Wnt-11 Expression Promotes Invasiveness and Correlates with Survival in Human Pancreatic Ductal Adeno Carcinoma

Dart, Dafydd Alwyn; Arısan, Elif Damla; Owen, Sioned; Hao, Chunyi; Jiang, Wen Guo; Uysal-Onganer, Pinar

doi:10.3390/genes10110921

Cited by 11 publications

(13 citation statements)

References 59 publications

(79 reference statements)

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“…This correlates with the differences observed in protein levels of the PAD isozymes in the cell lines and lack of positive signal for PAD4 at expected molecular size, also pointing to a negligible role for PAD4 in PDAC, while PAD2 was the most prominent isozyme. Some differences were furthermore observed between the two PDAC cell lines under study, pointing to stronger effects of PAD inhibitors in Panc-1 cells, which, interestingly, also showed substantial response to PAD3 inhibitor, which may correlate with previous observations that this cell line contains neuronal-like/stem-like properties [104].…”

Section: Discussionsupporting

confidence: 78%

“…PAD3 has been associated with neuronal stem cell properties [ 92 ] and found, for example, to be elevated in specific GBM cell lines, which may therefore also have stronger stem-like properties as GBM are known for stem-ness [ 15 , 17 ]. Importantly, previous PDAC in vitro studies reported that Panc-1 cells display most neuronal/stem-like properties [ 104 ], which may cause it to reflect a more aggressive form and also highlight possible roles for PAD3 in such stem-like cancers. Therefore it will be of great interest to further investigate a link between PAD3 and cancer stem-ness in a wider range of cancers and cancer cell lines, including PDAC.…”

Section: Discussionmentioning

confidence: 99%

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Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

Uysal-Onganer

D’Alessio

Mortoglou

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with limited survival rate. Roles for peptidylarginine deiminases (PADs) have been studied in relation to a range of cancers with roles in epigenetic regulation (including histone modification and microRNA regulation), cancer invasion, and extracellular vesicle (EV) release. Hitherto though, knowledge on PADs in PDAC is limited. In the current study, two PDAC cell lines (Panc-1 and MiaPaCa-2) were treated with pan-PAD inhibitor Cl-amidine as well as PAD2, PAD3, and PAD4 isozyme-specific inhibitors. Effects were assessed on changes in EV signatures, including EV microRNA cargo (miR-21, miR-126, and miR-221), on changes in cellular protein expression relevant for pancreatic cancer progression and invasion (moesin), for mitochondrial housekeeping (prohibitin, PHB), and gene regulation (deiminated histone H3, citH3). The two pancreatic cancer cell lines were found to predominantly express PAD2 and PAD3, which were furthermore expressed at higher levels in Panc-1, compared with MiaPaCa-2 cells. PAD2 isozyme-specific inhibitor had the strongest effects on reducing Panc-1 cell invasion capability, which was accompanied by an increase in moesin expression, which in pancreatic cancer is found to be reduced and associated with pancreatic cancer aggressiveness. Some reduction, but not significant, was also found on PHB levels while effects on histone H3 deimination were variable. EV signatures were modulated in response to PAD inhibitor treatment, with the strongest effects observed for PAD2 inhibitor, followed by PAD3 inhibitor, showing significant reduction in pro-oncogenic EV microRNA cargo (miR-21, miR-221) and increase in anti-oncogenic microRNA cargo (miR-126). While PAD2 inhibitor, followed by PAD3 inhibitor, had most effects on reducing cancer cell invasion, elevating moesin expression, and modulating EV signatures, PAD4 inhibitor had negligible effects and pan-PAD inhibitor Cl-amidine was also less effective. Compared with MiaPaCa-2 cells, stronger modulatory effects for the PAD inhibitors were observed in Panc-1 cells, which importantly also showed strong response to PAD3 inhibitor, correlating with previous observations that Panc-1 cells display neuronal/stem-like properties. Our findings report novel PAD isozyme regulatory roles in PDAC, highlighting roles for PAD isozyme-specific treatment, depending on cancer type and cancer subtypes, including in PDAC.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

Uysal-Onganer

D’Alessio

Mortoglou

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Analysis by real-time qPCR was performed using Taq SYBR Green premix (Qiagen, Manchester, United Kingdom), as reported before. Relative levels of mRNA expression were calculated using the Comparative CT/2-ΔΔCT method [ 33 , 34 ]. RPII (RNA polymerase II) was used as the reference gene.…”

Section: Methodsmentioning

confidence: 99%

“…The cDNA was generated by the reverse transcriptase reaction and used for real-time PCR (qRT-PCR). The following genes were studied: NSE, Asl1, Hes6, Nanog, Twist, Snail, E-cadherin, and Wnt-11 (corresponding primer sequences given previously [32,33]). Analysis by real-time qPCR was performed using Taq SYBR Green premix (Qiagen, Manchester, United Kingdom), as reported before.…”

Section: Real-time Pcrmentioning

confidence: 99%

Inhibition on JNK Mimics Silencing of Wnt-11 Mediated Cellular Response in Androgen-Independent Prostate Cancer Cells

Arısan

Rencüzoğulları

Keskin

et al. 2020

Biology

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Prostate cancer (PCa) is one of the most common cancers among men, and one of the leading causes of cancer death for men. The c-Jun N-terminal kinase (JNK) pathway is required for several cellular functions, such as survival, proliferation, differentiation, and migration. Wnt-11, a member of the Wnt family, has been identified for its upregulation in PCa; however, downstream signalling of Wnt-11 remains to be fully characterized. In this study, we investigated the role of the JNK pathway as a potential downstream factor for Wnt-11 signalling. For this purpose, LNCaP, DU145, and PC-3 PCa cells and normal epithelial PNT1A cells were treated with a specific JNK kinase inhibitor: JNKVIII. Our results showed that JNK inhibition decreased mitochondrial membrane potential and promoted cell death in a cell type-dependent manner. We found that JNK inhibition led to an increase in autophagy and prevented epithelial–mesenchymal transition (EMT) in independently growing androgen cells. JNK inhibition and the silencing of Wnt-11 showed similar responses in DU145 and PC-3 cells and decreased metastasis-related biomarkers, cell migration, and invasion. Overall, our results suggest that JNK signalling plays a significant role in the pathophysiology of PCa by mediating Wnt-11 induced signals. Our data highlights that both the JNK pathway and Wnt-11 could be a useful therapeutic target for the combinatory application of current PCa.

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“…Wnt-11 is a member of the Wnt signaling pathway, which is activated during embryogenesis for normal development, and recently, its upregulation was found in various malignancies, including PCa [12][13][14]. Wnt-11 is found to be upregulated in metastatic disease, and more importantly, it has been shown that it involves in TGF-β signaling pathways during the epithelial-to-mesenchymal transition (EMT), which is important for prostate cancer cell migration and invasion [13].…”

Section: Introductionmentioning

confidence: 99%

Upregulated Wnt-11 and miR-21 Expression Trigger Epithelial Mesenchymal Transition in Aggressive Prostate Cancer Cells

Arısan

Rencüzoğulları

Freitas

et al. 2020

Biology

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Prostate cancer (PCa) is the second-leading cause of cancer-related death among men. microRNAs have been identified as having potential roles in tumorigenesis. An oncomir, miR-21, is commonly highly upregulated in many cancers, including PCa, and showed correlation with the Wnt-signaling axis to increase invasion. Wnt-11 is a developmentally regulated gene and has been found to be upregulated in PCa, but its mechanism is unknown. The present study aimed to investigate the roles of miR-21 and Wnt-11 in PCa in vivo and in vitro. First, different Gleason score PCa tissue samples were used; both miR-21 and Wnt-11 expressions correlate with high Gleason scores in PCa patient tissues. This data then was confirmed with formalin-fixed paraffin cell blocks using PCa cell lines LNCaP and PC3. Cell survival and colony formation studies proved that miR-21 involves in cells’ behaviors, as well as the epithelial-mesenchymal transition. Consistent with the previous data, silencing miR-21 led to significant inhibition of cellular invasiveness. Overall, these results suggest that miR-21 plays a significant role related to Wnt-11 in the pathophysiology of PCa.

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Wnt-11 Expression Promotes Invasiveness and Correlates with Survival in Human Pancreatic Ductal Adeno Carcinoma

Cited by 11 publications

References 59 publications

Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

Inhibition on JNK Mimics Silencing of Wnt-11 Mediated Cellular Response in Androgen-Independent Prostate Cancer Cells

Upregulated Wnt-11 and miR-21 Expression Trigger Epithelial Mesenchymal Transition in Aggressive Prostate Cancer Cells

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