scholarly journals Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3233
Author(s):  
Giulia Raimondi ◽  
Sabrina Gea-Sorlí ◽  
Marc Otero-Mateo ◽  
Cristina Fillat
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Genetic Alterations ◽  
Oncolytic Adenovirus ◽  
Viral Fitness ◽  
Host Cells ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells ◽  
Cellular Environment ◽  
Viral Yield

Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is a trademark of pancreatic cancer, with several oncogenic miRNAs playing essential roles in cancer-associated pathways. The perturbed miRNome induces reprogramming of gene expression in host cells that can impact the complex interplay between cellular processes and viral replication. We have studied the effects of overexpressed miRNAs on oncolytic adenoviral activity and identified miRNAs modulators of adenoviral oncolysis in pancreatic cancer cells. Inhibition of the highly upregulated miR-222 sensitized cancer cells to oncolysis. To provide a therapeutic application to this insight, we engineered the oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, working as sponges to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells strongly improved the viral yield and enhanced the adenoviral cytotoxic effects. Antitumoral studies confirmed a high activity for AdNuPARmE1A-miR222-S in vivo, controlling tumor progression more effectively than the scrambled control virus in xenografts. We demonstrated that the increased antitumor potency of the novel oncolytic virus resulted from the combinatory effects of miR-222 oncomiR inhibition and the restoration of miR-222 target genes activity enhancing viral fitness.

Bufalin exerts antitumor effects by inducing cell cycle arrest and triggering apoptosis in pancreatic cancer cells

Tumor Biology ◽  
2013 ◽  
Vol 35 (3) ◽  
pp. 2461-2471 ◽  
Author(s):  
Meiying Li ◽  
Xuejun Yu ◽  
Hui Guo ◽  
Limei Sun ◽  
Aijun Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Antitumor Effects ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells

Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis

Gut ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2007-2018 ◽  
Author(s):  
Simone Benitz ◽  
Tobias Straub ◽  
Ujjwal Mukund Mahajan ◽  
Jurik Mutter ◽  
Stefan Czemmel ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Acinar Cell ◽  
Genetic Alterations ◽  
Cell Reprogramming ◽  
Drug Induced ◽  
Pancreatic Carcinogenesis ◽  
Chip Sequencing ◽  
Pancreatic Cancer Cells

Background and aimsBesides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis.DesignWith our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells.ResultsThe epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype.ConclusionsOur data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

Studying Antitumor Effects of Sirna Gene Silencing of some Metabolic Genes in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 13 ◽  
Author(s):  
Ahmad Sada Al hanjori ◽  
Walhan Alshaer ◽  
Bayan Anati ◽  
Suha Wehaibi ◽  
Malek Zihlif
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Line ◽  
Pentose Phosphate ◽  
Ductal Adenocarcinoma ◽  
Maximum Effect ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells

Background: Earlier diagnosis and advances in treatment strategies have increased the average survival of cancer patients over the last decades. Despite the increased number of new anti-neoplastic agents, there has been no adequate therapy for intricate malignancies such as pancreatic cancer. Cancer metabolism is the main building block standing behind cancer promotion and progression even in the presence of a harsh environment. Targeting metabolic pathways, such as glycolysis and pentose phosphate pathway, is regarded as a promising new strategy for cancer treatment. Objective: The current study is to investigate the effect of knocking-down pancreatic cancer glycolytic and pentose phosphate pathway's regulators (HIF-1α, ARNT, PFKFB4, and RBKS), on cell’s viability and resistance to gemcitabine and doxorubicin, using small interference RNA. Methodology: The human pancreatic ductal adenocarcinoma cell line, Panc-1, was used to study the anti-proliferative activity of targeting HIF-1α, ARNT, PFKFB4, and RBKS mRNAs by transfection with small interference RNAs, each one alone and in combination. The transfected cells were also treated with doxorubicin and gemcitabine to study the relationship between the concerned genes and the resistance of Panc-1 cells to these drugs. The effect on cell proliferation was determined using a colorimetric assay and Inhibitory Concentration (IC50) calculation. A cross-talk study was done to investigate the silencing effect of one of the above genes on the expression of others using Real Time-Polymerase Chain Reaction. Results: In vitro transfection with small interference-RNAs, siHIF-1α, siPFKFB4, and siARNT decreased tumor cell proliferation with a maximum effect shown with siPFKFB4; but there was no anti-proliferative effect with RBKS silencing. suppression of transcription of HIF-1α, ARNT, PFKFB4, and RBKS sensitize pancreatic cancer cells, Panc-1, to doxorubicin and gemcitabine. Conclusion: This study demonstrated the major tumor promoting and progressive effects of PFKFB4, while HIF-1α and ARNT had modulator effects in pancreatic cancer cells (Panc-1). RBKS had a chemo-resistant role justifying its enhanced expression in Panc-1 cells, but not a proliferative one. Silencing of all genes of interest decreased doxorubicin and gemcitabine's resistance and improved the antitumor effect of doxorubicin and gemcitabine in the pancreatic cancer cell line, Panc-1.

scholarly journals Sialofucosylated podocalyxin is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells

2012 ◽  
Vol 303 (6) ◽  
pp. C616-C624 ◽  
Author(s):  
Matthew R. Dallas ◽  
Shih-Hsun Chen ◽  
Mirte M. Streppel ◽  
Sidharth Sharma ◽  
Anirban Maitra ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Host Cells ◽  
Metastatic Pancreatic Cancer ◽  
Positive Staining ◽  
Primary Tumors ◽  
Pancreatic Cancer Cells ◽  
Selectin Ligand

Selectin-mediated interactions in the vasculature promote metastatic spread by facilitating circulating tumor cell binding to selectin-expressing host cells. Therefore, identifying the selectin ligand(s) on tumor cells is critical to the prevention of blood-borne metastasis. A current challenge is to distinguish between structures expressed by circulating tumor cells that can bind selectins in vitro from the functional ligands whose depletion suppresses selectin-dependent binding under flow in vivo. Interestingly, podocalyxin (PODXL), which can bind E- and L-selectin, is upregulated in a number of cancers, including those of the breast, colon, and pancreas. In this work, we show that metastatic pancreatic cancer cells overexpress PODXL compared with nonmalignant pancreatic epithelial cells. We further demonstrate via tissue microarray that 69% of pancreatic ductal adenocarcinomas stain positive for PODXL. In cases of focal expression, positive staining is restricted to the invasive front of primary tumors. By combining immunoblot, immunodepletion, short-hairpin RNA-mediated gene silencing, and flow-based adhesion assays, we evaluated the functional role of sialofucosylated PODXL in selectin-mediated adhesion under flow. Our data indicate that sialofucosylated PODXL is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells, as specific depletion of this molecule from the cell surface significantly interferes with selectin-dependent interactions. Cumulatively, these data support a correlation between sialofucosylated PODXL expression and enhanced binding to selectins by metastatic pancreatic cancer cells and offer additional perspective on the upregulation of PODXL in aggressive cancers.

Transcription factor Sp1 is upregulated by PKCι to drive the expression of YAP1 during pancreatic carcinogenesis

2020 ◽  
Author(s):  
Jinhe Yang ◽  
Junli Wang ◽  
Hongmei Zhang ◽  
Changlong Li ◽  
Changyan Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Pancreatic Tumors ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells ◽  
Factor Specificity ◽  
Underlying Mechanisms ◽  
Specificity Protein

Abstract Recently, we identified that the atypical protein kinase C isoform ι (PKCι) enhances the expression of YAP1 to promote the tumorigenesis of pancreatic adenocarcinoma harboring mutant KRAS (mu-KRAS). To advance our understanding about underlying mechanisms, we analyze the transcription of YAP1 in pancreatic cancer cells and reveal that transcription factor Specificity Protein 1 (Sp1) is upregulated by PKCι and subsequently binds to multiple sites in YAP1 promoter to drive the transactivation of YAP1 in pancreatic cancer cells carrying mu-KRAS. The bioinformatics analysis further substantiates that the expression of PKCι, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors. Moreover, our apoptotic detection data demonstrate that combination of PKCι and Sp1 inhibitors at subtoxic doses displays synergistic effects on inducing apoptosis and reversing the immunosuppression of pancreatic cancer cells, establishing the combination of PKCι and Sp1 inhibitors as a promising novel therapeutic approach, or an adjuvant strategy to potentiate the antitumor effects of other immunotherapeutic agents in pancreatic cancer treatment.

scholarly journals Disulfiram Alone Functions as a Radiosensitizer for Pancreatic Cancer Both In Vitro and In Vivo

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Xu ◽  
Lunjie Lu ◽  
Judong Luo ◽  
Lili Wang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Copper Ions ◽  
Dna Double Strand Breaks ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells ◽  
M Phase

The prognosis of pancreatic cancer remains very poor worldwide, partly due to the lack of specificity of early symptoms and innate resistance to chemo-/radiotherapy. Disulfiram (DSF), an anti-alcoholism drug widely used in the clinic, has been known for decades for its antitumor effects when simultaneously applied with copper ions, including pancreatic cancer. However, controversy still exists in the context of the antitumor effects of DSF alone in pancreatic cancer and related mechanisms, especially in its potential roles as a sensitizer for cancer radiotherapy. In the present study, we focused on whether and how DSF could facilitate ionizing radiation (IR) to eliminate pancreatic cancer. DSF alone significantly suppressed the survival of pancreatic cancer cells after exposure to IR, both in vitro and in vivo. Additionally, DSF treatment alone caused DNA double-strand breaks (DSBs) and further enhanced IR-induced DSBs in pancreatic cancer cells. In addition, DSF alone boosted IR-induced cell cycle G2/M phase arrest and apoptosis in pancreatic cancer exposed to IR. RNA sequencing and bioinformatics analysis results suggested that DSF could trigger cell adhesion molecule (CAM) signaling, which might be involved in its function in regulating the radiosensitivity of pancreatic cancer cells. In conclusion, we suggest that DSF alone may function as a radiosensitizer for pancreatic cancer, probably by regulating IR-induced DNA damage, cell cycle arrest and apoptosis, at least partially through the CAM signaling pathway.

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