Biology subjects

Choi, S.

Publications and source records attributed to Choi, S..

144 records · Page 8Linked to original sources

bioRxiv2020

Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

Colorectal cancers (CRCs) show variable response to immune checkpoint blockade, which can only partially be explained by the variability of tumour mutational burden. To dissect the cellular and molecular determinants of response we performed a multi-omic screen of 721 cancer regions from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab. Multi-regional whole exome, RNA and T-cell receptor sequencing show that, within hypermutated CRCs, response to both anti-PD1 agents is not positively associated with tumour mutational burden but with high clonality of immunogenic mutations, expanded T cells, low activation of the WNT pathway and active immune escape mechanisms. Coupling high-dimensional imaging mass cytometry with multiplexed immunofluorescence and computational spatial analysis, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 cells interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting cytotoxic anti-tumour activity.

cancer biology↗

bioRxiv2020

A Hybrid High-Resolution Anatomical MRI Atlas with Sub-parcellation of Cortical Gyri using Resting fMRI

We present a new high-quality, single-subject atlas with sub-millimeter voxel resolution, high SNR, and excellent grey-white tissue contrast to resolve fine anatomical details. The atlas is labeled into two parcellation schemes: 1) the anatomical BCI-DNI atlas, which is manually labeled based on known morphological and anatomical features, and 2) the hybrid USCBrain atlas, which incorporates functional information to guide the sub-parcellation of cerebral cortex. In both cases, we provide consistent volumetric and cortical surface-based parcellation and labeling. The intended use of the atlas is as a reference template for structural coregistration and labeling of individual brains. A single-subject T1-weighted image was acquired at a resolution of 0.547mm x 0.547mm x 0.800mm five times and averaged. Images were processed by an expert neuroanatomist using semi-automated methods in BrainSuite to extract the brain, classify tissue-types, and render anatomical surfaces. Sixty-six cortical and 29 noncortical regions were manually labeled to generate the BCI-DNI atlas. The cortical regions were further sub-parcellated into 130 cortical regions based on multi-subject connectivity analysis using resting fMRI (rfMRI) data from the Human Connectome Project (HCP) database to produce the USCBrain atlas. In addition, we provide a delineation between sulcal valleys and gyral crowns, which offer an additional set of 26 sulcal subregions per hemisphere. Lastly, a probabilistic map is provided to give users a quantitative measure of reliability for each gyral subdivision. Utility of the atlas was assessed by computing adjusted Rand indices between individual sub-parcellations obtained through structural-only coregistration to the USCBrain atlas and sub-parcellations obtained directly from each subjects resting fMRI data. Both atlas parcellations can be used with the BrainSuite, FreeSurfer, and FSL software packages.

bioinformatics↗

bioRxiv2020

Single-vessel cerebral blood flow fMRI to map blood velocity by phase-contrast imaging

Current approaches to high-field fMRI provide two means to map hemodynamics at the level of single vessels in the brain. One is through changes in deoxyhemoglobin in venules, i.e., blood oxygenation level-dependent (BOLD) fMRI, while the second is through changes in arteriole diameter, i.e., cerebral blood volume (CBV) fMRI. Here we introduce cerebral blood flow (CBF)-fMRI, which uses high-resolution phase-contrast MRI to form velocity measurements of flow and demonstrate CBF-fMRI in single penetrating microvessels across rat parietal cortex. In contrast to the venule-dominated BOLD and arteriole-dominated CBV fMRI signal, the phase-contrast -based CBF signal changes are highly comparable from both arterioles and venules. Thus, we have developed a single-vessel fMRI platform to map the BOLD, CBV, and CBF from penetrating microvessels throughout the cortex. This high-resolution single-vessel fMRI mapping scheme not only enables the vessel-specific hemodynamic mapping in diseased animal models but also presents a translational potential to map vascular dementia in diseased or injured human brains with ultra-high field fMRI. SummaryWe established a high-resolution PC-based single-vessel velocity mapping method using the high field MRI. This PC-based micro-vessel velocity measurement enables the development of the single-vessel CBF-fMRI method. In particular, in contrast to the arteriole-dominated CBV and venule-dominated BOLD responses, the CBF-fMRI shows similar velocity changes in penetrating arterioles and venules in activated brain regions. Thus, we have built a noninvasive single-vessel fMRI mapping scheme for BOLD, CBV, and CBF hemodynamic parameter measurements in animals.

neuroscience↗

bioRxiv2020

Start codon disruption with CRISPR/Cas9 prevents murine Fuchs' endothelial corneal dystrophy

A missense mutation of collagen type VIII alpha 2 chain (COL8A2) gene leads to early onset Fuchs endothelial corneal dystrophy (FECD), which progressively impairs vision through loss of corneal endothelial cells. We demonstrate that CRISPR/Cas9-based postnatal gene editing achieves structural and functional rescue in a mouse model of FECD. A single intraocular injection of an adenovirus encoding both the Cas9 gene and guide RNA (Ad-Cas9-Col8a2gRNA), efficiently knocked down mutant COL8A2 expression in corneal endothelial cells, prevented endothelial cell loss, and rescued corneal endothelium pumping function in adult Col8a2 mutant mice. There were no adverse sequelae on histology or electroretinography. Col8a2 start codon disruption represents a non-surgical strategy to prevent vision loss in early-onset FECD. As this demonstrates the ability of Ad-Cas9-gRNA to restore phenotype in adult post-mitotic cells, this method may be widely applicable to adult-onset diseases, even in tissues affected with disorders of non-reproducing cells.

genomics↗

bioRxiv2020

Sapphire Nanopores for Low-Noise DNA Sensing

Silicon-supported (SiS) solid-state nanopores have broad applications in single-molecule biosensing and diagnostics, but their high capacitive noise has seriously limited both their sensing accuracy and recording speed. Nanopores on insulating glass have demonstrated reduced capacitance and noise, but it remains challenging to bulk-etch amorphous glass to create membranes reproducibly and uniformly. Here a new approach is reported to form triangular sapphire-supported (SaS) nanopore membranes by batch-processing-compatible anisotropic wet etching of sapphire, with membrane dimension demonstrated from ~200 μm to 5 μm. A SaS nanopore in 68 μm-wide silicon nitride membrane has 130 times smaller capacitance (10 pF) compared to a SiS nanopore (~4 μm SiN membrane, ~1.3 nF), despite a 100 times larger membrane. It has a current noise of 18 pA over 100 kHz bandwidth, much smaller than that from our SiS nanopore (46 pA) and comparable with the best reported low-noise nanopores. Further, the SaS nanopore displays a higher signal-to-noise ratio (SNR, 21 versus 11 for SiS nanopore) in DNA sensing, although the SNR can be further improved using thinner membranes and smaller pores. The SaS nanopore presents a simple platform in both fabrication and structure that is particularly suitable for low-noise and high-speed molecular diagnostics.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

bioRxiv2020

Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments

Multivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluated the impact of low, prebiotically-relevant polyion multivalency in coacervate performance as functional compartments. As model polyions, we used positively and negatively charged homopeptides with one to 100 residues, and adenosine mono-, di-, and triphosphate nucleotides. Polycation/polyanion pairs were tested for coacervation, and resulting membraneless compartments were analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the relatively shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes. Hence, reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, but they can offer advantages over higher molecular weight analogues.

biophysics↗

bioRxiv2019

A metal artifact reduction method for small field of view CT imaging.

To reduce metal artifacts, several sinogram inpainting-based metal artifact reduction (MAR) methods have been proposed where projection data within the metal trace region of the sinogram are treated as missing and subsequently estimated. However, these methods generally assume data truncation does not occur and all metal objects reside inside the field-of-view (FOV). For small FOV imaging, these assumptions are violated, and thus existing inpainting-based MAR methods would not be effective. In this paper, we propose a new MAR method to reduce metal artifacts effectively in the presence of data truncation. The main idea behind the proposed method is the synthesis of a sinogram, which is treated as the originally measured sinogram. First, an initial reconstruction step is performed to remove truncation artifacts. The next step consists of a forward projection of the small FOV image, replacing the original sinogram with the synthesized sinogram. The final step is the application of sinogram inpainting based MAR methods using the synthesized sinogram. Verification of the proposed method was performed for three situations: extended cardiac-torso (XCAT) simulation, clinical data, and experimental data. The proposed method was applied with linear MAR (LMAR) and normalized MAR (NMAR), and the performance of the proposed method was compared with that of the previous method. For quantitative evaluation, normalized mean squared error (NMSE) and structure similarity (SSIM) were used. The results show the effectiveness of the proposed method to reduce residual metal artifacts, which are present in the results obtained with the previous method. The evaluation results using NMSE and SSIM also indicate that the proposed method is more effective than the previous method.

bioengineering↗

bioRxiv2019

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression.

IntroductionIts imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression.\n\nMethodsPolygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank.\n\nResultsAll cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression.\n\nConclusionsThe phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

genetics↗

bioRxiv2019

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMMB promoted liver metastasis. It was unknown whether RHAMMB is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMMA and RHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMMB, but not RHAMMA, was significantly upregulated in liver metastases. RHAMMB was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMMB was substantially higher than RHAMMA in pancreatic ductal adenocarcinoma (PDAC). RHAMMB, but not RHAMMA, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMMB, but not RHAMMA, in promoting PNET metastasis in part through EGFR signaling. RHAMMB can thus serve as a prognostic factor for pancreatic cancer.

cancer biology↗

bioRxiv2019

Determination of glucosinolate contents in Brassica germplasm collections and inter- & intra-leaves distribution pattern using UPLC-MS/MS Multiple Reaction Monitoring scan mode

Intact glucosinolate (GSL) profile (five aliphatic; three aromatic, and one indolic glucosinolate) in the leaves of 50 germplasm collections and commercial cultivars of Brassica rapa, Brassica juncea, and Brassica oleracea collected from six different countries and grown under uniform cultural conditions were compared by UPLC-MS/MS. Total GSLs content ranged from 36.80 to 2383.12 mol/kg DW. Aliphatic GSLs predominated among the entire samples representing from 23.0 to 98.9% of the total GSLs content, where gluconapin and glucobrassicanapin contributed the greatest proportion. Other GSLs such as, progoitrin (PRO), glucotropaeolin (TRO), and glucobarbarin (BAR) were found in relatively low concentrations. Principal Component Analysis (PCA) yielded three principal components with eigenvalue [≥] 1, representing 70.33% of the total variation across the entire data set. Accessions IT260822 & IT32750, and commercial cultivar, \"Hangamssam2\", were well distinguished from other samples in the PCA plot due to their significantly high amount of BAR, glucobrassicin (GBC), and glucoerucin (ERU), respectively. The inter- and intra-leaf variations of GSLs were examined in three kimichi cabbage varieties. The GSLs content varied significantly among leaves in different positions (outer, middle, and inner) and sections within the leaves (top, middle, bottom, green/red, and white). Higher GSL contents were observed in the proximal half & white section of the leaves and inner positions (younger leaves) in most of the samples. GBC, gluconasturtiin (NAS), and glucoberteroin (BER) should be studied profusely in Brassica plants as some of their degradation products of GBC and NAS are useful in cancer chemopreventive functions, whereas BER takes part in the process of suppressing aging of the skin. GSLs are regarded as allelochemicals; hence, the data related to the patterns of GSLs within the leaf and between leaves at different position could be useful to understand the defense mechanism of Brassica plants. The observed variability could be useful for breeders to develop Brassica crops with high GSL content or specific profiles of GSLs as required.

biochemistry↗

bioRxiv2019

H2A.Z-dependent and -independent recruitment of metabolic enzymes to chromatin required for histone modifications

H2A.Z plays a fundamental role in the regulation of transcription and epigenetics, however, the mechanisms that underlie its functions are not fully understood. Using rapid chromatin immunoprecipitation-mass spectrometry, we uncovered the association of H2A.Z-bound chromatin with an array of tricarboxylic acid cycle and beta-oxidation enzymes in the mouse heart. Recombinant green florescence fusion proteins combined with mutations of putative nuclear localization signals of select enzymes, including acetyl-CoA acyltransferase 2 (ACAA2), oxoglutarate dehydrogenase (OGDH), and isocitrate dehydrogenase 2 confirmed their nuclear localization and chromatin binding in both rodent and human cells. Conclusively, chromatin immunoprecipitation-deep sequencing, confirmed the selective association of ACAA2 and OGDH with H2A.Z-occupied transcription start sites. Finally, human H2A.Z-deficient HAP1 cells exhibited reduced chromatin-bound metabolic enzymes, with the exception of pyruvate dehydrogenase, accompanied with reduced posttranslational histone modifications. Thus, the data show that metabolic enzymes are recruited to active promoters for potential site-directed epigenetic modifications.

molecular biology↗

bioRxiv2019

The impact of coregistration of gradient recalled echo images on quantitative susceptibility and R2* mapping at 7T

IntroductionWhile image coregistration is inevitable and quantitative parametric maps, such as R2* and QSM, are increasingly used in multi-parametric studies of the brain, there is a lack of investigations on the reliability of quantitative metrics after coregistration. The purposes of this study were 1) to evaluate the reliability of R2* and QSM at 7T and 2) to assess the statistical agreement in the quantitative metrics obtained by two different coregistration approaches. MethodsWe compared the reliability of R2* and quantitative susceptibility maps obtained from brains of eight healthy participants by two coregistration approaches: 1) transformation of pre-processed quantitative maps and 2) processing quantitative maps after transformation using pixel- and ROI-based analyses. Two-sample Kolmogorov-Smirnov, Mann-Whitney U, Paired T, Intraclass-correlation tests were performed appropriately. ResultsR2* remained invariant regardless of the cogeneration timing. However, magnetic susceptibility was significantly altered when processed in transformed space, whereas it remained invariant in all KS-tests and pixel values were only different in 2 out of 64 U-tests for direct QSM coregistration. Paired t-test revealed that ROI-based group-mean R2* was invariant to both approaches, while group-mean susceptibility was invariant to direct coregistration but differed in one structure processed in transformed space. For all pairs of measurements of R2*, ICCs were excellent. ICCs for magnetic susceptibility were excellent when processed in its native space while the ICCs were lower than 0.9 or poor when processed in transformed space. Further analysis revealed that the choice of interpolation approach affected the resultant QSM. ConclusionsOur study shows that R2* could be safely processed in a transformed space, whereas QSM was less reliable when processed in the transformed space. Hence, caution is advised when using QSM in a multi-parametric study, and it is strongly recommended to process QSM in its native space prior to any coregistration or spatial transformation.

bioengineering↗

bioRxiv2018

Integrated ligand and structure-based investigation of structural requirements for silent information regulator activation

A series of imidazothiazole and oxazolopyridine derivatives as human silent information regulator (SIRT1) activators were subjected to the integrated 2D and 3D QSAR approaches. The derived 3D QSAR models yielded high cross validated q2 values of 0.682 and 0.628 for CoMFA and CoMSIA respectively. The non-cross validated correlation values of r2training = 0.89; predictive r2test = 0.69 for CoMFA and r2=0.87; predictive r2test =0.67 for CoMSIA reflected the statistical significance of the developed model. The steric, electrostatic, hydrophobic and hydrogen bond acceptor interactions have been found important in describing the variation in human SIRT1 activation. Further, 2D QSAR model for the same dataset yielded high statistical significance and derived 2D models parameters corroborated with 3D model in terms of features. The developed model was also validated through the available active conformation structure of SIRT1. Developed models may be useful for the identification of potential novel human SIRT1 activators as therapeutic agent.

biophysics↗

bioRxiv2018

Quantitative Real-Time Imaging of Glutathione with Sub-Cellular Resolution

Quantitative imaging of glutathione with high spatial and temporal resolution is essential for studying the roles of glutathione in redox biology. We developed a fluorescent glutathione probe--HaloRT--that targets organelles of interest through expressing organelle-specific HaloTag proteins. Using HaloRT, we quantitatively measure the glutathione concentrations in the nucleus and the cytosol and find no appreciable concentration gradient between these two organelles, challenging the view of nuclear compartmentalization of glutathione.

cell biology↗

bioRxiv2018

Pseudomonas syringae evades phagocytosis in animal cells through type III effector-mediated inhibition of the LIM kinase-cofilin system

Certain animal and plant pathogenic bacteria have developed virulence factors (including effector proteins) that enable them to overcome host immunity. A plant pathogen, Pseudomonas syringae pv. tomato (Pto), secretes a large repertoire of effectors into plant cells via a type III secretory apparatus, thereby suppressing plant immunity. Here, we show that exposure to Pto caused sepsis in mice. Surprisingly, the effector HopQ1 disrupted phagocytosis by inhibiting actin rearrangement via a direct interaction with the LIM domain of the animal target protein LIM kinase, a key regulator of actin polymerization. The results provide new insights into cross-kingdom pathogenicity of bacteria. The current studies demonstrate that certain plant pathogenic bacteria such as Pto can be fatal in animals due to cross-kingdom host immune suppression.

microbiology↗

bioRxiv2018

The C. elegans heterochronic gene lin-28 coordinates the timing of hypodermal and somatic gonadal programs for hermaphrodite reproductive system morphogenesis

C. elegans heterochronic genes determine the timing of expression of specific cell fates in particular stages of developing larva. However, their broader roles in coordinating developmental events across diverse tissues has been less well investigated. Here, we show that loss of lin-28, a central heterochronic regulator of hypodermal development, causes reduced fertility associated with abnormal somatic gonad morphology. In particular, the abnormal spermatheca-uterine valve morphology of lin-28(lf) hermaphrodites trap embryos in the spermatheca, which disrupts ovulation and causes embryonic lethality. The same genes that act downstream of lin-28 in the regulation of hypodermal developmental timing also act downstream of lin-28 in somatic gonad morphogenesis and fertility. Importantly, we find that hypodermal expression, but not somatic gonadal expression, of lin-28 is sufficient for restoring normal somatic gonad morphology in lin-28(lf) mutants. We propose that the abnormal somatic gonad morphogenesis of lin-28(lf) hermaphrodites results from temporal discoordination between the accelerated hypodermal development and normally timed somatic gonad development. Thus, our findings exemplify how a cell-intrinsic developmental timing program can also control cell non-autonomous signaling critical for proper development of other interacting tissues.

developmental biology↗

bioRxiv2018

The Specificity of IQGAP1 Toward the PI3K-Akt Pathway is Dependent on the IQ3 motif

Epidermal growth factor receptor (EGFR) and its downstream phosphatidylinositol 3-kinase (PI3K) pathway are commonly deregulated in many cancers including head and neck cancer (HNC). Recently, we have shown that the IQ motif-containing GTPase-activating protein 1 (IQGAP1) provides a molecular platform to scaffold all the components from the PI3K-Akt pathway and results in the sequential generation of phosphatidylinositol-3,4,5-triphosphate (PI3,4,5P3). This makes the IQGAP1-PI3K scaffold a promising therapeutic target. In addition to the PI3K-Akt pathway, IQGAP1 also scaffolds the Ras-ERK pathway. To identify an IQGAP1 mutant that specifically loses IQGAP1-PI3K signaling but not other functions, we have focused on the IQ3 motif since this region binds with both the PIPK1 and PI3K enzymes and a short peptide derived from this sequence blocks binding and PI3K signaling. An IQ3 deletion mutant ({Delta}IQ3) in IQGAP1 was functionally compared with wild-type (WT) IQGAP1. We found that the IQ3 domain specifically mediates the PI3K-Akt pathway but does not regulate the Ras-ERK pathway. The IQ3 deletion mutant lost interactions with PI3K-Akt components but retained its binding of ERK pathway components and cell surface receptors, EGFR and integrins. In addition, the IQ3 deletion mutant lost regulation of cell migration. Consistently, the IQ3 motif derived peptide blocked Akt activation and led to the blockage of invasion mediated by EGFR organized into an integrin complex by syndecan-4. Taken together, this work has defined the IQGAP1 IQ3 motif as a specific target sequence for the scaffolding of the PI3K-AKT pathway.

cell biology↗

bioRxiv2018

Role of IQGAP1 in Head and Neck Carcinogenesis

Head and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.

cancer biology↗