Potential Prognostic Biomarkers of OSBPL Family Genes in Patients with Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan–Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.

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Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-01465-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mitsuhito Koizumi ◽

Takao Watanabe ◽

Junya Masumoto ◽

Kotaro Sunago ◽

Yoshiki Imamura ◽

...

Keyword(s):

Cell Cycle ◽

Pancreatic Ductal Adenocarcinoma ◽

Adaptor Protein ◽

Ductal Adenocarcinoma ◽

Kaplan Meier ◽

Cell Cycle Modulation ◽

Interfering Rna ◽

Kaplan Meier Plotter ◽

In Vitro Data

AbstractApoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan–Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

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Gasdermin C as a potential prognostic biomarker and its correlation with immune infiltration in pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16256 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16256-e16256

Author(s):

Xianghou Xia ◽

Yang Yu ◽

Hongjian Yang ◽

Dehong Zou ◽

Canming Wang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Prognostic Value ◽

Immune Cell ◽

Prognostic Significance ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Immune Infiltration ◽

Kaplan Meier ◽

Kaplan Meier Plotter

e16256 Background: Although pyroptosis is critical for macrophages against pathogen infection, its role in cancer cells remains elusive. GSDMC is a pyroptosis executioner newly identified in cancer cells and have been shown to facilitate inflammatory tumor death. However, the expression of GSDMC in Pancreatic Ductal Adenocarcinoma (PDAC), its prognostic significance and possible impact on reshaping tumor immune microenviroment in PDAC is still unknown. Methods: We investigated the expression level of GSDMC using TNM plotter with TCGA and GTEx databases, the prognostic value of GSDMC in PDAC using Kaplan-Meier plotter with TCGA, GTEx and TCGA databases. The correlations between GSDMC and immune infiltration in PDAC were calculated using TIMER2.0 and TIDE with TCGA database. We further validated the prognostic value of GSDMC with immunohistochemistry(IHC) staining on a tissue microarray of 172 cases of PDAC patients receiving treatment in our institution. Correlations between expression of GSDMC and tumor infiltration lymphacytes(TILs) cells were also analyzed on tissue samples of those 172 PDAC patients. Results: TNM plotter analysis shows that the expression of GSDMC in PDAC tumor tissue is 10.49 folds higher than it is in pancreatic normal tissues (p = 8.86*e-56). Results from Kaplan-Meier plotter analysis shows high expression of GSDMC is significantly correlated with poorer overall survival(OS), HR = 1.8(1.19−2.71) logrank P = 0.004 and shorter relapse free survival (RFS), HR = 4.6(1.94−10.88), Logrank P = 0.00014 in PDAC. Analysis with TIMER2.0 and TIDE platform shows that expression of GSDMC is positively correlated with immunosuppressive cells, Cancer Associated Fiberblast (CAF) and Meyloid Derived Tumor Suprresso Cells(MDTSC). IHC staining analysis results is also consistent with aformentioned bioinformatic analysis, showing that high GSDMC expression correlated with shorter OS and reduced Tils infiltration. Conclusions: Our findings suggest that high expression of GSDMC is related to poor prognosis and compromised immune cell infiltration in PDAC. GSDMC holds promise for serving as a valuable prognostic marker and therapeutic target in PDAC.

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Expression and prognostic roles of PRDXs gene family in hepatocellular carcinoma

Journal of Translational Medicine ◽

10.1186/s12967-021-02792-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Mingxing Xu ◽

Jianliang Xu ◽

Dun Zhu ◽

Rishun Su ◽

Baoding Zhuang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Acid Metabolism ◽

Family Members ◽

Interaction Network ◽

Genetic Alterations ◽

Database Analysis ◽

Kaplan Meier ◽

Canonical Pathways ◽

Human Protein Atlas ◽

Kaplan Meier Plotter

Abstract Background As the fourth leading cause of cancer-related death in the world, the therapeutic effect and 5-year overall survival of hepatocellular carcinoma (HCC) are not optimistic. Previous researches indicated that the disorder of PRDXs was related to the occurrence and development of cancers. Methods In this study, PRDXs were found in various tumor cell lines by CCLE database analysis. The analysis results of UALCAN, HCCDB and Human Protein Atlas databases showed the expression of PRDXs mRNA and protein in HCC tissues was dysregulated. Besides, UALCAN was used to assess the correlations between PRDXs mRNA as well as methylation levels and clinical characterization. Results High expression of PRDX1 or low expression of PRDX2/3 suggested poor prognosis for HCC patients which was demonstrated by Kaplan–Meier Plotter. The genetic alterations and biological interaction network of PRDXs in HCC samples were obtained from c-Bioportal. In addition, LinkedOmics was employed to analyze PRDXs related differentially expressed genes, and on this basis, enrichment of KEGG pathway and miRNAs targets of PRDXs were conducted. The results indicated that these genes were involved in several canonical pathways and certain amino acid metabolism, some of which may effect on the progression of HCC. Conclusions In conclusion, the disordered expression of some PRDX family members was associated with the prognosis of HCC patients, suggesting that these PRDX family members may become new molecular targets for the treatment and prognosis prediction of HCC.

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Effect of neoadjuvant radiotherapy on survival of non-metastatic Pancreatic Ductal Adenocarcinoma: A SEER Database Analysis

10.21203/rs.3.rs-21437/v2 ◽

2020 ◽

Author(s):

Dan Wang ◽

Chongshun Liu ◽

Yuan Zhou ◽

Tingyu Yan ◽

Chenglong Li ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Adjuvant Radiotherapy ◽

Risk Model ◽

Ductal Adenocarcinoma ◽

Seer Database ◽

Database Analysis ◽

Neoadjuvant Radiotherapy ◽

Kaplan Meier ◽

Stage T1 ◽

Better Than

Abstract Background: Neoadjuvant radiotherapy has been shown to improve marginal negative resection and local control of Pancreatic Ductal Adenocarcinoma (PDAC). However, whether it improves overall survival (OS) in patients with non-metastatic PDAC remains controversial. Therefore, the purpose of this study was to analyze the benefits of only surgery, neoadjuvant radiotherapy, adjuvant radiotherapy, and surgery plus chemotherapy for OS in patients with non-metastatic PDAC. Methods: PDAC diagnosed by surgical histopathology in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016 was selected. Kaplan-Meier analysis was used to compare the prognosis of patients with different treatments. Cox proportional risk model was used to analyze independent predictors of OS.Propensity score matching (PSM) was used to analyze the tumor prognosis of different treatment methods. Results: Before PSM analysis, the OS of surgery plus chemotherapy (HRs = 0.896, 95%CIs, 0.827-0.970; P=0.007) were significantly better than the other three treatments for stage T1-3N0M0 PDAC patients. For stage T1-3N+M0 patients, adjuvant radiotherapy (HRs=0.613, 95% CIs, 0.579-0.649; P< 0.001) had significantly better OS than surgery plus chemotherapy and neoadjuvant radiotherapy. For stage T4N0M0 patients, neoadjuvant radiotherapy (HRs=0.482, 95% CIs, 0.347-0.670; P < 0.001) had significantly better OS than surgery plus chemotherapy and adjuvant radiotherapy. For stage T4N+M0 patients, neoadjuvant radiotherapy (HRs=0.338, 95% CIs, 0.215-0.532; P < 0.001) had significantly longer OS than adjuvant radiotherapy and surgery plus chemotherapy.Even after PSM, Chemotherapy plus surgery was still the best treatment for T1-3N0M0 patients. Postoperative adjuvant radiotherapy had the best prognosis among T1-3N+M0 patients, and neoadjuvant radiotherapy was the best treatment for T4 patients. Conclusions: For patients with non-metastatic PDAC, neoadjuvant radiotherapy, adjuvant radiotherapy and surgery plus chemotherapy were superior to only surgery in OS. For patients with stage T4 non-metastatic PDAC, neoadjuvant radiotherapy had the potential to be strongly recommended over adjuvant radiotherapy and surgery plus chemotherapy. However, neoadjuvant radiotherapy failed to benefit the survival of T1-3N0M0 stage patients, and surgery plus chemotherapy was preferred. For T1-3N+M0, neoadjuvant radiotherapy had no obvious advantage over adjuvant radiotherapy or surgery plus chemotherapy in OS, and adjuvant radiotherapy was more recommended.

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Transcriptomic analysis of the Aquaporin (AQP) gene family interactome identifies a molecular panel of four prognostic markers in patients with pancreatic ductal adenocarcinoma

Pancreatology ◽

10.1016/j.pan.2019.02.006 ◽

2019 ◽

Vol 19 (3) ◽

pp. 436-442 ◽

Cited By ~ 1

Author(s):

Dimitrios E. Magouliotis ◽

Vasiliki S. Tasiopoulou ◽

Konstantinos Dimas ◽

Nikos Sakellaridis ◽

Konstantina A. Svokos ◽

...

Keyword(s):

Gene Family ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Markers ◽

Transcriptomic Analysis ◽

Ductal Adenocarcinoma

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Clinical Characteristics and Overall Survival in Patients with Anaplastic Pancreatic Cancer

The American Surgeon ◽

10.1177/000313481408000218 ◽

2014 ◽

Vol 80 (2) ◽

pp. 117-123 ◽

Cited By ~ 3

Author(s):

Clancy J. Clark ◽

Janani S. Arun ◽

Rondell P. Graham ◽

Lizhi Zhang ◽

Michael Farnell ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Stage ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Poor Overall Survival ◽

Perioperative Morbidity ◽

Log Rank Test ◽

Kaplan Meier

Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma with poor overall survival (OS). The aim of this study was to evaluate the clinical outcomes of APC compared with differentiated pancreatic ductal adenocarcinoma. We conducted a retrospective review of all patients treated at the Mayo Clinic with pathologically confirmed APC from 1987 to 2011. After matching with control subjects with pancreatic ductal adenocarcinoma, OS was evaluated using Kaplan-Meier estimates and log-rank test. Sixteen patients were identified with APC (56.3% male, median age 57 years). Ten patients underwent exploration of whom eight underwent pancreatectomy. Perioperative morbidity was 60 per cent with no mortality. The median OS was 12.8 months. However, patients with APC who underwent resection had longer OS compared with those who were not resected, 34.1 versus 3.3 months ( P = 0.001). After matching age, sex, tumor stage, and year of operation, the median OS was similar between patients with APC and those with ductal adenocarcinoma treated with pancreatic resection, 44.1 versus 39.9 months, ( P = 0.763). Overall survival for APC is poor; however, when resected, survival is similar to differentiated pancreatic ductal adenocarcinoma.

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Multivariate assessment of SPARC expression in resected pancreatic ductal adenocarcinoma to identify subgroups that are sensitive to adjuvant gemcitabine.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.297 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 297-297

Author(s):

Steve Kalloger ◽

Joanna Karasinska ◽

Hui-li Wong ◽

Daniel John Renouf ◽

David F. Schaeffer

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Advanced Disease ◽

A Priori ◽

Predictive Ability ◽

Ductal Adenocarcinoma ◽

Secreted Protein ◽

Kaplan Meier ◽

Observation Methods ◽

Sparc Expression ◽

Disease Specific

297 Background: Secreted Protein, Acid, Cysteine-Rich (SPARC) has recently been postulated as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The clinical trial findings investigating SPARC expression and nab-paclitaxel sensitivity have been discordant. This study aims to develop an integrated component based approach to the quantification of SPARC in PDAC to identify discrete predictive subgroups in a cohort of resected patients treated with an gemcitabine (GEM) or subjected to post-surgical observation. Methods: Immunohistochemical quantification of SPARC was performed on the epithelial and stromal compartments of resected PDAC on 219 patient samples on a tissue-microarray. The staining was assessed by the generation of H-Scores. The resultant scores were subjected to unsupervised hierarchical clustering. The maximum number of clusters was determined through an a priori decision that no cluster could be composed of less than 15% of the cohort. Univariable disease specific survival (DSS) analysis was performed with the Kaplan-Meier method to examine the cluster specific survival profiles with regard to gemcitabine sensitivity. Results: Mean age was 67 [38-88] with 56% being male. Most of the cohort had advanced disease with pT3 = 95% and pN1 = 72%. Lymphovascular and perinueural invasion were found in 58% and 93% of the cohort respectively. Clusters ranging in size from 35 to 76 cases were derived and represented the four-biomarker combinations of Low/Low, Low/High, High/High, and High/Low for the epithelial and stromal components respectively. None of the clinico-pathologic variables were significantly enriched in the clusters. Assessment of the predictive ability of the 4 clusters demonstrated that only one cluster (High/High) representing 76 (35%) patients in this cohort was sensitive to adjuvant GEM (p = 0.0067). Conclusions: This study shows that there is enhanced value in a combinatorial approach to the examination of SPARC in the stromal and epithelial components of PDAC where we have discovered that co-expression in both the epithelial and stromal components is significantly associated with sensitivity to adjuvant GEM.

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First line gemcitabine and nab-paclitaxel chemotherapy for localized pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.369 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 369-369

Author(s):

Pat Gulhati ◽

Laura Prakash ◽

Matthew H. G. Katz ◽

Xuemei Wang ◽

Milind M. Javle ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Metastatic Disease ◽

Locally Advanced ◽

Standard Of Care ◽

Clinical Staging ◽

Ductal Adenocarcinoma ◽

First Line ◽

First Line Therapy ◽

Kaplan Meier ◽

Ecog Ps

369 Background: Chemotherapy is widely used as a component of treatment of localized pancreatic ductal adenocarcinoma (PDAC). Pre-operative chemotherapy is associated with early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy. For locally advanced (LA) PDAC, induction chemotherapy is standard of care. We evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy in localized PDAC. Methods: Records of pts with localized PDAC who initiated Gem/nab-P at a single institution from 2013-2015 were retrospectively reviewed. Clinicopathologic features, dose and outcomes were evaluated. Pts were staged using our previously published criteria: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (co-morbidities requiring medical optimization), and LA. Co-morbidities were classified using adult comorbidity evaluation-27 score. Overall survival (OS) was analyzed using Kaplan Meier method. Results:99 pts [M/F: 50/49; median age: 70 yrs (range 30-85); PR/BR/LA: 45/14/40] were treated with Gem/nab-P. Clinical staging showed PR+BR-A/BR-B+C: 20/39. BR-B+C included one or more of the following factors: age ≥80 yrs [13%], ECOG PS ≥2 [13%], moderate/severe co-morbidities [55%], CA19-9≥1000 [28%], suspicion for metastatic disease [21%]. Majority of pts received biweekly Gem/nab-P dosing [standard/biweekly/other: 10/80/9] with minimal grade 4 toxicity. 45/99 pts received chemoradiation after Gem/nab-P [30Gy/50.4Gy: 15/30]. 12/20 (60%) PR+BR-A, 2/39 (5%) BR-B+C and 1/40 (3%) LA pts underwent pancreatectomy. 13/15 resected pts received adjuvant chemotherapy. At median follow-up of 26 mo, median OS was 18 (95% CI: 15.6-20.5) mo for all, 17 (95% CI: 14.6-19.5) mo for unresected and not reached for resected pts (p = 0.03). Conclusions: A significant number of pts with resectable PDAC albeit aggressive biology (BR-B) and/or medically inoperable disease (BR-C) received first-line Gem/nab-P; resection rates were lower compared to PR/BR-A pts. Biweekly dosing is being used in localized PDAC and is well tolerated.

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