An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression

Khan, Aamir Ali; Liu, Xinhui; Yan, Xinlong; Tahir, Muhammad; Ali, Sakhawat; Huang, Hua

doi:10.1007/s10555-020-09952-0

Cited by 43 publications

(25 citation statements)

References 199 publications

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“…Here we found that SFN hypomethylation was associated with increased gene expression and worse survival of patients with PCA. Accordingly, previous studies have described SFN hypomethylation in PCA (reviewed in [ 17 , 87 ]) and identified its increased expression as an independent prognostic PCA biomarker [ 63 ]. The clinical significance of SFN methylation identified in our analysis is also corroborated by reports in other cancer types where these epigenetic events in SFN gene were considered promising biomarkers [ 88 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Faleiro

Roberto

Canli

et al. 2021

Cancers

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Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Faleiro

Roberto

Canli

et al. 2021

Cancers

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“…These signaling molecules mediate early distant metastasis, resistance to conventional chemotherapy [ 6 , 7 ], and development of pancreatic cancer stem cell (CSC) characteristics [ 8 ]. In addition to the genetic alterations, it is found that aberrant activation of epigenetic regulatory mechanisms, DNA methylation and post-translational histone modifications also play an important role in PDAC progression [ 9 ]. The epigenetic alterations are also responsible for over-activation of the growth signaling pathway and the silencing of tumor suppressor and cell cycle checkpoint genes in PDAC [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

Chaudhary

Guragain

Chang

et al. 2021

Cancers

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In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT7, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT7. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT7. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT7 effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT7 axis leading to gemcitabine resistance and CSC population in PDAC.

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“…PC is a complex molecular biological process involving multi-genes, multi-signal pathways, and multi-steps ( 26 ). Based on the rapid development of gene sequencing technology, the researchers discovered that PC is accompanied by massive genetic mutations (including K-ras, TP53, and CDKN2A) ( 27 ), which offer the potential for the occurrence of cancer. Moreover, the tumor microenvironment provides a hotbed for cancer development and promotes tumor immune escape ( 28 ).…”

Section: Hinting On the Pathogenesis Of Pc By Msmentioning

confidence: 99%

Application of Mass Spectrometry in Pancreatic Cancer Translational Research

Luo

Chen

et al. 2021

Front. Oncol.

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Pancreatic cancer (PC) is one of the most common malignant tumors in the digestive tract worldwide, with increased morbidity and mortality. In recent years, with the development of surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and the change of the medical thinking model, remarkable progress has been made in researching comprehensive diagnosis and treatment of PC. However, the present situation of diagnostic and treatment of PC is still unsatisfactory. There is an urgent need for academia to fully integrate the basic research and clinical data from PC to form a research model conducive to clinical translation and promote the proper treatment of PC. This paper summarized the translation progress of mass spectrometry (MS) in the pathogenesis, diagnosis, prognosis, and PC treatment to promote the basic research results of PC into clinical diagnosis and treatment.

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An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression

Cited by 43 publications

References 199 publications

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

Application of Mass Spectrometry in Pancreatic Cancer Translational Research

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