scholarly journals EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Hwa-Ryeon Kim ◽  
Juhye Yim ◽  
Hye-Been Yoo ◽  
Seung Eon Lee ◽  
Sumin Oh ◽  
...  
Keyword(s):  
Integration Site ◽  
Ductal Adenocarcinoma ◽  
Epigenetic Alterations ◽  
Cis Acting ◽  
Transcriptional Enhancers ◽  
Active Enhancer ◽  
Aggressive Tumor

Abstract Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells utilize super-enhancers (SEs) to activate the transcription factor EVI1 (ecotropic viral integration site 1) gene, resulting in activation of an EVI1-dependent transcription program conferring PDA tumorigenesis. Our data indicate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Consistent with disease progression and inferior survival outcomes of PDA patients, we further show that EVI1 upregulation is a major cause of aggressive tumor phenotypes. Specifically, EVI1 promotes anchorage-independent growth and motility in vitro and enhances tumor propagation in vivo. Mechanistically, EVI1-dependent activation of tumor-promoting gene expression programs through the stepwise configuration of the active enhancer chromatin attributes to these phenotypes. In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

scholarly journals Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells

Oncogene ◽  
2021 ◽  
Author(s):  
Mengyi Lao ◽  
Xiaozhen Zhang ◽  
Tao Ma ◽  
Jian Xu ◽  
Hanshen Yang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Vital Role ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Metastasis Model ◽  
Inducible Protein

AbstractTherapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

scholarly journals Upregulation of lncRNA DQ679794 contributes to preventing the progression of hepatocellular carcinoma both in vitro and in vivo

2020 ◽  
Author(s):  
Ze-wei Lin ◽  
Qing-qi Ren ◽  
Zhi-feng Huang ◽  
Ji-kui Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Development ◽  
Quantitative Real Time Pcr ◽  
Transplanted Tumors ◽  
Normal Tissues ◽  
Transplanted Tumor ◽  
Aggressive Tumor

Abstract Background Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Long noncoding RNAs (lncRNAs) are key regulators of tumor development. However, lncRNA profiles in HCC remain largely unknown. In previous studies, we found that lncRNA DQ786243 plays an important role in the pathogenesis of HCC and promotes the development of HCC. In this study, we investigated the role of lncRNA DQ679794 in the pathogenesis of HCC. Methods and Results We first used quantitative real-time PCR among 64 paired HCC tissues, and the level of lncRNA DQ679794 was found to be significantly lower in tumors than in normal tissues. In addition, the effects of lncRNA DQ679794 were assessed by overexpression in vitro and in vivo . We found that the level of apoptosis was increased and that cell proliferation was weakened in HepG2 cells overexpressing DQ679794. Finally, the transplanted tumor experiment confirmed that after the overexpression of lncRNA DQ679794, the growth of transplanted tumors formed by liver cancer cells was inhibited. Conclusion This study suggests that lncRNA DQ679794 is an oncogene that inhibits tumor progression, and we believe that lncRNAs may be a key regulatory center in HCC progression.

scholarly journals In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma

Oncotarget ◽  
2018 ◽  
Vol 9 (6) ◽  
pp. 6952-6967 ◽  
Author(s):  
Stéphanie Dayot ◽  
Daniela Speisky ◽  
Anne Couvelard ◽  
Pierre Bourgoin ◽  
Valérie Gratio ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Ductal Adenocarcinoma ◽  
Orexin A ◽  
Hypocretin 1

scholarly journals Epigenetic Effects of Nanomaterials and Nanoparticles

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Marta Pogribna ◽  
George Hammons
Keyword(s):  
Adverse Effects ◽  
Human Life ◽  
Potential Effect ◽  
Current Evidence ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Epigenetic Effects

AbstractThe rise of nanotechnology and widespread use of engineered nanomaterials in everyday human life has led to concerns regarding their potential effect on human health. Adverse effects of nanomaterials and nanoparticles on various molecular and cellular alterations have been well-studied. In contrast, the role of epigenetic alterations in their toxicity remains relatively unexplored. This review summarizes current evidence of alterations in cytosine DNA methylation and histone modifications in response to nanomaterials and nanoparticles exposures in vivo and in vitro. This review also highlights existing knowledge gaps regarding the role of epigenetic alterations in nanomaterials and nanoparticles toxicity. Additionally, the role of epigenetic changes as potential translational biomarkers for detecting adverse effects of nanomaterials and nanoparticles is discussed.

scholarly journals Auxin-degron system identifies immediate mechanisms of Oct4

2020 ◽  
Author(s):  
Lawrence E Bates ◽  
Mariana R P Alves ◽  
José C R Silva
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Pluripotent Stem Cells ◽  
Histone Mark ◽  
Pluripotency Factors ◽  
Active Enhancer ◽  
Subsequent Event

AbstractThe pluripotency factor Oct4 is essential for the maintenance of naïve pluripotent stem cells in vitro and in vivo. However, the specific role of Oct4 in this process remains unknown. Here, we developed a rapid protein-level Oct4 depletion system that demonstrates that the immediate downstream response to loss of Oct4 is reduced expression of key pluripotency factors. Our data show a requirement for Oct4 for the efficient transcription of several key pluripotency factors, and suggest that expression of trophectoderm markers is a subsequent event. Additionally, we find that Nanog is competent to bind to the genome in the absence of Oct4, and this binding is in fact enhanced. Globally, however, active enhancer associated histone mark H3K27ac is depleted. Our work establishes that while Oct4 is required for the maintenance of the naïve transcription factor network, at a normal ESC level it antagonises this network through inhibition of Nanog binding.

scholarly journals 99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1531 ◽  
Author(s):  
Montemagno ◽  
Cassim ◽  
Trichanh ◽  
Savary ◽  
Pouyssegur ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Targeted Therapies ◽  
Ductal Adenocarcinoma ◽  
Prognostic Role ◽  
Single Domain Antibody ◽  
Domain Antibody ◽  
Mesothelin Expression

: Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (P < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (P < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.

scholarly journals Stromal cues regulate the pancreatic cancer epigenome and metabolome

2017 ◽  
Vol 114 (5) ◽  
pp. 1129-1134 ◽  
Author(s):  
Mara H. Sherman ◽  
Ruth T. Yu ◽  
Tiffany W. Tseng ◽  
Cristovao M. Sousa ◽  
Sihao Liu ◽  
...  
Keyword(s):  
Ductal Adenocarcinoma ◽  
Oncogenic Signaling ◽  
Potential Therapeutic Target ◽  
Key Driver ◽  
Accelerated Growth ◽  
Induced Changes ◽  
Insight Into

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling—a hallmark and key driver of PDAC—is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular “AND-gate” such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.

The Role of Epigenetic Alterations Involved in Sepsis: An Overview

2018 ◽  
Vol 24 (24) ◽  
pp. 2862-2869 ◽  
Author(s):  
Fatima Ismail Hassan ◽  
Tina Didari ◽  
Fazlullah Khan ◽  
Mojtaba Mojtahedzadeh ◽  
Mohammad Abdollahi
Keyword(s):  
Disease Progression ◽  
Accurate Method ◽  
Body Fluids ◽  
Morbidity And Mortality ◽  
Diagnosis And Treatment ◽  
Treatment Modalities ◽  
Epigenetic Alterations

Background: Sepsis is among the leading causes of death with no specific etiology or treatment. Increase in health burden in terms of cost, morbidity, and mortality is the reason behind the continuous search for different treatment modalities which involve several targets/approach and one of them includes the involvement of epigenetics in sepsis. Objective: This review was carried out to explain the epigenetic alterations involved in sepsis, as it affects the disease progression, diagnosis, and treatment. Methods: Information used in this review was obtained from different databases including PUBMED, SCOPUS, Web of Science, and EMBASE. Keywords were used as search terms. Result: In this review, we provided a concise overview of the significant role of epigenetic alterations in sepsis pathophysiology as it relates to disease progression, diagnosis and treatment derived from in vitro, in vivo, and human studies. These mechanisms affected various targets and pathways involved in sepsis modulation, which correlates with morbidity and mortality. Change in DNA methylation pattern, histone modification, and microRNA regulation has been shown in sepsis models to silence or activate pro-inflammatory genes such as TNF-α and interleukins, anti-oxidant enzymes, and many signaling pathways. Drugs that target these pathways have proven effective in sepsis treatment. Conclusion: Epigenetic processes involve specific enzymes detected in the blood and other body fluids which can potentially serve as diagnostic, therapeutic, as well as prognostic tools in sepsis. Epigenetic mechanisms can provide a highly sensitive and accurate method for sepsis diagnosis using blood and other body fluids.

scholarly journals ELK3 Mediated by ZEB1 Facilitates the Growth and Metastasis of Pancreatic Carcinoma by Activating the Wnt/β-Catenin Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiuyan Zhao ◽  
Yingchun Ren ◽  
Haoran Xie ◽  
Lanting Yu ◽  
Jiawei Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Tissues ◽  
Online Databases ◽  
Ternary Complex Factor

Rapid progression and metastasis are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). ELK3, a member of the ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC is not yet fully understood. Online databases and immunohistochemistry were used to analyze the ELK3 levels in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blotting and immunofluorescence were used to detect the molecular mechanisms of PDAC. ChIP-qPCR was used to study the mechanism responsible for the elevation of ELK3 expression in PDAC. The ELK3 levels were higher in PDAC tissues than in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further study suggested that ELK3 promoted PDAC cell migration and invasion by activating the Wnt/β-catenin pathway, and proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both were associated with the patients’ clinicopathological features and worse overall survival. Conclusively, our findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies for the treatment of PDAC.

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