Survival Rate Of Pancreatic Cancer Patients Research Articles

MicroRNA-485-5p targets keratin17 to regulate pancreatic cancer cell proliferation and invasion via the FAK / SRC / ERK pathway.

Background: It is crucial to probe into the biological effect and mechanism of miRNA-485-5p regulating keratin 17 (KRT17) in pancreatic cancer (PC) to understand its pathogenesis and identify potential biological targets. Methods: The bioinformatics means were used to evaluate the clinical significance of KRT17 expression in the Cancer Genome Atlas (TCGA) database. TargetScan database analysis in conjunction with dual luciferase and RNA Immunoprecipitation (RIP) experiments was used to probe the interaction relationship of miRNA-485-5p with KRT17. The expression of miRNA-485-5p and KRT17 in PC tissue and cancer cell lines was detected by Q-PCR paired with western blot assay. The biological function of miRNA-485-5p in regulating KRT17 was investigated in the PC cell line via gene silencing/overexpression technique. A western blot experiment was utilized to investigate the regulatory effect of KRT17 on cell cycle-related proteins and the FAK/Src/ERK signal pathway. Results: The level of KRT17 was increased in PC tissues and this significantly decreased the survival rate of PC patients. TargetScan in combination with dual luciferase and RIP experiments verified the miRNA-485-5p target KRT17. The expression of KRT17 was high in the PC cell line, although the expression of miRNA-485-5p was low. Silencing KRT17 or overexpression of miRNA-485-5p significantly inhibited PC cell viability, proliferation, invasion, and colony formation, while promoting apoptosis. Overexpression of KRT17 drastically reversed the function of miRNA-485-5p. The silenced KRT17 remarkably downregulated the expression of cyclinD1, Cyclin Dependent Kinase 1 (CDK1), CDK2, Phospho-Focal Adhesion Kinase (p-FAK), p-Src, and p-ERK proteins in the PC cells. Conclusion: Generally, an essential signaling cascade of miRNA-485-5p/KRT17/FAK/Src/ERK influences the biological functions of PC cells.

A Novel Molecular Signature of Cancer-Associated Fibroblasts Predicts Prognosis and Immunotherapy Response in Pancreatic Cancer.

Cancer-associated fibroblasts (CAFs), a prominent population of stromal cells, play a crucial role in tumor progression, prognosis, and treatment response. However, the relationship among CAF-based molecular signatures, clinical outcomes, and tumor microenvironment infiltration remains largely elusive in pancreatic cancer (PC). Here, we collected multicenter PC data and performed integrated analysis to investigate the role of CAF-related genes (CRGs) in PC. Firstly, we demonstrated that α-SMA+ CAFs were the most prominent stromal components and correlated with the poor survival rates of PC patients in our tissue microarrays. Then, we discriminated two diverse molecular subtypes (CAF clusters A and B) and revealed the significant differences in the tumor immune microenvironment (TME), four reported CAF subpopulations, clinical characteristics, and prognosis in PC samples. Furthermore, we analyzed their association with the immunotherapy response of PC patients. Lastly, a CRG score was constructed to predict prognosis, immunotherapy responses, and chemosensitivity in pancreatic cancer patients. In summary, these findings provide insights into further research targeting CAFs and their TME, and they pave a new road for the prognosis evaluation and individualized treatment of PC patients.

Integrin β1 in Pancreatic Cancer: Expressions, Functions, and Clinical Implications

Simple SummaryPancreatic cancer (PC) is a highly aggressive malignant tumor with an extremely poor prognosis. Early diagnosis and treatment are key to improving the survival rate of PC patients. Emerging studies show that integrins might contribute to the pathogenesis of PC. This review presents the various signaling pathways that are mediated by integrins in PC and emphasizes the multiple functions of integrin β1 in malignant behaviors of PC. It also discusses the clinical significance of integrin β1 as well as integrin β1-based therapy in PC patients.Pancreatic cancer (PC) is characterized by rapid progression and a high mortality rate. The current treatment is still based on surgical treatment, supplemented by radiotherapy and chemotherapy, and new methods of combining immune and molecular biological treatments are being explored. Despite this, the survival rate of PC patients is still very disappointing. Therefore, clarifying the molecular mechanism of PC pathogenesis and developing precisely targeted drugs are key to improving PC prognosis. As the most common β subunit of the integrin family, integrin β1 has been proved to be closely related to the vascular invasion, distant metastasis, and survival of PC patients, and treatment targeting integrin β1 in PC has gained initial success in animal models. In this review, we summarize the various signaling pathways by which integrins are involved in PC, focusing on the roles of integrin β1 in the malignant behaviors of PC. Additionally, recent studies regarding the feasibility of integrin β1 as a diagnostic and prognostic biomarker in PC are also discussed. Finally, we present the progress of several integrin β1-based clinical trials to highlight the potential of integrin β1 as a target for personalized therapy in PC.

Identification of DNA methylation-driven genes and construction of a nomogram to predict overall survival in pancreatic cancer

BackgroundThe incidence and mortality of pancreatic cancer (PC) has gradually increased. The aim of this study was to identify survival-related DNA methylation (DNAm)-driven genes and establish a nomogram to predict outcomes in patients with PC.MethodsThe gene expression, DNA methylation database, and PC clinical samples were downloaded from TCGA. DNAm-driven genes were identified by integrating analyses of gene expression and DNA methylation data. Survival-related DNAm-driven genes were screened via univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to develop a risk score model for prognosis. Based on analyses of clinical parameters and risk score, a nomogram was built and validated. The independent cohort from GEO database were used for external validation.ResultsA total of 16 differentially expressed methylation-driven genes were identified. Based on LASSO Cox regression and multivariate Cox regression analysis, six genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) were chosen to develop the risk score model. In the Kaplan–Meier analysis, age, T stage, N stage, AJCC stage, radiation therapy history, tumor size, surgery type performed, pathological type, chemotherapy history, and risk score were potential prognostic factors in PC (P < 0.1). In the multivariate analysis, stage, chemotherapy, and risk score were significantly correlated to overall survival (P < 0.05). The nomogram was constructed with the three variables (stage, chemotherapy, and risk score) for predicting the 1-year, 2-year, and 3-year survival rates of PC patients. Nomogram performance was assessed by receiver operating characteristic (ROC) curves and calibration curves. 1-year, 2-year and 3-year AUC of nomogram model was 0.899, 0.765 and 0.776, respectively.ConclusionsIn our study, we successfully identified the six DNAm-driven genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) with a relationship to the outcomes of PC patients. The nomogram including stage, chemotherapy, and risk score could be used to predict survival in PC patients.

PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1.

Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 (n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells — suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.

Identification of Circ_001569 as a Potential Biomarker in the Diagnosis and Prognosis of Pancreatic Cancer.

Emerging evidence has shown that circular RNAs (circRNAs) serve as a promising biomarker in different malignancies. Specifically, circ_001569 has been found to be upregulated in some types of human gastrointestinal cancer. In this study, we aimed to investigate clinical significances, diagnostic and prognostic values of circ_001569 in pancreatic cancer (PC), and identify its effects on the malignant behaviors of PC cells. The expression of circ_001569 was determined in 26 tissues samples and 97 plasma samples from PC patients by qRT-PCR. Relationship between circ_001569 expression and clinicopathological parameters was analyzed by Chi-square test. Diagnostic and prognostic values of circ_001569 were evaluated by ROC curves, Kaplan-Meier curves, and Cox regression analysis. The effects of circ_001569 on the proliferation, migration, invasion, and apoptosis of PC cells were assessed by MTT, wound healing, Transwell invasion assays, and flow cytometric analysis, respectively. Results showed that the expression of circ_001569 was upregulated in tissues and plasma of PC patients. High circ_001569 level was positively correlated with lymphatic metastasis, clinical stage, and venous invasion. Circ_001569 level was an independent prognostic indicator for overall survival rates of PC patients, and patients with high circ_001569 level had a poor prognosis. The AUC of circ_001569 was 0.716 (95% CI: 0.642-0.790) with a sensitivity and specificity of 62.76% and 74.29%, respectively. In vitro, circ_001569 silencing decreased cell proliferation, migration, and invasion, but promoted cell apoptosis of PC cells. Our data demonstrate that high circ_001569 level associates with tumor malignant behaviors, and may serve as a potential biomarker in the diagnosis and prognosis of PC.

LncRNA CASC19 contributed to the progression of pancreatic cancer through modulating miR-148b/E2F7 axis.

Cancer susceptibility 19 (CASC19), a crucial lncRNA associated with multiple cancers, has been reported to play a vital role in the progression of human malignant tumors. However, the underlying mechanism of CASC19 in pancreatic cancer (PC) was still unknown. The purpose of this study was to explore the biological and clinical significance of CASC19 in PC. RT-qPCR assay was adopted to analyze CASC19 expression in PC tissues and cell lines. Furthermore, the correlation between the CASC19 level and the survival rate of PC patients was assessed by Kaplan-Meier analysis. Bioinformatics analysis and Luciferase reporter assay were utilized to confirm the interaction between miR-148b and CASC19 or E2F7. Cell viability, migration, invasion, and apoptosis were analyzed using MTT, transwell, and TUNEL assays. The results elucidated that CASC19 expression was markedly increased in PC tissues and cell lines. Patients with high expression of CASC19 had a short survival time. Silencing of CASC19 attenuated PC cell proliferation, migration, and invasion. Moreover, we identified that miR-148b was a target of CASC19. CASC19 was negatively correlated with miR-148b and positively correlated with E2F7. The inhibitory effect of CASC19 knockdown on the progression of PC was reversed by the down-regulation of miR-148b or up-regulation of E2F7. These results demonstrated that CASC19 participated in the development of PC. The CASC19/miR-148b/E2F7 axis might be a new study direction for PC treatment.

Survival of pancreatic cancer patients is negatively correlated with age at diagnosis: a population-based retrospective study

In this population-based retrospective study, we aimed to investigate the association between age at diagnosis and prognosis of pancreatic cancer (PC) patients using data from the National Cancer Institute’s Surveillance, Epidemiology, and the End Results database. Different factors for stratification, like race, sex, year of diagnosis, pathological grade, American Joint Committee on Cancer stage, historic stage, and tumour location, were included to compare the survival rates of patients of different age groups, and the five-year survival rate was calculated. Multivariate analysis using Cox regression was performed to control for confounder bias, and the hazard ratio was calculated. In total, 126,066 patients were enrolled in this study. The five-year PC-specific survival of patients aged 20–40 years was almost three times that of patients aged >40 years. Stratified by race, sex, year of diagnosis, pathological grade, clinical stage, and tumour location, a descending trend of survival was observed with an increase in age. On multivariate analysis, the mortality risk of PC patients aged 40–80 years was twice that of patients aged <40 years; however, patients aged >80 years had a mortality risk three times that of patients aged <40 years. The survival rate of PC patients has improved in the last few decades. Age at diagnosis is a significant and negative prognostic factor for PC, and patients diagnosed at a relatively earlier stage had the best survival.

Metabolomics identified new biomarkers for the precise diagnosis of pancreatic cancer and associated tissue metastasis

Pancreatic cancer (PC) is one of the most aggressive malignancies with high mortality due to a complex and latent pathogenesis leading to the severe lack of early diagnosis methods. To improve clinical diagnosis and enhance therapeutic outcome, we employed the newly developed precision-targeted metabolomics method to identify and validate metabolite biomarkers from the plasma samples of patients with pancreatic cancer that can sensitively and efficiently diagnose the onsite progression of the disease. Many differential metabolites have the capacity to markedly distinguish patients with pancreatic cancer (n = 60) from healthy controls (n = 60). To further enhance the specificity and selectivity of metabolite biomarkers, a dozen tumor tissues from PC patients and paired normal tissues were used to clinically validate the biomarker performance. We eventually verified five new metabolite biomarkers in plasma (creatine, inosine, beta-sitosterol, sphinganine and glycocholic acid), which can be used to readily diagnose pancreatic cancer in a clinical setting. Excitingly, we proposed a panel biomarker by integrating these five individual metabolites into one pattern, demonstrating much higher accuracy and specificity to precisely diagnose pancreatic cancer than conventional biomarkers (CA125, CA19-9, CA242 and CEA); moreover, this plasma panel biomarker used for PC diagnosis is also quite convenient to implement in clinical practice. Using the same metabolomics method, we characterized succinic acid and gluconic acid as having a great capability to monitor the progression and metastasis of pancreatic cancer at different stages. Taken together, this metabolomics method was used to identify and validate metabolite biomarkers that can precisely and sensitively diagnose the onsite progression and metastasis of pancreatic cancer in a clinical setting. Furthermore, such effort should leave clinicians with the correct time frame to facilitate early and efficient therapeutic interventions, which could largely improve the five-year survival rate of PC patients by significantly lowering clinical mortality.

Abstract B26: Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity

Abstract Background: Pancreatic cancer (PC) is an aggressive disease that is in most cases advanced at the time of diagnosis. The overall 5-year survival rate for PC patients is less than 5 %. African-Americans show the highest incidence of obesity and PC as well as mortality rate. How obesity is associated to PC incidence and health disparity is still an unanswered question. High levels of leptin shown by obese African American patients could impact negatively on PC. We hypothesize that leptin signaling induces PC proliferation, stem cells (PCSC) and drug resistance. Methods: Human PC cell lines derived from primary pancreatic adenocarcinoma (Panc-1 and MiaPaCa-2-highly aggressive, BxPC-3-less aggressive) and from metastatic tumor (AsPC-1) were challenged with leptin and chemotherapeutic agents. Cell proliferation, apoptosis rate, and the expression levels of molecular markers were analyzed. PCSC markers were determined in cell lines and tumor biopsies. Effects of leptin and chemotherapeutics on PC-tumorsphere formation were also determined. Results: Leptin stimulated proliferation of PC cells, induced the expression of PCSC markers and increased tumorsphere formation. Moreover, leptin impaired the efficacy of chemotherapeutics on PC cells. Conclusions: Present data suggest leptin is a proliferative and survival factor for PC that reduces chemotherapeutic effectiveness. These observations are of paramount importance for obese African American PC patients, who show the highest levels of leptin, poor prognosis and outcome of chemotherapeutic treatment. Acknowledgements: this work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386). Citation Format: Adriana Harbuzariu, Danielle S. Daley-Brown, Tia L. Harmon, Robin C. Garrison, Derrick J. Beech, Frederick D. Cason, Christopher Klug, Ruben R. Gonzalez-Perez. Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B26.