lead to a more reliable prognostic estimation, as the beneficial supplement of the differentiation, and clinical stage to judge the prognosis of pancreatic cancer. Key words: Pancreatic neoplasms; Prognosis; Matrix metalloproteinase 9; Urinary plasminogen actirator

Overexpression of RhoGDI2 correlates with the progression and prognosis of pancreatic carcinoma.

Rho GDP dissociation inhibitor 2 (RhoGDI2) has been found to be a regulator of tumor metastasis. However, the expression of RhoGDI2 and its clinicopathological significance as well as the pathway of RhoGDI2 in tumor metastasis have yet to be investigated. To investigate the role of RhoGDI2 in the progression and prognosis of pancreatic carcinoma (PC), the expression of RhoGDI2 in human PC tissues was examined and compared with the clinicopathological characteristics and prognosis. Moreover, the relationship between RhoGDI2 and E-cadherin was examined. The results indicated that RhoGDI2 was overexpressed in PC tissues and associated with clinicopathological characteristics, including clinical stage and lymph node metastasis. Patients with a RhoGDI2‑negative expression had a significantly longer survival time than those with a RhoGDI2‑positive expression. Additionally, the expression of RhoGDI2 was negatively correlated with the expression of E-cadherin in PC tissues. Taken together, the findings suggest that RhoGDI2 is important in the progression and prognosis of PC, and may be used as a potential prognostic biomarker and a therapeutic target for PC.

Abstract 376: P-cadherin overexpression is associated with poor prognosis in pancreatic carcinoma and is regulated by its promoter hypomethylation

Abstract [Background] P-cadherin belongs to the family of classic cadherin, and accumulating evidences shows hat P-cadherin is strongly associated with carcinogenesis and confers alignant phenotype of various cancers. Pancreatic cancer has a poor prognosis, with an overall 5-year survival rate of only 5%. Despite advances in therapy recently, its survival rate still remains poor. This study aimed to analyze P-cadherin expression and its prognostic value in pancreatic carcinoma and to validate the P-cadherin gene (CDH3) promoter methylation status as the mechanism of this gene regulation. [Methods] Seventy-three patients diagnosed with pancreatic cancer were enrolled in this study. P-cadherin expression was examined by immunohistochemistry, and correlated with various clinicopathological features and prognosis. Furthermore, P-cadherin expression and its promoter methylation status were analyzed in pancreatic cancer cell lines. [Results] In pancreatic tissues, 50.7% (37/73) of cases shows a high expression of P-cadherin by immunohistochemical analysis, and high expression of P-cadherin was significantly correlated with gender, posterior tissue invasion and other organs invasion. In multivariate analyses, P-cadherin expression was the independent prognostic factors for disease-free survival (relative risk:2.68, p=0.005). P-cadherin expression was found to be related to its promoter methylation status in pancreatic cancer cell lines. Furthermore, when P-cadherin was down-regulated by specific siRNA, cell migration and invasion were significantly reduced. [Conclusion] These results suggested that expression of P-cadherin is a useful prognostic marker and seems to be important in the malignant behavior in pancreatic cancer. We are now conducting experiments to validate the CDH3 methylation status in the cancerous tissues and their adjacent normal counterpart, and investigating the biological role of P-cadherin in pancreatic cancer. Note: This abstract was not presented at the meeting. Citation Format: Keita Sakamoto, Katsunori Imai, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo BaBa. P-cadherin overexpression is associated with poor prognosis in pancreatic carcinoma and is regulated by its promoter hypomethylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 376. doi:10.1158/1538-7445.AM2014-376

Co-expression of CD133, CD44v6 and human tissue factor is associated with metastasis and poor prognosis in pancreatic carcinoma.

The metastasis-related molecules CD133, CD44v6 and human tissue factor (TF) have been shown to be associated with tumor invasion and metastasis. This study aimed to determine whether co-expression of these three molecules was associated with metastasis and overall prognosis in pancreatic carcinoma. We analyzed the expression profiles of these three molecules by immunohistochemistry and evaluated the relationship of their expression profiles with metastasis and prognosis in 109 pancreatic carcinomas. The results showed that the expression levels of CD133, CD44v6 and TF were increased in pancreatic carcinoma. Co-expression of CD133, CD44v6 and TF (tri-expression) was also detected in pancreatic carcinoma. Clinical analysis showed that individual expression of CD133, CD44v6 or TF was associated with vessel invasion, lymph node metastasis and liver metastasis, while tri-expression was associated with lymph node metastasis. Survival analysis showed that patients with co-expression of CD133 and TF or tri-expression had lower and the lowest overall survival rates, respectively. Univariate analysis showed that T-factor, lymph node metastasis, TNM stage, and individual levels or tri-expression of CD133, CD44v6 and TF were survival risk factors. Multivariate analysis showed that tri-expression of CD133, CD44v6 and TF was an independent predictor of survival. These results suggest that overexpression of CD133, CD44v6 and TF is associated with pancreatic carcinoma metastasis. Tri-expression of these three molecules may be a useful predictor for pancreatic carcinoma prognosis.

Expression of RECK in pancreatic carcinoma and its relationship with prognosis

Objective To study the expression of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) in human pancreatic carcinoma tissues and pancreatic carcinoma cell lines; the effects of recombinant lentiviruses carrying RECK gene(LV-RECK) therapy on human pancreatic carcinoma xenograft in nude mice; and to find out the relationship between the expression of RECK and the prognosis of pancreatic carcinoma.Methods Immunohistochemical method was used to detect the expression of RECK in the resected specimens of pancreatic carcinoma and their corresponding normal pancreatic tissues in 42 patients.Western blotting was used to examine the expression of RECK in human pancreatic carcinoma cell lines (PANC-1,MIAPaCa-2,AsPC-1).Statistical analyses were performed to determine the relationship between RECK expression and the clinicopathological characteristics and prognosis in pancreatic carcinoma.Subcutaneous xenograft tumor models of human pancreatic carcinoma were established in nude mice.These nude mice were then divided into the experimental group,the negative control group and the blank control group randomly.The three groups of nude mice were intratumorally injected with LV-RECK,LV-EGFP and normal saline (NS) respectively.The antitumor effect was studied.Immunohistochemical method was used to detect the expression of RECK and microvessel density (MVD).Terminal deoxynucleotidyl transferase mediated dUTP-DIG nick end labeling (TUNEL) was used to detect the apoptosis of tumor cells.Survival analysis was performed.Results All three pancreatic carcinoma cell lines did not express RECK.The overall positive rate of RECK expression was 45.2 ％ (19/42) in pancreatic carcinoma,and 88.1 ％ (37/42) in normal pancreatic tissue.The expression level of RECK was significantly lower in the tumor tissues than in the normal tissues (P＜0.01).The expression of RECK was significantly associated with TNM stage,lymph node metastasis and local infiltration of pancreatic carcinoma (P＜0.05).Kaplan-Meier survival analysis revealed that the survival time was significantly longer in the RECK positive patient group than in the RECK negative patient group.Univariate Cox regression analysis revealed that RECK expression,TNM stage,lymph node metastasis and local infiltration were significantly related with prognosis for pancreatic carcinoma (P＜0.05).Multivariate Cox regression analysis revealed that only RECK expression remained as an independent significant factor in predicting the prognosis of pancreatic carcinoma (P ＜ 0.001).When compared with the negative control and the blank control groups,the volume of subcutaneous xenograft tumor in the experimental group was significantly decreased (P＜0.05).RECK protein in the experimental group was re-expressed.MVD of the experimental group was significantly less than those of the control groups (P＜0.05).Apoptotic index (AI)of the experimental group was significantly higher than those of the control groups (P＜0.05).The survival time of nude mice in the experimental group was significantly longer than those in the control groups (P＜0.05).Conclusions RECK expression was closely related to invasion,metastasis and prognosis of pancreatic carcinoma and it was an independent prognostic marker.RECK gene over-expression inhibited neovascularization of pancreatic carcinoma,induced apoptosis of tumor cells,inhibited the growth of tumor xenograft and improved the prognosis of tumor-bearing mice.These results suggest a possible new treatment for pancreatic carcinoma. Key words: Pancreatic neoplasms; Matrix metalloproteinases ; Prognosis ; Reversion-inducing-cysteine-rich protein with Kazal motifs

Apoptosis of Human Pancreatic Carcinoma PC-2 Cells by an Antisense Oligonucleotide Specific to Point Mutated K-ras

The prognosis of pancreatic carcinoma is poor due to the difficulty in early diagnosis, insensitivity to routine therapies and limited understanding of its pathological mechanisms. Gene therapy is now becoming an important strategy for the treatment of pancreatic carcinoma, which includes antisense gene therapy. In this study, we investigated the effect of an antisense oligonucleotide specific to point mutated K-ras on the apoptosis of human pancreatic carcinoma cells in vitro. Human pancreatic carcinoma PC-2 cells were transfected with an antisense oligonucleotide specific to a K-ras point mutation by liposomes. The effect of the antisense oligonucleotide on the apoptosis of PC-2 cells was studied using flow cytometry, TUNEL, and phase contrast microscopy. An apoptotic peak was observed in the experimental group, and most cells were arrested at the G1 phase with few cells at the S phase. The numbers of apoptotic cells in the experimental group increased as indicated by TUNEL and phase contrast microscopy. An antisense oligonucleotide specific to a K-ras point mutation promotes apoptosis in PC-2 cells in vitro perhaps by inhibition of ras gene expression.

Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma

Background:Inflammatory mediators may have decisive roles at different stages of tumour development. Mediators within the pentraxin family may be used as strong biomarkers in prognosis of advanced pancreatic carcinoma patients.Methods:Using pancreatic carcinoma cell lines and gene transfectant, we measured long pentraxin (PTX3) level in culture solution and carried out cellular migration assay in vitro. In vivo study of the treatment-naive patients with advanced pancreatic carcinoma assigned to undergo gemcitabine therapy was prospectively conducted to measure and investigate the role of plasma PTX3, C-reactive protein (CRP), and eight inflammatory mediators by using collected clinical data.Results:Elevated PTX3 production was observed in several cell lines, and a direct relationship between migratory activity and PTX3 level was identified in vitro. High PTX3 level (117 days) was significantly less than that of patients with low PTX3 level (357 days, P<0.001). Multivariate analysis of the pancreatic carcinoma revealed a strong correlation between pentraxin family member expression and prognosis of pancreatic carcinoma. The relationship between PTX3 expression and the expression of other pro-inflammatory mediators indicated that PTX3 level is positively correlated with levels of CRP, interleukin-6, and macrophage-inhibitory factor.Conclusion:Pentraxin family members, especially PTX3, may be used as promising biomarkers in the prognosis of pancreatic carcinoma patients.