YOD1 Serves as a Potential Prognostic Biomarker For Pancreatic Cancer

Abstract Background Ubiquitination is a basic post-translational modification of intracellular proteins and can be reversed enzymatically by DUBs (deubiquitinating enzymes). More than 90 DUBs have been identified. Among them, the deubiquitinating enzyme YOD1, a member of the ovarian tumor domain protease (OTUs) subfamily, is involved in the regulation of endoplasmic reticulum (ER)-related degradation pathways. In fact, it is reported that YOD1 is an important proliferation and metastasis-inducing gene, which can stimulate the characteristics of cancer stem cells and maintain circulating tumor cells (CTC). However, the expression level, prognostic effect, biological function and mechanism of YOD1 in pancreatic cancer are still unclear. ResultsIn the GEO and TCGA databases, YOD1 mRNA expression is significantly up-regulated in a variety of human pancreatic cancer tissues. Survival analysis showed that the up-regulation of YOD1 can predict poor prognosis of pancreatic cancer. Cox analysis showed that high YOD1 expression is an independent prognostic factor of pancreatic cancer. ROC analysis shows that YOD1 has significant diagnostic value. The immunohistochemistry (IHC) results showed that the protein expression level of YOD1 in pancreatic cancer tissue was higher than that in neighboring non-pancreatic cancer tissues (P<0.001). In addition, we found that YOD1 expression is negatively correlated with the infiltration level of CD8+ T cells, macrophages, neutrophils and dendritic cells (DC) in pancreatic cancer. The expression of YOD1 has a strong correlation with the different immune marker sets in PAAD. Co-expression network and functional enrichment analysis indicate that YOD1 may participate in the development of pancreatic cancer through cell adhesion molecules, p53, Hippo, TGF-β and other pathways. The experimental results of EDU, Transwell and Western blot indicate that YOD1 is highly expressed in pancreatic cancer cells and pancreatic cancer tissues, and its overexpression can promote the proliferation and metastasis of pancreatic cancer cells.Conclusion Our results indicate that YOD1 may be a useful biomarker for the prognosis of human pancreatic cancer, and it may also be a potential molecular target for the diagnosis and treatment of pancreatic cancer.

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SIRT1 promotes the proliferation and metastasis of human pancreatic cancer cells

Tumor Biology ◽

10.1177/1010428317691180 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769118 ◽

Cited By ~ 11

Author(s):

Jianguang Jin ◽

Zhijie Chu ◽

Pengfei Ma ◽

Yuanpu Meng ◽

Yanhui Yang

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Cancer Cell Proliferation ◽

Pancreatic Cancer Cells ◽

Cell Proliferation And Migration ◽

Proliferation And Metastasis ◽

And Migration ◽

Cancer Tissues ◽

Proliferation And Migration

SIRT1 plays an important role in human malignant progression, inducing cancer cell proliferation and metastasis by regulating downstream gene expressions. However, little is known about the underlying mechanisms in which SIRT1 promotes pancreatic cancer tumorigenesis. The aim of this study is to investigate the SIRT1 expression levels and biological functions in promoting pancreatic cancer progression. We first investigated the expression of SIRT1 in a series of pancreatic cancer tissues as well as in a panel of pancreatic cancer cell lines. The effect of SIRT1 on cell activity was explored by knockdown experiments. Cell growth was measured using the MTT assay and colony-formation assay. Migration and invasion were tested using transwell assay. Our results showed that the expression of SIRT1 was significantly up-regulated both in pancreatic cancer tissues and cell lines. Knockdown of SIRT1 suppressed cell proliferation and migration of pancreatic cancer cells. This is the first report to disclose the role of SIRT1 in regulation of pancreatic cancer cell proliferation and migration, which may provide a potential therapeutic target for pancreatic cancer patients.

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Influence of type‐I Interferon receptor expression level on the response to type‐I Interferons in human pancreatic cancer cells

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.12200 ◽

2014 ◽

Vol 18 (3) ◽

pp. 492-502 ◽

Cited By ~ 25

Author(s):

Stephanie Booy ◽

Casper H. J. Eijck ◽

Fadime Dogan ◽

Peter M. Koetsveld ◽

Leo J. Hofland

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Type I Interferon ◽

Receptor Expression ◽

Type I Interferons ◽

Expression Level ◽

Human Pancreatic Cancer ◽

Type I ◽

Pancreatic Cancer Cells ◽

Interferon Receptor

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[6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling

Cancer Cell International ◽

10.1186/s12935-021-02118-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xueyi Jiang ◽

Jie Wang ◽

Peng Chen ◽

Zhiwei He ◽

Jian Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Molecular Docking ◽

Mrna Expression ◽

Enrichment Analysis ◽

Akt Signaling ◽

Expression Level ◽

Docking Analysis ◽

Proliferation And Metastasis ◽

Molecular Docking Analysis

Abstract Background The underlying mechanism behind the tumorigenesis and progression of pancreatic cancer is not clear, and treatment failure is generally caused by early metastasis, recurrence, drug resistance and vascular invasion. Exploring novel therapeutic regimens is necessary to overcome drug resistance and improve patients outcomes. Methods Functional assays were performed to investigate the role of [6]-Paradol (6-P) in proliferation and metastasis of pancreatic cancer in vitro and in vivo. The interaction between EGFR and 6-P was tested by KEGG enrichment analysis and molecular docking analysis. qRT-PCR was performed to detect the mRNA expression of EGFR in 6-P treated groups. Involvement of the PI3K/AKT pathway was measured by western blotting. Results 6-P significantly suppressed pancreatic cancer cell proliferation and metastasis. KEGG enrichment analysis and molecular docking analysis suggested that there existed certain interaction between EGFR and 6-P. In addition, 6-P obviously decreased EGFR protein expression level but did not change the mRNA expression level of EGFR. 6-P could induce degradation of EGFR through decreasing the protein stability of EGFR and enhancing the ubiquitin-mediated proteasome-dependent degradation, 6-P-mediated EGFR degradation led to inactivation of PI3K/AKT signaling pathway. However, ectopic expression of EGFR protein resulted in resistance to 6-P-mediated inactivity of PI3K/AKT signaling and inhibition of malignant phenotype of pancreatic cancer. Inversely, erlotinib could enhance the 6-P-mediated anticancer activity. Conclusion Our data indicated that 6-P/EGFR/PI3K/AKT signaling axis might become one of the potential therapies for the treatment of pancreatic cancer.

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Pioglitazone inhibits the proliferation and metastasis of human pancreatic cancer cells

Oncology Letters ◽

10.3892/ol.2014.2553 ◽

2014 ◽

Vol 8 (6) ◽

pp. 2709-2714 ◽

Cited By ~ 20

Author(s):

ITASU NINOMIYA ◽

KEISUKE YAMAZAKI ◽

KATSUNOBU OYAMA ◽

HIRONORI HAYASHI ◽

HIDEHIRO TAJIMA ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

Proliferation And Metastasis

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LncRNA TP73-AS1 sponges miR-141-3p to promote the migration and invasion of pancreatic cancer cells through the up-regulation of BDH2

Bioscience Reports ◽

10.1042/bsr20181937 ◽

2019 ◽

Vol 39 (3) ◽

Cited By ~ 11

Author(s):

Xian-Ping Cui ◽

Chuan-Xi Wang ◽

Zhi-Yi Wang ◽

Jian Li ◽

Ya-Wen Tan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Human Pancreatic Cancer ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Cancer Tissue ◽

Pancreatic Cancer Cells ◽

Candidate Target ◽

Direct Target

Abstract LncRNA TP73 antisense RNA 1T (TP73-AS1) plays an important role in human malignancies. However, the levels of TP73-AS1 and its functional mechanisms in pancreatic cancer metastasis remain unknown, and the clinical significance of TP73-AS1 in human pancreatic cancer is also unclear. In the present study, the levels of TP73-AS1 and its candidate target miR-141 in pancreatic cancer and adjacent normal tissue were detected using qRT-PCR. The association between TP73-AS1 levels and the clinicopathologic characteristics of pancreatic cancer patients were analyzed. The relationship between TP73-AS1 and miR-141, and miR-141 and its candidate target 3-hydroxybutyrate dehydrogenase type 2 (BDH2) was confirmed using dual-luciferase reporter assays. TP73-AS1 and/or miR-141 were knocked down using siRNA or an inhibitor in pancreatic cancer cells and cell migration and invasion then examined. The results showed that TP73-AS1 was up-regulated in pancreatic cancer tissue and cell lines. High levels of TP73-AS1 were correlated with poor clinicopathological characteristics and shorter overall survival. MiR-141 was a direct target for TP73-AS1, while BDH2 was a direct target for miR-141. The knockdown of TP73-AS1 significantly inhibited the migration and invasion of pancreatic cancer cells, while the miR-141 inhibitor significantly restored the migration and invasion. Therefore, TP73-AS1 positively regulated BDH2 expression by sponging miR-141. These findings suggest that TP73-AS1 serves as an oncogene and promotes the metastasis of pancreatic cancer. Moreover, TP73-AS1 could serve as a predictor and a potential drug biotarget for pancreatic cancer.

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Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

10.21203/rs.3.rs-95055/v1 ◽

2020 ◽

Author(s):

Qing Hua ◽

Tianjiao Li ◽

Yixuan Liu ◽

Xuefang Shen ◽

Xiaoyan Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Poor Prognosis ◽

Disease Free Survival ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. Results: KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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bax, but notbcl-2, influences the prognosis of human pancreatic cancer

Gut ◽

10.1136/gut.43.3.414 ◽

1998 ◽

Vol 43 (3) ◽

pp. 414-421 ◽

Cited By ~ 82

Author(s):

H Friess ◽

Z Lu ◽

H U Graber ◽

A Zimmermann ◽

G Adler ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Northern Blot ◽

In Situ Hybridisation ◽

Biological Significance ◽

Human Pancreatic Cancer ◽

Cancer Tissue ◽

Mrna Levels ◽

Pancreatic Cancer Cells

Background—bcl-2and bax belong to thebcl-2-related gene family, which marks a new class of genes that influence apoptosis. Thebcl-2 oncogene acts as a broad antiapoptotic factor and extends both normal and tumour cell survival. In contrast, the bax gene is a promoter of apoptosis.Aims—To analyse the expression of bcl-2 andbax in pancreatic cancer and correlate the results with clinical parameters.Patients—Pancreatic cancer tissue samples were obtained from 28 female and 32 male patients (median age 63, range 43–79 years) having surgery for pancreatic cancer. Normal pancreatic tissues obtained from 18 previously healthy organ donors served as controls.Methods—The levels ofbcl-2 and baxmRNA expression were analysed by northern blot and the exact site of mRNA transcription was determined by in situ hybridisation. The presence of the corresponding proteins was determined by immunohistochemistry.Results—Northern blot analysis indicated that, in comparison with the normal pancreas,bcl-2 mRNA was overexpressed in 30% andbax mRNA in 61% of the pancreatic cancer samples. Concomitant overexpression ofbcl-2 and bax was present in 26% of the cancer samples. Pancreatic adenocarcinomas exhibited 3.7-fold and 5.4-fold increases (p<0.001) inbcl-2 and baxmRNA levels respectively. In situ hybridisation showed that bothbcl-2 and baxmRNA were expressed in the cancer cells. Immunohistochemical analysis showed positive Bcl-2 and Bax immunostaining in 28 and 83% of the cancer samples respectively. In multivariate analysis (Cox regression model), bax expression was found to be a strong indicator of survival (p<0.001). Patients whose tumours exhibited Bax immunostaining lived significantly longer (12 months) than those whose tumours were Bax negative (five months) (p<0.039). In contrast, no relation was found between Bcl-2 and survival time.Conclusions—The data indicate that genes that are involved in the regulation of apoptosis are upregulated in human pancreatic cancer cells. Prolonged survival times in patients in whom apoptosis promoting factors are upregulated indicate that apoptotic pathways are of biological significance in pancreatic cancer.

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Role of Peroxisome Proliferator-Activated Receptorβ/δand B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells

PPAR Research ◽

10.1155/2013/121956 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 16

Author(s):

Jeffrey D. Coleman ◽

Jerry T. Thompson ◽

Russell W. Smith ◽

Bogdan Prokopczyk ◽

John P. Vanden Heuvel

Keyword(s):

Pancreatic Cancer ◽

Basement Membrane ◽

Cancer Cells ◽

Target Genes ◽

B Cell Lymphoma ◽

Human Pancreatic Cancer ◽

Cancer Tissue ◽

Peroxisome Proliferator ◽

Matrix Remodeling ◽

Pancreatic Cancer Cells

PPARβ/δis a ligand-activated transcription factor that regulates various cellular functions via induction of target genes directly or in concert with its associated transcriptional repressor,BCL-6. Matrix remodeling proteinases are frequently over-expressed in pancreatic cancer and are involved with metastasis. The present study tested the hypothesis thatPPARβ/δis expressed in human pancreatic cancer cells and that its activation could regulateMMP-9, decreasing cancer cells ability to transverse the basement membrane. In human pancreatic cancer tissue there was significantly higher expression ofMMP-9andPPARβ/δ, and lower levels ofBCL-6mRNA.PPARβ/δactivation reduced the TNFα-induced expression of various genes implicated in metastasis and reduced the invasion through a basement membrane in cell culture models. Through the use of short hairpin RNA inhibitors ofPPARβ/δ,BCL-6, andMMP-9, it was evident thatPPARβ/δwas responsible for the ligand-dependent effects whereasBCL-6dissociation upon GW501516 treatment was ultimately responsible for decreasingMMP-9expression and hence invasion activity. These results suggest thatPPARβ/δplays a role in regulating pancreatic cancer cell invasion through regulation of genes via ligand-dependent release ofBCL-6and that activation of the receptor may provide an alternative therapeutic method for controlling migration and metastasis.

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