Linkage Disequilibrium and Physical Mapping of Pas1 in Mice

By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a ∼1.5-Mb region on distal mouse chromosome 6 the Pas1locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1s susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1s allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.

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Requirement for PKC Epsilon in Kras-Driven Lung Tumorigenesis

10.1101/2020.06.26.173690 ◽

2020 ◽

Author(s):

Rachana Garg ◽

Mariana Cooke ◽

Shaofei Wang ◽

Fernando Benavides ◽

Martin C. Abba ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Therapeutics ◽

Rna Seq ◽

Lung Tumorigenesis ◽

Mechanistic Analysis ◽

Oncogenic Driver ◽

Histological Form

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.

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Application of Linkage Disequilibrium Mapping Methods to Detect QTL for Carcass Quality on Chromosome 6 Using a High Density SNP Map in Hanwoo

Asian-Australasian Journal of Animal Sciences ◽

10.5713/ajas.2011.11019 ◽

2011 ◽

Vol 24 (4) ◽

pp. 457-462 ◽

Cited By ~ 6

Author(s):

Y. Li ◽

J.-H. Lee ◽

Y.-M. Lee ◽

J.-J. Kim

Keyword(s):

Linkage Disequilibrium ◽

High Density ◽

Linkage Disequilibrium Mapping ◽

Carcass Quality ◽

Chromosome 6 ◽

Snp Map

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Circulating miR-16-5p, miR-92a-3p, and miR-451a in Plasma from Lung Cancer Patients: Potential Application in Early Detection and a Regulatory Role in Tumorigenesis Pathways

Cancers ◽

10.3390/cancers12082071 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2071 ◽

Cited By ~ 2

Author(s):

Patricia P. Reis ◽

Sandra A. Drigo ◽

Robson F. Carvalho ◽

Rainer Marco Lopez Lapa ◽

Tainara F. Felix ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Target Genes ◽

Lung Squamous Cell Carcinoma ◽

High Specificity ◽

Mirna Signature ◽

Lung Tumorigenesis ◽

Lung Cancer Patients

Background: Micro(mi)RNAs, potent gene expression regulators associated with tumorigenesis, are stable, abundant circulating molecules, and detectable in plasma. Thus, miRNAs could potentially be useful in early lung cancer detection. We aimed to identify circulating miRNA signatures in plasma from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and to verify whether miRNAs regulate lung oncogenesis pathways. Methods: RNA isolated from 139 plasma samples (40 LUAD, 38 LUSC; 61 healthy/non-diseased individuals) were divided into discovery (38 patients; 21 controls for expression quantification using an 800-miRNA panel; Nanostring nCounter®) and validation (40 patients; 40 controls; TaqMan® RT-qPCR) cohorts. Elastic net, Maximizing-R-Square Analysis (MARSA), and C-Statistics were applied for miRNA signature identification. Results: When compared to healthy individuals, 580 of 606 deregulated miRNAs in LUAD and 221 of 226 deregulated miRNAs in LUSC had significantly increased levels. Among the 10 most significantly overexpressed miRNAs, 6 were common to patients with LUAD and LUSC. Further analysis identified three signatures composed of 12 miRNAs. Signatures included miRNAs commonly overexpressed in patient plasma. Enriched pathways included target genes modulated by three miRNAs in the C-Statistics signature: miR-16-5p, miR-92a-3p, and miR-451a. Conclusions: The 3-miRNA signature (miR-16-5p, miR-92a-3p, miR-451a) had high specificity (100%) and sensitivity (84%) to predict cancer (LUAD and LUSC). These miRNAs are predicted to modulate genes and pathways with known roles in lung tumorigenesis, including EGFR, K-RAS, and PI3K/AKT signaling, suggesting that the 3-miRNA signature is biologically relevant in adenocarcinoma and squamous cell carcinoma of the lung.

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Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21020619 ◽

2020 ◽

Vol 21 (2) ◽

pp. 619

Author(s):

Yu-Ting Kang ◽

Wen-Cheng Hsu ◽

Chu-Chyn Ou ◽

Hui-Chun Tai ◽

Hui-Ting Hsu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Time Course ◽

Cancer Chemoprevention ◽

Binding Activity ◽

Luciferase Assay ◽

Lung Cells ◽

Lung Carcinogenesis ◽

Lung Tumorigenesis ◽

Nickel Exposure

Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.

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USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms20215300 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5300 ◽

Cited By ~ 6

Author(s):

Kyung Ho Han ◽

Minseok Kwak ◽

Tae Hyeong Lee ◽

Min-soo Park ◽

In-ho Jeong ◽

...

Keyword(s):

Lung Cancer ◽

Ubiquitin Proteasome System ◽

Migration And Invasion ◽

Deubiquitinating Enzyme ◽

Lung Tumorigenesis ◽

Ubiquitin Chain ◽

Specific Protease ◽

Ubiquitin Proteasome ◽

Autophagy Pathway

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.

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Molecular Genetic Analysis of Distal Mouse Chromosome 6 Defines Gene Order and Positions of the deafwaddler and opisthotonos Mutations

Genomics ◽

10.1006/geno.1995.1222 ◽

1995 ◽

Vol 29 (1) ◽

pp. 123-130 ◽

Cited By ~ 15

Author(s):

Valerie A. Street ◽

Linda C. Robinson ◽

Shelly K. Erford ◽

Bruce L. Tempel

Keyword(s):

Genetic Analysis ◽

Mouse Chromosome ◽

Gene Order ◽

Molecular Genetic ◽

Molecular Genetic Analysis ◽

Chromosome 6 ◽

Distal Mouse Chromosome ◽

Distal Mouse

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An allele at the triose phosphate isomerase, Tpi-1 locus on chromosome 6 recovered from feral mice

Genetics Research ◽

10.1017/s0016672300023764 ◽

1987 ◽

Vol 50 (3) ◽

pp. 239-243 ◽

Cited By ~ 5

Author(s):

Grahame Bulfield ◽

Simon T. Ball ◽

Josephine Peters

Keyword(s):

Preliminary Report ◽

Dominant Gene ◽

Heat Stability ◽

Inbred Strains ◽

Triose Phosphate Isomerase ◽

Marker Genes ◽

Chromosome 6 ◽

Structural Locus ◽

Triose Phosphate ◽

The Common

SummaryAn animal with low erythrocyte triose phosphate isomerase (TPI) activity was found amongst mice trapped on a farm in Leicestershire. The low TPI activity was caused by the segregation of a single co-dominant gene which also affected the Km for glyceraldehyde-3-phosphate and heat stability of the enzyme. We designate the gene Tpi-1, the structural locus for TPI, with the a allele in the common inbred strains and the b allele derived from the wild-caught mouse. Tpi-1 was known to be on chromosome 6 by somatic cell techniques and, as shown in a preliminary report (Peters & Bulfield, 1984), we have confirmed and extended this finding using three chromosome-6 marker genes giving the order: Sig-28-Lc-11-Miwh-16-Tpi-1.

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