scholarly journals Analysis of DGAT2 mutations reveals potential links between cancer and lipid droplet deregulation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 675-675
Author(s):  
Meghan Graber ◽  
Hayley Barta
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Cellular Proliferation ◽  
Transmembrane Protein ◽  
Tissue Type ◽  
Cancer Tissue ◽  
Triacylglycerol Synthesis

Abstract Diacylglycerol O-acyltransferase 2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Since cancer cells exhibit altered lipid metabolism, it has been proposed that mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all reported DGAT2 mutations in human cancers. Bioinformatics analyses were performed to highlight the connections between age, pathogenicity, and cancer tissue type. Mutations are generally associated with samples from older individuals, except for those in glioblastomas which occur earlier. We also found that several DGAT2 mutations fall within the catalytic site of the enzyme and may affect enzyme function. Thus, these mutations may contribute to altered cancer metabolism. We identified D222V as a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers indicating it is inhibitory to cancer progression. Further analysis showed that most mutations do not affect DGAT2 gene expression suggesting this change is not a major contributor to cancer development. Intriguingly, although most cancers are characterized by low DGAT2 gene expression, some show high expression levels, indicating that, at least in certain cases, over-expression is not inhibitory to cellular proliferation. This work uncovers unknown roles of DGAT2 in cancers and suggests that its function may be more complex than previously appreciated.

scholarly journals Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 714
Author(s):  
Meghan Graber ◽  
Hayley Barta ◽  
Ryan Wood ◽  
Amrit Pappula ◽  
Martin Vo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Copy Number ◽  
Cellular Proliferation ◽  
Transmembrane Protein ◽  
Expression Patterns ◽  
Cellular Transformation ◽  
Copy Number Variations ◽  
Human Populations ◽  
Triacylglycerol Synthesis

DGAT2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Cancer cells exhibit altered lipid metabolism and mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all cancer genetic DGAT2 alterations, including mutations, copy number variations and gene expression. We find that several DGAT2 mutations fall within the catalytic site of the enzyme. Using the Variant Effect Scoring Tool (VEST), we identify multiple mutations with a high likelihood of contributing to cellular transformation. We also found that D222V is a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers, suggesting that it is inhibitory to cancer progression. We also identify several single nucleotide polymorphisms (SNP) with high VEST scores, indicating that certain alleles in human populations have a pathogenic predisposition. Most mutations do not correlate with a change in gene expression, nor is gene expression dependent on high allele copy number. However, we did identify eight alleles with high expression levels, suggesting that at least in certain cases, the excess DGAT2 gene product is not inhibitory to cellular proliferation. This work uncovers unknown functions of DGAT2 in cancers and suggests that its role may be more complex than previously appreciated.

Signal Transducer and Activator of Transcription6 Signaling Pathway in Tumor-Associated Macrophage Aggravates Lung Cancer Progression

2021 ◽  
Vol 11 (9) ◽  
pp. 1707-1713
Author(s):  
Jun Wan ◽  
Jian Wang ◽  
Qiurong Huang ◽  
Guanggui Ding ◽  
Xiean Ling
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
T Cell ◽  
Cancer Progression ◽  
Cancer Tissue ◽  
M2 Macrophage ◽  
Normal Tissues ◽  
Tumor Associated Macrophage ◽  
M1 Macrophage ◽  
And Migration

Lung cancer is a most common cancer worldwide. Tumor-associated macrophage (TAM) is known a key effector cell in tumor microenvironment. Meanwhile, STAT6 is crucial to cancer development. We aimed to determine the interaction between STAT6 and TAMs in lung cancer. In this work, firstly, we established mouse model of lung cancer. Then, immunofluorescence was performed to determine STAT6 and CD206 level in lung cancer tissue and adjacent normal tissues as well as model mice. RT-qPCR was applied to detect differentiation of macrophage and determine related gene expression. After treatment of siRNA of STAT6 or STAT6 inhibitor (AS1517499), Transwell assay and MTT were used to determine cell proliferation and migration. STAT6 was upregulated in lung cancer tissues while arginase was more active in M2 macrophage rather than M1 macrophage. Transfection of si-STAT6 not only decreased differentiation in M2 macrophage but also inhibited proliferative, migratory and invasive ability of cancer cells while AS1517499 led to reduced tumor growth. STAT6 inhibition caused decreased expression of M2 macrophages. Similarly, intratumoral T cell markers showed that CD8+T cell gene expression and CD4-mediated T cell marker FoxP3 was increased slightly. Taken altogether, macrophage-STAT6 promotes cell migration and proliferation in lung cancer.

scholarly journals Lipid-Lowering Effects of Lotus Leaf Alcoholic Extract on Serum, Hepatopancreas, and Muscle of Juvenile Grass Carp via Gene Expression

2020 ◽  
Vol 11 ◽  
Author(s):  
Junpeng Yao ◽  
Pengcheng Hu ◽  
Yanhong Zhu ◽  
Yingyan Xu ◽  
Qingsong Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Grass Carp ◽  
Lipid Lowering ◽  
Lipid Deposition ◽  
Alcoholic Extract ◽  
Mrna Levels ◽  
Lotus Leaf

Compared with wild grass carp (Ctenopharyngodon idellus), intensively cultured fish displayed disordered lipid metabolism, showing excess lipid deposition in the hepatopancreas and muscle. Lotus leaf prevents fat accumulation in humans and may have similar effects on fish. This study explored the regulatory mechanisms by which the dietary addition of an alcoholic extract of lotus leaf (AELL) reduced lipid deposition in the hepatopancreas and muscle of juvenile grass carp. The fish (average initial weight: 34.00 ± 0.40 g) were fed four experimental diets containing different AELL levels (0, 0.07, 0.14, and 0.21%) for 8 weeks. Serum components, lipid droplet size, triacylglycerol (TAG) content, enzymatic activities, and mRNA levels of genes related to lipid metabolism in the hepatopancreas and muscle were analyzed. The results show that dietary AELL supplementation significantly reduced the TAG content and lipid droplet area in the histological sections as well as the fatty acid synthase (FAS) activity in both the hepatopancreas and muscle but enhanced the activities of lipoprotein lipase (LPL) and carnitine palmitoyltransferase I (CPT1) in both tissues. In addition, dietary AELL supplementation decreased the mRNA expression of genes involved in fatty acid uptake (cd36, fatp1/fatp4/fatp6, fabp10/fabp11, acsl1/acsl4) and de novo lipid synthesis (pgd, g6pd, and fasn) as well as the transcription factors pparg and srebf1 in the hepatopancreas and muscle but increased the mRNA levels of genes relating to lipid catabolism (cpt1a, lipe, pnpla2, lpl), lipid transportation (apob), and the transcription factor ppara in both tissues. In conclusion, dietary AELL supplementation reduced lipid accumulation in the hepatopancreas and muscle by affecting the gene expression of proteins with known effects on lipid metabolism in juvenile grass carp.

scholarly journals Distinct nitrogen isotopic compositions of healthy and cancerous tissue in mice brain and head&neck micro-biopsies

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. Straub ◽  
D. M. Sigman ◽  
A. Auderset ◽  
J. Ollivier ◽  
B. Petit ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
High Sensitivity ◽  
Nitrogen Isotope ◽  
Isotopic Analysis ◽  
Healthy Tissue ◽  
Tissue Type ◽  
Cancer Tissue ◽  
Neck Tumors ◽  
Surrounding Healthy Tissue ◽  
The Difference

Abstract Background Cancerous cells can recycle metabolic ammonium for their growth. As this ammonium has a low nitrogen isotope ratio (15N/14N), its recycling may cause cancer tissue to have lower 15N/14N than surrounding healthy tissue. We investigated whether, within a given tissue type in individual mice, tumoral and healthy tissues could be distinguished based on their 15N/14N. Methods Micro-biopsies of murine tumors and adjacent tissues were analyzed for 15N/14N using novel high-sensitivity methods. Isotopic analysis was pursued in Nude and C57BL/6 mice models with mature orthotopic brain and head&neck tumors generated by implantation of H454 and MEERL95 murine cells, respectively. Results In the 7 mice analyzed, the brain tumors had distinctly lower 15N/14N than healthy neural tissue. In the 5 mice with head&neck tumors, the difference was smaller and more variable. This was at least partly due to infiltration of healthy head&neck tissue by tumor cells. However, it may also indicate that the 15N/14N difference between tumoral and healthy tissue depends on the nitrogen metabolism of the healthy organ in question. Conclusions The findings, coupled with the high sensitivity of the 15N/14N measurement method used here, suggest a new approach for micro-biopsy-based diagnosis of malignancy as well as an avenue for investigation of cancer metabolism.

scholarly journals Study of FGF14 gene expression and cancer progression in colorectal cancer tissue samples

2019 ◽  
Vol 29 (3) ◽  
pp. 210-215
Author(s):  
Homayoun Jalali Tafti ◽  
Mehrdad Hashemi ◽  
Khalil Alimohammadzadeh ◽  
◽  
◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cancer Tissue ◽  
Tissue Samples ◽  
Colorectal Cancer Tissue

scholarly journals Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Sreejata Chatterjee ◽  
Sa Do Kang ◽  
Samina Alam ◽  
Anna C. Salzberg ◽  
Janice Milici ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Papillomavirus ◽  
High Risk ◽  
Cancer Progression ◽  
Tissue Type ◽  
Tissue Specific ◽  
Cervical Epithelium ◽  
Human Papillomavirus 16 ◽  
Cellular Pathways ◽  
Hpv16 Infection

ABSTRACT Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression changes varied considerably across the tissue types, with only 32 genes being regulated in common. Among them, we confirmed the Kelch-like family protein KLHL35 and the laminin-5 complex to be upregulated and downregulated, respectively, in all the three tissues. HPV16 infection induces upregulation of genes involved in cell cycle control, cell division, mitosis, DNA replication, and DNA damage repair in all the three tissues, indicative of a hyperproliferative environment. In the cervical and tonsil epithelium, we observe significant downregulation of genes involved in epidermis development, keratinocyte differentiation, and extracellular matrix organization. On the other hand, in HPV16-positive foreskin (HPV16 foreskin) tissue, several genes involved in interferon-mediated innate immunity, cytokine signaling, and cellular defenses were downregulated. Furthermore, pathway analysis and experimental validations identified important cellular pathways like STAT1 and transforming growth factor β (TGF-β) to be differentially regulated among the three tissue types. The differential modulation of important cellular pathways like TGF-β1 and STAT1 can explain the sensitivity of tissues to HPV cancer progression. IMPORTANCE Although the high-risk human papillomavirus 16 infects anogenital and oropharyngeal sites, the cervical epithelium has a unique vulnerability to progression of cancer. Host responses during persistent infection and preneoplastic stages can shape the outcome of cancer progression in a tissue-dependent manner. Our study for the first time reports differential regulation of critical cellular functions and signaling pathways during productive HPV16 infection of cervical, foreskin, and tonsil tissues. While the virus induces hyperproliferation in infected cells, it downregulates epithelial differentiation, epidermal development, and innate immune responses, according to the tissue type. Modulation of these biological functions can determine virus fitness and pathogenesis and illuminate key cellular mechanisms that the virus employs to establish persistence and finally initiate disease progression.

scholarly journals Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sajina Shakya ◽  
Anthony D. Gromovsky ◽  
James S. Hale ◽  
Arnon M. Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Striking Difference ◽  
Significant Shift ◽  
Lower Grade ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

AbstractGlioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM.

IS tRNA DRIVING BREAST CANCER PROGRESSION?

2019 ◽  
Author(s):  
Zil-e- Rubab
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Developing Countries ◽  
Molecular Mechanism ◽  
Cancer Progression ◽  
Critical Review ◽  
Driving Forces ◽  
Treatment Modalities ◽  
Critical Research ◽  
Research Article

This critical research periodical is mainly based on critical review of research article titled ‘Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression published in Cell by Goodarzi et al1. According to Globocan, 2008 report2, breast is among the leading site of new cancer cases and deaths (691,300/268,900) in females of developing countries and second leading site in USA (Globocan, 2012)3. The extensive research is in progress on different aspects of molecular mechanism of driving forces and different treatment modalities to ease this burden. The above mentioned research article is also part of this effort.

The correlation between lipid metabolism disorders and the prostate cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Justyna Dłubek ◽  
Jacek Rysz ◽  
Zbigniew Jabłonowski ◽  
Anna Gluba-Brzózka ◽  
Beata Franczyk
Keyword(s):  
Prostate Cancer ◽  
Fatty Acids ◽  
Lipid Metabolism ◽  
Cancer Progression ◽  
De Novo ◽  
Prostate Gland ◽  
Hdl Cholesterol ◽  
Atp Citrate Lyase ◽  
Male Population ◽  
Lipid Metabolism Disorders

: Prostate cancer is second most common cancer affecting male population all over the world. The existence of a correlation between lipid metabolism disorders and cancer of the prostate gland has been widely known for a long time. According to hypotheses, cholesterol may contribute to prostate cancer progression as a result of its participation as a signalling molecule in prostate growth and differentiation via numerous biologic mechanisms including Akt signalling and de novo steroidogenesis. The results of some studies suggest that increased cholesterol levels may be associated with higher risk of more aggressive course of disease. The aforementioned alterations in the synthesis of fatty acids are a unique feature of cancer and, therefore, it constitutes an attractive target for therapeutic intervention in the treatment of prostate cancer. Pharmacological or gene therapy aimed to reduce the activity of enzymes involved in de novo synthesis of fatty acids, FASN, ACLY (ATP citrate lyase) or SCD-1 (stearoyl-CoA desaturase) in particular, may result in cells growth arrest. Nevertheless, not all cancers are unequivocally associated with hypocholesterolaemia. It cannot be ruled out that the relationship between prostate cancer and lipid disorders is not a direct quantitative correlation between carcinogenesis and the amount of the circulating cholesterol. Perhaps the correspondence is more sophisticated and connected to the distribution of cholesterol fractions, or even sub-fractions of e.g. HDL cholesterol.

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