Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Atay, Sevcan

doi:10.7717/peerj.10141

Cited by 35 publications

(38 citation statements)

References 75 publications

(77 reference statements)

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“…Pancreatic cancer has been a common and most importantly lethal malignancy worldwide. The overall 5-year survival rate was 7 ~ 9% and 1-year rate less than 20% [ 1 ]. Despite the improvements in clinical treatment strategies for many other cancer types, the treatment methods and survival rate of pancreatic cancer remained steady for the past few decades [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, curative surgery is still considered the main option for PAAD treatment. However, attributing to the indistinctive symptoms during the early stage of disease, distant metastasis has occurred to 50 ~ 60% patients at the time they were hospitalized [ 1 , 6 ]. And even if curative surgeries were performed at early stage, the recurrence and subsequent metastasis rate is still as high as 60% within the first 12 months after surgery [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma

Wei

Zeng

et al. 2021

Cancer Cell Int

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Background Pancreatic cancer has been a threateningly lethal malignant tumor worldwide. Despite the promising survival improvement in other cancer types attributing to the fast development of molecular precise medicine, the current treatment situation of pancreatic cancer is still woefully challenging since its limited response to neither traditional radiotherapy and chemotherapy nor emerging immunotherapy. The study is to explore potential responsible genes during the development of pancreatic cancer, thus identifying promising gene indicators and probable drug targets. Methods Different bioinformatic analysis were used to interpret the genetic events in pancreatic cancer development. Firstly, based on multiple cDNA microarray profiles from Gene Expression Omnibus (GEO) database, the genes with differently mRNA expression in cancer comparing to normal pancreatic tissues were identified, followed by being grouped based on the difference level. Then, GO and KEGG were performed to separately interpret the multiple groups of genes, and further Kaplan–Meier survival and Cox Regression analysis assisted us to scale down the candidate genes and select the potential key genes. Further, the basic physicochemical properties, the association with immune cells infiltration, mutation or other types variations besides expression gap in pancreatic cancer comparing to normal tissues of the selected key genes were analyzed. Moreover, the aberrant changed expression of key genes was validated by immunohistochemistry (IHC) experiment using local hospital tissue microarray samples and the clinical significance was explored based on TCGA clinical data. Results Firstly, a total of 22,491 genes were identified to express differently in cancer comparing to normal pancreatic tissues based on 5 cDNA expression profiles, and the difference of 487/22491 genes was over eightfold, and 55/487 genes were shared in multi profiles. Moreover, after genes interpretation which showed the > eightfold genes were mainly related to extracellular matrix structural constituent regulation, Kaplan–Meier survival and Cox-regression analysis were performed continually, and the result indicated that of the 55 extracellular locating genes, GPRC5A and IMUP were the only two independent prognostic indicators of pancreatic cancer. Further, detailed information of IMUP and GPRC5A were analyzed including their physicochemical properties, their expression and variation ratio and their association with immune cells infiltration in cancer, as well as the probable signaling pathways of genes regulation on pancreatic cancer development. Lastly, local IHC experiment performed on PAAD tissue array which was produced with 62 local hospital patients samples confirmed that GPRC5A and IMUP were abnormally up-regulated in pancreatic cancer, which directly associated with worse patients both overall (OS) and recurrence free survival (RFS). Conclusions Using multiple bioinformatic analysis as well as local hospital samples validation, we revealed that GPRC5A and IMUP expression were abnormally up-regulated in pancreatic cancer which associated statistical significantly with patients survival, and the genes’ biological features and clinical significance were also explored. However, more detailed experiments and clinical trials are obligatory to support their further potential drug-target role in clinical medical treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma

Wei

Zeng

et al. 2021

Cancer Cell Int

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“…In our analyses we chose to use Our SPCS method contributed to identify many more differentially expressed genes than the other smoothing methods for most of the slides. Among the DEGs, the up regulation of IL1RN, KRT7, LAMB3, LAMC2, NOTCH3, and S100A16 , which have previously been reported associate with poor survival in PDAC, was also detected in the SPCS smoothed PDACA1 slide [56, 63]. IL1RN and LAMB3 were also found using unsmoothed data and LAMB3 was detected with MAGIC smoothed data, but the other genes were uniquely detected by SPCS.…”

Section: Discussionmentioning

confidence: 77%

SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression

Liu

Duggan

Huang

et al. 2021

Preprint

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The recently developed spatial transcriptomics (ST) technique has made it possible to view spatial transcriptional heterogeneity in a high throughput manner. It is based on highly multiplexed sequence analysis and uses barcodes to split the sequenced reads into respective tissue locations. However, this type of sequencing technique suffers from high noise and drop-out events in the data, which makes smoothing a necessary step before performing downstream analysis. Traditional smoothing methods used in the similar single cell RNA sequencing (scRNA-seq) data are one-factor methods that can only utilize associations in transcriptome space. Since they do not account for associations in the Euclidean space, i.e. tissue location distances on the ST slide, these one-factor methods cannot take full advantage of all the knowledge in ST data. In this study, we present a novel two-factor smoothing technique, Spatial and Pattern Combined Smoothing (SPCS), that employs k-nearest neighbor technique to utilize associations from transcriptome and Euclidean space from the ST data. By performing SPCS on 10 ST slides from pancreatic ductal adenocarcinoma (PDAC), smoothed ST slides have better separability, partition accuracy, and biological interpretability than the ones smoothed by pre-existing one-factor smoothing methods. Source code of SPCS is provided in Github (https://github.com/Usos/SPCS).

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“…FN1 is primarily expressed in fibroblasts but can also be produced by other cell types, including cancer and endothelial cells [50]. Its expression is significantly increased in many solid tumors, including PDAC [51], promoting progression and metastasis [52]. High FN1 expression in PDAC tissues correlates with higher tumor weight, more advanced disease, and poorer prognosis after resection [53].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Urbanova

Buociková

Trnkova

et al. 2022

IJMS

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Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O2) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.

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Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Cited by 35 publications

References 75 publications

IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma

IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma

SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression

DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines

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