scholarly journals Comparative transcriptional profiling of canine acanthomatous ameloblastoma and homology with human ameloblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Santiago Peralta ◽  
Gerald E. Duhamel ◽  
William P. Katt ◽  
Kristiina Heikinheimo ◽  
Andrew D. Miller ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Tooth Development ◽  
Transcriptional Profiling ◽  
Ras Signaling ◽  
Genomic Expression ◽  
Mesenchymal Transition ◽  
Therapeutic Modalities ◽  
Molecular Features ◽  
High Prevalence ◽  
High Level

AbstractAmeloblastomas are odontogenic tumors that are rare in people but have a relatively high prevalence in dogs. Because canine acanthomatous ameloblastomas (CAA) have clinicopathologic and molecular features in common with human ameloblastomas (AM), spontaneous CAA can serve as a useful translational model of disease. However, the molecular basis of CAA and how it compares to AM are incompletely understood. In this study, we compared the global genomic expression profile of CAA with AM and evaluated its dental origin by using a bulk RNA-seq approach. For these studies, healthy gingiva and canine oral squamous cell carcinoma served as controls. We found that aberrant RAS signaling, and activation of the epithelial-to-mesenchymal transition cellular program are involved in the pathogenesis of CAA, and that CAA is enriched with genes known to be upregulated in AM including those expressed during the early stages of tooth development, suggesting a high level of molecular homology. These results support the model that domestic dogs with spontaneous CAA have potential for pre-clinical assessment of targeted therapeutic modalities against AM.

scholarly journals O39: THE HISTOPATHOLOGICAL AND MOLECULAR FEATURES OF BREAST CARCINOMA WITH HIGH-GRADE TUMOUR BUDDING

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
A Lloyd ◽  
E Ryan ◽  
M Boland ◽  
S Medani ◽  
Abd Elwahab ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Lymph Node Involvement ◽  
Low Grade ◽  
High Grade ◽  
Prognostic Variables ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Newcastle Ottawa Scale ◽  
Tumour Budding

Abstract Background Tumour budding (TB) is an adverse histological feature in many cancers. It is thought to represent epithelial-to-mesenchymal transition, a key step in the metastatic process. The role of TB in breast carcinoma (BC) remains unclear. Aim To investigate the relationship between TB and other histological and molecular features of BC. Method A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Cochran–Mantel–Haenszel method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS). Result Seven studies with a total of 1040 patients (high grade TB n=519, 49.9%; low grade TB n=521, 50.1%) were included. A moderate- to high-risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node involvement (OR 2.28, 95% c.i. 1.74 to 2.98, P<0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P<0.001). Regarding molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen- (OR 1.66, 95% c.i. 1.21 to 2.29, P=0.002) and progesterone-receptor positive (OR 1.68, 95% c.i. 1.10 to 2.59, P=0.02) tumours. In contrast triple negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P=0.0006). Conclusion High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC. Take-home message High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.

scholarly journals Nanoparticle mediated alteration of EMT dynamics: an approach to modulate cancer therapeutics

2020 ◽  
Vol 1 (8) ◽  
pp. 2614-2630
Author(s):  
Plaboni Sen ◽  
Muktashree Saha ◽  
Siddhartha Sankar Ghosh
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Cancer Therapeutics ◽  
Mesenchymal Transition ◽  
Therapeutic Modalities

Metastasis is the cause of approximately 90% of cancer-related morbidities and mortalities, which is ascribed to the phenomenon of EMT (epithelial to mesenchymal transition). The nanoparticle mediated suppression of EMT exhibit strong therapeutic modalities.

scholarly journals Cancer Stem Cell Plasticity – A Deadly Deal

2019 ◽  
Author(s):  
P. T. Archana ◽  
Saxena Kritika ◽  
Reshma Murali ◽  
Mohit Kumar Jolly ◽  
Radhika Nair
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Resistance ◽  
Extensive Investigation ◽  
Epigenetic Factors ◽  
Therapeutic Approaches ◽  
Cell Plasticity ◽  
Mesenchymal Transition ◽  
Recent Developments ◽  
High Level

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

scholarly journals Human papillomavirus 16 E2 repression of TWIST1 transcription is a potential mediator of HPV16 cancer outcomes

2020 ◽  
Author(s):  
Christian T Fontan ◽  
Dipon Das ◽  
Molly L Bristol ◽  
Claire D James ◽  
Xu Wang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Human Papillomaviruses ◽  
Cancer Outcomes ◽  
Mesenchymal Transition ◽  
Human Papillomavirus 16 ◽  
Potential Mediator ◽  
Causative Agents ◽  
High Level

AbstractHuman papillomaviruses are causative agents in around 5% of all cancers, including cervical and oropharyngeal. A feature of HPV cancers is their better clinical outcome compared with non-HPV anatomical counterparts. In turn, the presence of E2 predicts a better clinical outcome in HPV positive cancers; the reason(s) for the better outcome of E2 positive patients is not fully understood. Previously, we demonstrated that HPV16 E2 regulates host gene transcription that is relevant to the HPV16 life cycle in N/Tert-1 cells. One of the genes repressed by E2 and the entire HPV16 genome in N/Tert-1 cells is TWIST1. Here we demonstrate that TWIST1 RNA levels are reduced in HPV positive versus negative head and neck cancer, and that E2 and HPV16 downregulate both TWIST1 RNA and protein in our N/Tert-1 model; E6/E7 cannot repress TWIST1. E2 represses the TWIST1 promoter in transient assays, and is localized to the TWIST1 promoter; E2 also induces repressive epigenetic changes on the TWIST1 promoter. TWIST1 is a master transcriptional regulator of the epithelial to mesenchymal transition (EMT) and a high level of TWIST1 is a prognostic marker indicative of poor cancer outcomes. We demonstrate that TWIST1 target genes are also downregulated in E2 positive N/Tert-1 cells, and that E2 promotes a failure in wound healing, a phenotype of low TWIST1 levels. We propose that the presence of E2 in HPV positive tumors leads to TWIST1 repression, and that this plays a role in the better clinical response of E2 positive HPV tumors.ImportanceHPV16 positive cancers have a better clinical outcome that their non-HPV anatomical counterparts. Furthermore, the presence of HPV16 E2 RNA predicts a better outcome for HPV16 positive tumors; the reasons for this are not known. Here we demonstrate that E2 represses expression of the TWIST1 gene; an elevated level of this gene is a marker of poor prognosis for a variety of cancers. We demonstrate that E2 directly binds to the TWIST1 promoter and actively represses transcription. TWIST1 is a master regulator promoting EMT and here we demonstrate that the presence of E2 reduces the ability of N/Tert-1 cells to wound heal. Overall, we propose that the E2 repression of TWIST1 may contribute to the better clinical outcome of E2 positive HPV16 positive tumors.

scholarly journals Human Papillomavirus 16 (HPV16) E2 Repression of TWIST1 Transcription Is a Potential Mediator of HPV16 Cancer Outcomes

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Christian T. Fontan ◽  
Dipon Das ◽  
Molly L. Bristol ◽  
Claire D. James ◽  
Xu Wang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Human Papillomaviruses ◽  
Cancer Outcomes ◽  
Mesenchymal Transition ◽  
Human Papillomavirus 16 ◽  
Potential Mediator ◽  
Causative Agents ◽  
High Level

ABSTRACT Human papillomaviruses (HPVs) are causative agents in around 5% of all cancers, including cervical and oropharyngeal. A feature of HPV cancers is their better clinical outcome compared with non-HPV anatomical counterparts. In turn, the presence of E2 predicts a better clinical outcome in HPV-positive cancers; the reason(s) for the better outcome of E2-positive patients is not fully understood. Previously, we demonstrated that HPV16 E2 regulates host gene transcription that is relevant to the HPV16 life cycle in N/Tert-1 cells. One of the genes repressed by E2 and the entire HPV16 genome in N/Tert-1 cells is TWIST1. Here, we demonstrate that TWIST1 RNA levels are reduced in HPV-positive versus HPV-negative head and neck cancer and that E2 and HPV16 downregulate both TWIST1 RNA and protein in our N/Tert-1 model; E6/E7 cannot repress TWIST1. E2 represses the TWIST1 promoter in transient assays and is localized to the TWIST1 promoter; E2 also induces repressive epigenetic changes on the TWIST1 promoter. TWIST1 is a master transcriptional regulator of the epithelial to mesenchymal transition (EMT), and a high level of TWIST1 is a prognostic marker indicative of poor cancer outcomes. We demonstrate that TWIST1 target genes are also downregulated in E2-positive N/Tert-1 cells and that E2 promotes a failure in wound healing, a phenotype of low TWIST1 levels. We propose that the presence of E2 in HPV-positive tumors leads to TWIST1 repression and that this plays a role in the better clinical response of E2-positive HPV tumors. IMPORTANCE HPV16-positive cancers have a better clinical outcome that their non-HPV anatomical counterparts. Furthermore, the presence of HPV16 E2 RNA predicts a better outcome for HPV16-positive tumors; the reasons for this are not known. Here, we demonstrate that E2 represses expression of the TWIST1 gene; an elevated level of this gene is a marker of poor prognosis for a variety of cancers. We demonstrate that E2 directly binds to the TWIST1 promoter and actively represses transcription. TWIST1 is a master regulator promoting EMT, and here, we demonstrate that the presence of E2 reduces the ability of N/Tert-1 cells to wound heal. Overall, we propose that the E2 repression of TWIST1 may contribute to the better clinical outcome of E2-positive HPV16-positive tumors.

scholarly journals YBX3 Mediates the Metastasis of Nasopharyngeal Carcinoma via PI3K/AKT Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoqin Fan ◽  
Xina Xie ◽  
Ming Yang ◽  
Yujie Wang ◽  
Hanwei Wu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Rna Binding ◽  
Akt Signaling ◽  
Ras Signaling ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition

The metastasis of nasopharyngeal carcinoma (NPC) is a complex process associated with oncogenic dysfunction, the deciphering of which remains a challenge and requires more in-depth studies. Y-box protein 3 (YBX3) is a DNA/RNA binding protein associated with gene transcription, DNA repair, and the progression of various diseases. However, whether and how YBX3 affects the metastasis of NPC remains unknown. Thus, in this study, we aimed to investigate the role of YBX3 in the metastasis of NPC and determine its underlying mechanism. Interestingly, it was found that the expression of YBX3, which was associated with NPC metastasis, was upregulated in the clinical NPC tissues and cell lines. Moreover, we found that knockdown of YBX3 expression by lentivirus shRNA significantly suppressed NPC cells migration in vitro and metastasis in vivo. Mechanistically, RNA sequencing results suggested that the genes regulated by YBX3 were significantly enriched in cell adhesion molecules, cAMP signaling pathway, calcium signaling pathway, focal adhesion, PI3K/AKT signaling pathway, Ras signaling pathway, Rap1 signaling pathway, NF-κB signaling pathway, and Chemokine signaling pathway. Of these, PI3K/AKT signaling pathway contained the most genes. Accordingly, YBX3 knockdown decreased the activation of PI3K/AKT signaling pathway, thereby inhibit epithelial-to-mesenchymal transition (EMT) and MMP1. These results have demonstrated that YBX3 are involved in the metastasis of NPC through regulating PI3K/AKT signaling pathway, and serve as a potential therapeutic target for patients with NPC.

scholarly journals Ectopic expression of aquaporin-5 in noncancerous epithelial MDCK cells changes cellular morphology and actin fiber formation without inducing epithelial-to-mesenchymal transition

2018 ◽  
Vol 314 (6) ◽  
pp. C654-C661 ◽  
Author(s):  
Helene H. Jensen ◽  
Mikkel R. Holst ◽  
Frédéric H. Login ◽  
Jeanette J. Morgen ◽  
Lene N. Nejsum
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mdck Cells ◽  
Fiber Formation ◽  
Cellular Morphology ◽  
Ras Signaling ◽  
Actin Stress Fiber ◽  
Aquaporin 5 ◽  
Mesenchymal Transition ◽  
Actin Fiber ◽  
Aqp5 Expression

Aquaporin-5 (AQP5) is a plasma membrane water channel mainly expressed in secretory glands. Increased expression of AQP5 is observed in multiple cancers, including breast cancer, where high expression correlates with the degree of metastasis and poor prognosis. Moreover, studies in cancer cells have suggested that AQP5 activates Ras signaling, drives morphological changes, and in particular increased invasiveness. To design intervention strategies, it is of utmost importance to characterize and dissect the cell biological changes induced by altered AQP5 expression. To isolate the effect of AQP5 overexpression from the cancer background, AQP5 was overexpressed in normal epithelial MDCK cells which have no endogenous AQP5 expression. AQP5 overexpression promoted actin stress fiber formation and lamellipodia dynamics. Moreover, AQP5 decreased cell circularity. Phosphorylation of AQP5 on serine 156 in the second intracellular loop has been shown to activate the Ras pathway. When serine 156 was mutated to alanine to mimic the nonphosphorylated state, the decrease in cell circularity was reversed, indicating that the AQP5-Ras axis is involved in the effect on cell shape. Interestingly, the cellular changes mediated by AQP5 were not associated with induction of epithelial-to-mesenchymal transition. Thus, AQP5 may contribute to cancer by altering cellular morphology and actin organization, which increase the metastatic potential.

scholarly journals Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1541
Author(s):  
Pradip De ◽  
Brett James Rozeboom ◽  
Jennifer Carlson Aske ◽  
Nandini Dey
Keyword(s):  
Botulinum Toxin ◽  
Solid Tumors ◽  
Epithelial To Mesenchymal Transition ◽  
Critical Role ◽  
Copy Number Gain ◽  
Therapy Resistance ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Therapeutic Modalities ◽  
Development Of Resistance

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.

Molecular and clinical characterization of a claudin (CLDN)-low subtype of gastric cancer (GC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 67-67
Author(s):  
Tomohiro F. Nishijima ◽  
Jordan Kardos ◽  
Shengjie Chai ◽  
Christof C Smith ◽  
Dante S. Bortone ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Nk Cell ◽  
Immune Gene ◽  
Minimal Set ◽  
Mesenchymal Transition ◽  
Gene Signatures ◽  
Molecular Features ◽  
Gene Sets ◽  
Further Development

67 Background: A CLDN-low subtype has been identified in breast and bladder cancers and is characterized by low expression of tight junction proteins CLDN, enrichment for epithelial-to-mesenchymal transition (EMT) and tumor initiating cell (TIC) features. Given the genomically stable (GS) subtype of GC defined by TCGA has features suggestive of CLDN-low tumors, we evaluated whether the CLDN-low subtype also exists in GC. Methods: 415 tumors from TCGA GC mRNA dataset were clustered on the CLDN, EMT and TIC gene sets with significance testing using SigClust2 to identify CLDN-low GC. A minimal set of genes that could accurately classify CLDN-low GC was defined by prediction analysis of microarrays (PAM). Tumors identified by SigClust2 or the PAM were called CLDN-low GC regardless of the original subtype call. The 300 GCs in the Asian Cancer Research Group (ACRG) dataset [GSE62254] were used to validate the predictor. We characterized clinical and molecular (gene expression, mutation and copy number alteration) features of CLDN-low GC. Results: We identified 46 tumors that had consensus enrichment for CLDN-low features in TCGA. CLDN-low tumors were most commonly diffuse (35/42=83%, 4 tumors=mixed) and GS (36/46=78%). CLDN-low GC showed high expression of immune gene signatures including T and NK cell signatures, but not an immunosuppression signature. Compared to GS subtype, CLDN-low GC had increased frequency of CD44, GATA4, and GATA6 amplification. In ACRG, 28/300 GCs were CLDN-low using the PAM predictor. The CLDN-low GC in ACRG was phenotypically similar to the CLDN-low GC in TCGA based on the CLDN, EMT and TIC gene signatures. Clinically, CLDN-low GC was associated with the shortest overall survival of the 5 subtypes (CLDN-low plus TCGA defined 4 subtypes). Notably, a hazard ratio comparing CLDN-low GC vs GS was 2.10 (95%CI; 1.07-4.11) in TCGA and 2.32 (95%CI; 1.18-4.55) in ACRG cohort, adjusting for age and pathological stage. Conclusions: We identified a CLDN-low GC which has a poor prognosis likely related to the resistance to conventional chemotherapy due to its EMT and TIC-like properties. Further development of targeted therapies against these molecular features is warranted to improve the outcome of CLDN-low GC.

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