An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.

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Carboxypeptidase E-ΔN promotes migration, invasiveness, and epithelial–mesenchymal transition of human osteosarcoma cells via the Wnt–β-catenin pathway

Biochemistry and Cell Biology ◽

10.1139/bcb-2018-0236 ◽

2019 ◽

Vol 97 (4) ◽

pp. 446-453 ◽

Cited By ~ 9

Author(s):

Shuli Fan ◽

Xiang Gao ◽

Peng Chen ◽

Xu Li

Keyword(s):

Cell Migration ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Human Osteosarcoma ◽

Carboxypeptidase E ◽

Human Osteosarcoma Cells ◽

Cancer Types ◽

Interfering Rna

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents, and metastatic OS is the major cause of OS-related death. Carboxypeptidase E (CPE) is known to be highly expressed in some cancer types, and its N-terminal truncated form, CPE-ΔN, is implicated in tumor metastasis and poor prognosis. In this study, we investigated the effect of CPE-ΔN on cell migration, invasiveness, and the epithelial–mesenchymal transition (EMT) of OS cells, and illustrated the molecular mechanisms. We first constructed CPE-ΔN overexpressing human OS cell lines (143B and U2OS cells), and found that ectopic CPE-ΔN expression in OS cells enhanced cell migration and invasiveness, and promoted the EMT process. Further, overexpression of CPE-ΔN increased the levels of c-myc and nuclear β-catenin in OS cells, which suggested the CPE-ΔN promotes activation of the Wnt–β-catenin pathway in OS cells. Treatment with β-catenin small interfering RNA (siRNA) inhibited the migration and invasiveness of CPE-ΔN-overexpressing cells, and reduced the expression of E-cadherin. Together, these results suggest that CPE-ΔN promotes migration, invasiveness, and the EMT of OS cells via the Wnt–β-catenin signaling pathway.

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Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽

10.3390/cells9010114 ◽

2020 ◽

Vol 9 (1) ◽

pp. 114

Author(s):

Lisa Linck-Paulus ◽

Claus Hellerbrand ◽

Anja K. Bosserhoff ◽

Peter Dietrich

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Therapeutic Targets ◽

Genetic Alterations ◽

Therapeutic Strategies ◽

The Future ◽

Associated Proteins ◽

Cancer Types ◽

Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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The Association of Vitamin D with Brain Cognitive Functions: A Literature Review

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i3530982 ◽

2020 ◽

pp. 97-113

Author(s):

Yahya A. Alzahrani ◽

Mohammed A. Alomary ◽

Abdulmajeed A. Alzahrani ◽

Mawaddah M. Eskandarani ◽

Iman S. Aljabry ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Molecular Mechanisms ◽

Randomized Clinical Trials ◽

Current Knowledge ◽

Neuroprotective Effect ◽

Cochrane Library ◽

Calcium Balance ◽

Increased Risk

Vitamin D is a well-known steroid hormone that plays an important role in controlling bone levels of calcium, phosphorus, and overall mineralization. Several animal and human studies indicate that vitamin D hypovitaminosis may be linked to an increased risk of developing Alzheimer's disease and dementia. The objective of the present review is to summarize current knowledge of the effects of vitamin D deficiency and vitamin D intake on cognitive function. The possible underline mechanisms of these effects were also discussed. We reviewed the literature starting from 1986 to 2019 by searching PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases for all observational studies, randomized clinical trials, meta-analyses, and systematic reviews using the keywords “vitamin D and Alzheimer disease”, “neuroprotective effect of vitamin D”, “vitamin D deficiency and Alzheimer ”, “role of vitamin D in neurodegenerative diseases ”, ” vitamin D and amyloidogenesis”, “acetylcholine and vitamin D”, and “memory and vitamin D ”.We also referred to animal and in vitro studies that dealt with the possible mechanisms of actions of the neuroprotective effect of vitamin D. Our findings showed that Vitamin D supplementation improves cognitive performance via reducing amyloidogenesis, restoration of neurotransmission, maintaining calcium balance, regulating neurotrophic factors, anti-inflammatory action, apoptosis regulation, antioxidant, and vascular processes. This review might be open new horizons in the understanding of the molecular mechanisms of the disease and neurodegeneration and enable the development of new approaches in treatment and prevention of the disease.

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B7-H3 Immune Checkpoint Protein in Human Cancer

Current Medicinal Chemistry ◽

10.2174/0929867326666190517115515 ◽

2020 ◽

Vol 27 (24) ◽

pp. 4062-4086 ◽

Cited By ~ 6

Author(s):

Karine Flem-Karlsen ◽

Øystein Fodstad ◽

Caroline E. Nunes-Xavier

Keyword(s):

Immune Response ◽

Immune Checkpoint ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Human Cancer ◽

Transmembrane Protein ◽

Adaptive Immune Response ◽

Cancer Drug ◽

Potential Biomarker ◽

Anti Cancer

B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.

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Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Proceedings of The Nutrition Society ◽

10.1017/s0029665111003259 ◽

2011 ◽

Vol 71 (1) ◽

pp. 175-180 ◽

Cited By ~ 45

Author(s):

Janice E. Drew

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Molecular Mechanisms ◽

Leptin Receptor ◽

Growth Promotion ◽

Human Cancer ◽

Hormone Secretion ◽

Receptor Expression ◽

Increased Risk

Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.

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Cellular exocytosis gene (EXOC6/6B): a potential molecular link for the susceptibility and mortality of COVID-19 in diabetic patients

10.1101/2020.06.25.170936 ◽

2020 ◽

Author(s):

Mahmood Yaseen Hachim ◽

Ibrahim Yaseen Hachim ◽

Saba Al Heialy ◽

Jalal Taneera ◽

Nabil sulaiman

Keyword(s):

United Arab Emirates ◽

Molecular Mechanisms ◽

High Rate ◽

Diabetic Patients ◽

Lung Epithelium ◽

Transcriptomic Data ◽

Insulin Granules ◽

Increased Risk ◽

Novel Biomarkers ◽

Lower Expression

AbstractDiabetes is one of the most critical comorbidities linked to an increased risk of severe complications in the current coronavirus disease 2019 (COVID-19) pandemic. A better molecular understanding of COVID-19 in people with type diabetes mellitus (T2D) is mandatory, especially in countries with a high rate of T2D, such as the United Arab Emirates (UAE). Identification of the cellular and molecular mechanisms that make T2D patients prone to aggressive course of the disease can help in the discovery of novel biomarkers and therapeutic targets to improve our response to the disease pandemic. Herein, we employed a system genetics approach to explore potential genomic, transcriptomic alterations in genes specific to lung and pancreas tissues, affected by SARS-CoV-2 infection, and study their association with susceptibility to T2D in Emirati patients. Our results identified the Exocyst complex component, 6 (EXOC6/6B) gene (a component for docks insulin granules to the plasma membrane) with documented INDEL in 3 of 4 whole genome sequenced Emirati diabetic patients. Publically available transcriptomic data showed that lung infected with SARS-CoV-2 showed significantly lower expression of EXOC6/6B compared to healthy lungs.In conclusion, our data suggest that EXOC6/6B might be an important molecular link between dysfunctional pancreatic islets and ciliated lung epithelium that makes diabetic patients more susceptible to severe SARS-COV-2 complication.

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Germline Structural Variations in Cancer Predisposition Genes

Frontiers in Genetics ◽

10.3389/fgene.2021.634217 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tímea Pócza ◽

Vince Kornél Grolmusz ◽

János Papp ◽

Henriett Butz ◽

Attila Patócs ◽

...

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Cancer Predisposition ◽

Detection Methods ◽

Small Scale ◽

Structural Variations ◽

Increased Risk ◽

Predisposition Genes ◽

Cancer Syndromes ◽

Risk Of Cancer

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

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Riddle of the Sphinx: Emerging Role of Transfer RNAs in Human Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.794986 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhilin Qiu ◽

Qin Wang ◽

Lei Liu ◽

Guozheng Li ◽

Yi Hao ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Susceptibility ◽

Current Knowledge ◽

Human Cancer ◽

Special Focus ◽

Basic Characteristics ◽

Knowledge Of Cancer ◽

Cancer Diagnosis And Therapy

The dysregulation of transfer RNA (tRNA) expression contributes to the diversity of proteomics, heterogeneity of cell populations, and instability of the genome, which may be related to human cancer susceptibility. However, the relationship between tRNA dysregulation and cancer susceptibility remains elusive because the landscape of cancer-associated tRNAs has not been portrayed yet. Furthermore, the molecular mechanisms of tRNAs involved in tumorigenesis and cancer progression have not been systematically understood. In this review, we detail current knowledge of cancer-related tRNAs and comprehensively summarize the basic characteristics and functions of these tRNAs, with a special focus on their role and involvement in human cancer. This review bridges the gap between tRNAs and cancer and broadens our understanding of their relationship, thus providing new insights and strategies to improve the potential clinical applications of tRNAs for cancer diagnosis and therapy.

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Investigating the Biological and Molecular Mechanisms Underpinning the Engraftment/Selection Advantage Conferred to Hematopoietic Stem Cells by HOXB4.

Blood ◽

10.1182/blood.v104.11.2101.2101 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2101-2101

Author(s):

Michael D. Milsom ◽

Laura Hollins ◽

Dorothy Gagen ◽

Lorna B. Woolford ◽

Leslie J. Fairbairn

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Cellular Transformation ◽

Model Systems ◽

Self Renewal ◽

Hematopoietic Stem ◽

Increased Risk ◽

Vitro Analysis

Abstract We have recently demonstrated that co-expression of HOXB4 enables the enhanced delivery of HSC harbouring a second therapeutic trans-gene. Nonetheless, it is of great importance to elaborate the current knowledge about the mechanism of HOXB4 action in order to both evaluate the safety implications of its use in a clinical strategy, and to gain greater insight into the regulation of HSC self-renewal/expansion. To these ends we have performed an extensive in vitro analysis of the consequences of HOXB4 overexpression in primary murine BMC and in a murine multipotent myeloid progenitor cell line (FDCP-mix). We demonstrate for the first time in murine cells, that ectopic HOXB4 reduces the responsiveness of murine hematopoietic cells to differentiation stimuli. Furthermore, by performing a detailed investigation into the kinetics of FDCP-mix differentiation, we reveal that HOXB4 overexpression results in a specific differentiation delay as opposed to an outright block. We propose that an analogous delay is in operation in repopulating cells in order that the shift to increased assymetrical self-renewal, a requirement for stem cell expansion, is achieved. Notwithstanding this, it is clear that any perturbation in differentiation constitutes an increased risk of cellular transformation if this technology were transferred to a clinical setting. In order to further define the repercussions of ectopic HOXB4 delivery, we have developed a retroviral vector which encodes an activatable version of HOXB4. We have shown that this vector is able to mediate an in vitro differentiation delay in primary murine BMC and FDCP-mix as well as enable enhanced engraftment of BMC in vivo, both dependent upon the addition of the estrogen analogue; tamoxifen. Using this system, we are currently examining the effect of ectopic HOXB4 on the transcriptome of FDCP-mix cells, in addition to performing an in depth study into the biological mechanisms affected by HOXB4 overexpression in BMC in vivo. We envisage that these model systems will be particularly amenable to the manipulation required for target gene identification/validation.

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Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications

Diagnostics ◽

10.3390/diagnostics10080563 ◽

2020 ◽

Vol 10 (8) ◽

pp. 563

Author(s):

David Kalfert ◽

Marie Ludvikova ◽

Martin Pesta ◽

Jaroslav Ludvik ◽

Lucie Dostalova ◽

...

Keyword(s):

Thyroid Cancer ◽

Head And Neck ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Current Knowledge ◽

Human Cancer ◽

Squamous Carcinoma ◽

Transcriptional Level ◽

Mesenchymal Transition

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology.

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