Potential association between IQGAP1 and RNA splicing in the context of head and neck cancer via in vivo phosphoproteomics
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Joshua Coon Paul Lambert
PROVIDER: MSV000087770 | MassIVE | Tue Jul 06 16:47:00 BST 2021
REPOSITORIES: MassIVE
Similar Datasets
Project description:IQGAP1 (IQ motif-containing GTPase-activating protein 1) scaffolds several signaling pathways in mammalian cells that are implicated in carcinogenesis, including the RAS and PI3K pathways that involve multiple protein kinases. IQGAP1 has been shown to promote head and neck squamous cell carcinoma (HNSCC); however, the underlying mechanism(s) remains unclear. Here, we report a mass spectrometry-based analysis identifying differences in phosphorylation of cellular proteins in vivo and in vitro in the presence or absence of IQGAP1. By comparing the esophageal phosphoproteome profiles between Iqgap1+/+ and Iqgap1-/- mice, we identified RNA splicing as one of the most altered cellular processes. Serine/arginine-rich splicing factor 6 (SRSF6) was the protein with the most downregulated levels of phosphorylation in Iqgap1-/- tissue. We confirmed that the absence of IQGAP1 reduced SRSF6 phosphorylation both in vivo and in vitro. We then expanded our analysis to human normal oral keratinocytes. Again, we found factors involved in RNA splicing to be highly altered in the phosphoproteome profile upon genetic disruption of IQGAP1. Both the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Cancer Genome Atlas (TCGA) data sets indicate that phosphorylation of splicing-related proteins is important in HNSCC prognosis. The Biological General Repository for Interaction Datasets (BioGRID) repository also suggested multiple interactions between IQGAP1 and splicing-related proteins. Based on these collective observations, we propose that IQGAP1 regulates the phosphorylation of splicing proteins, which potentially affects their splicing activities and, therefore, contributes to HNSCC. Raw data are available from the MassIVE database with identifier MSV000087770.
| S-EPMC9833422 | biostudies-literature
Project description:Approximately 25% of head and neck squamous cell carcinomas (HNSCC) are associated with human papillomavirus (HPV) infection. In these cancers as well as in HPV-associated anogenital cancers, PI3K signaling is highly activated. We previously showed that IQ motif-containing GTPase activating protein 1 (IQGAP1), a PI3K pathway scaffolding protein, is overexpressed in and contributes to HNSCC and that blocking IQGAP1-mediated PI3K signaling reduces HPV-positive HNSCC cell survival and migration. In this study, we tested whether IQGAP1 promotes papillomavirus (PV)-associated HNSCCs. IQGAP1 was necessary for optimal PI3K signaling induced by HPV16 oncoproteins in transgenic mice and MmuPV1 infection, a mouse papillomavirus that causes HNSCC in mice. Furthermore, we found that, at 6 months post-infection, MmuPV1-infected Iqgap1-/- mice developed significantly less severe tumor phenotypes than MmuPV1-infected Iqgap1+/+ mice, indicating a role of IQGAP1 in MmuPV1-associated HNSCC. The tumors resulting from MmuPV1 infection showed features consistent with HPV infection and HPV-associated cancer. However, such IQGAP1-dependent effects on disease severity were not observed in an HPV16 transgenic mouse model for HNC. This may reflect that IQGAP1 plays a role in earlier stages of viral pathogenesis, or other activities of HPV16 oncogenes are more dominant in driving carcinogenesis than their influence on PI3K signaling.
| S-EPMC8126105 | biostudies-literature
Project description:BackgroundPeople with head and neck cancer have higher comorbidity levels but it remains unclear if pretreatment comorbidity is an independent prognosticator in head and neck cancer.MethodsSurvival analyses were performed using data from participants in a UK multicentre cohort study with cancers of the oral cavity (n = 668), oropharynx (n = 1074), and larynx (n = 530). Survival analyses were incrementally adjusted for age, sex, marital status, income, education, stage, alcohol, and smoking.ResultsAfter adjusting for demographic, clinical, and behavioral confounders, higher baseline comorbidity was associated with reduced overall survival (mild comorbidity HR = 1.4, 95% CI = 1.1, 1.7; moderate comorbidity HR = 1.7, 95% CI = 1.3, 2.2; severe comorbidity HR = 2.8, 95% CI = 1.9, 4.; P-trend<.001).ConclusionsOur findings suggest that comorbidity is an independent prognosticator for overall survival in head and neck cancer. Comorbid illnesses should be considered in the assessment and treatment planning of people with head and neck cancer.
| S-EPMC6890487 | biostudies-literature
Project description:Hepatitis C virus (HCV) infection is associated with hepatocellular carcinoma and non-Hodgkin's lymphoma. In 2009, MD Anderson established the first US clinic for treating HCV-infected cancer patients, where we observed an unexpectedly large number of patients with head and neck cancers (HNCs). We sought to determine whether HCV is associated with HNCs. In this case-control study, medical records of cancer patients tested for HCV antibodies at our center from 2004 through 2014 were identified. Case subjects had new-onset primary oropharyngeal or nonoropharyngeal (oral cavity, nasopharynx, hypopharynx, or larynx) HNCs. Control subjects had smoking-associated (lung, esophagus, or urinary bladder) cancers. Biopsy reports of oropharyngeal cancers tested for human papillomavirus (HPV) were reviewed. Patients with lymphoma were excluded. Multivariable logistic regression models were constructed. All statistical tests were two-sided. Of 34 545 cancer patients tested for HCV antibodies, 409 case subjects (164 oropharyngeal and 245 nonoropharyngeal) and 694 control subjects (378 lung, 168 esophagus, and 148 urinary bladder) were studied. The prevalence of HCV seropositivity was higher in oropharyngeal cancer patients (14.0%, 95% confidence interval [CI] = 8.7% to 19.4%, vs 6.5%, 95% CI = 4.6% to 8.3%), particularly HPV-positive oropharyngeal cancer patients (16.9%, 95% CI = 8.7% to 24.9%, vs 6.5%, 95% CI = 4.6% to 8.3%), and nonoropharyngeal HNC patients (20.0%, 95% CI = 14.9% to 25.0%, vs 6.5%, 95% CI = 4.6% to 8.3%) than in control subjects. Adjusted models showed a statistically significant association of HCV seropositivity with nonoropharyngeal (except nasopharyngeal) HNCs (odds ratio [OR] = 2.85, 95% CI = 1.38 to 5.88) and HPV-positive oropharyngeal cancers (OR = 2.97, 95% CI = 1.31 to 6.76). HCV is associated with nonoropharyngeal (except nasopharyngeal) and HPV-positive oropharyngeal HNCs. Further studies are required to explore the possible interaction between HCV and HPV, and the association between HCV and other HPV-related malignancies.
| S-EPMC5017939 | biostudies-literature
Project description:We aimed to identify a novel prognostic biomarker for head and neck squamous cell carcinoma (HNSCC) based on tumor immunology-related alternative splicing (AS). Data for 502 HNSCC and 44 normal samples were obtained from the TCGA database and used to establish an AS-related risk model through univariate, least absolute shrinkage, and selection operator Cox regression analyses. Fresh HNSCC and normal oral tissues were surgically obtained from 44 HNSCC patients. Western blotting and quantitative reverse transcription-PCR were used to assess gene expression levels. Kaplan-Meier was performed to evaluate patients' overall survival (OS) rate. The CIBERSORT algorithm, single-sample gene set enrichment analysis, and immune checkpoint analyses were performed to compare immune activities between subgroups. The risk model was established using 10 pivotal AS events first. Collagen Type III Alpha 1 Chain (COL3A1) were screened based on |log2FC| ≥ 1 and FDR < 0.05 criteria. COL3A1 expression levels in HNSCC tissues were elevated relative to normal tissues (p < 0.001). Moreover, COL3A1 was a reliable biomarker for HNSCC patients' prognostic prediction in both cohorts (p < 0.001, p = 0.0085, respectively). COL3A1 protein (p = 0.0054) and mRNA (p < 0.0001) levels were correlated with HNSCC differentiation. Furthermore, the T stage was correlated with COL3A1 expression (p = 0.043), and COL3A1 expression was an independent prognostic predictor for HNSCC patients (p = 0.006). Compared with the risk model, COL3A1 was better at evaluating immune cell infiltrations, immune activities, and immune checkpoint gene expressions of HNSCC lesions.
| S-EPMC9972170 | biostudies-literature
Project description:Abstract Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration. Graphical Abstract Graphical Abstract
| S-EPMC10448856 | biostudies-literature
Project description:ObjectiveTo investigate associations between femoral head necrosis (FHN) and injury to the retinaculum of Weitbrecht in patients with femoral neck fractures who had undergone initial trials of either closed reduction or direct open reduction.MethodsThis prospective observational study included 110 patients with displaced femoral neck fractures admitted to the Sixth People's Hospital Affiliated to Shanghai Jiaotong University and Shanghai Tongji Hospital between January 2008 and May 2017. Among these, 25 patients underwent initial closed reductions, and 85 patients underwent an open reduction directly. Watson-Jones anterolateral approach was used during the surgery for injury to the retinaculum of Weitbrecht, and FHN was assessed as a surgical outcome. The severity of injury to the retinaculum of Weitbrecht was evaluated using a scoring system developed by our surgical team. Follow-up was at least 24 months.ResultsThe initial closed reduction treatment group had significantly higher total scores of injury to the retinaculum of Weitbrecht (6.24 ± 2.20 vs 4.62 ± 2.12, p = 0.009) compared to the open reduction group. High total scores were significantly associated with initial trials of closed reduction treatment, especially for the broken and released injury to the superior and anterior retinacula (both p = 0.01). Twenty-six patients experienced FHN postoperatively, with mean onset time of 19.42 ± 3.87 months. FHN was significantly associated with the severity of injury to the retinaculum of Weitbrecht (p < 0.001) at the superior, anterior, and inferior retinacula. FHN was significantly associated with injury to the retinaculum of Weitbrecht in females.ConclusionsFemoral neck displacement in patients treated initially with closed reduction is associated with subsequent injury to the retinaculum of Weibrecht, which may lead to FHN. Severity of injury to the retinaculum of Weibrecht may be used as a biomarker to evaluate bone necrosis in patients with femoral neck fractures.
| S-EPMC9363731 | biostudies-literature
Project description:ImportanceDiagnostic delay can negatively affect patient outcomes in head and neck cancer (HNC). Neck mass and other symptoms of undiagnosed HNC may be treated with antibiotics, delaying diagnosis and treatment, despite current clinical practice guidelines.ObjectiveTo investigate temporal trends, associated factors, and time from symptom onset to antibiotic prescribing before an HNC diagnosis.Design, setting, and participantsA retrospective cohort study was conducted using data obtained from a deidentified electronic health records data set from January 1, 2011, to December 31, 2018. Patients with HNC enrolled in the data set for at least 1 year before diagnosis date determined by either 1 inpatient encounter or first of 2 outpatient encounters within 6 months were included. Data analysis was conducted from May 1 to November 9, 2022.ExposureAntibiotic prescription within 3 months before HNC diagnosis date.Main outcomes and measuresThe primary outcome was days from the first documented symptom to HNC diagnosis.ResultsThe cohort included 7811 patients with HNC (4151 [53.1%] men, mean [SD] age, 60.2 [15.8] years). At least 1 antibiotic was prescribed for 1219 patients (15.6%) within 3 months before HNC diagnosis. This represented an increase over the 8.9% prescribing rate during the baseline period 12 to 9 months before diagnosis. The rate of antibiotic prescribing within 3 months before diagnosis did not change significantly over time (quarterly percent change, 0.49%; 95% CI, -3.06% to 4.16%). Patients receiving an antibiotic prescription within 3 months of an HNC diagnosis had a 21.1% longer time between symptom onset and HNC diagnoses (adjusted rate ratio [ARR], 1.21; 95% CI, 1.14-1.29). Compared with diagnosis by otolaryngologists, primary care/internal medicine physicians were most likely to prescribe antibiotics for patients who were diagnosed with a presenting symptom (adjusted prevalence ratio, 1.60; 95% CI, 1.27-2.02). In patients presenting with neck mass/swelling, those presenting with other symptoms were more likely to have longer intervals from symptom onset to diagnosis (ARR, 1.31; 95% CI, 1.08-1.59).Conclusions and relevanceThe findings of this cohort study suggest there is an increased rate of antibiotic prescription in the 3 months before HNC diagnosis, which is associated with an increased time to diagnosis. These findings identify an area for improvement in HNC care and guidelines.
| S-EPMC10450587 | biostudies-literature
Project description:A growing body of evidence indicates that telomere dysfunction is a biological marker of progression in several types of cancer. However, the association between head and neck squamous cell carcinoma (HNSCC) and telomere length (TL) remains unknown. We measured the absolute TL levels in a well-characterised dataset of 211 tumoral vs normal tissues obtained from the same patients by quantitative polymerase chain reaction assay. Normalised TL levels were significantly lower in tumour samples than in normal tissue (P < 0.001) and there was a positive correlation between tumour tissue and normal mucosal tissue (R2 = 0.176, P < 0.001). We were able to distinguish two classes, one with a tumour/normal TL ratio ≤ 0.3 (38.4%), which showed clear telomere erosion, and the other with a tumour/normal TL ratio > 0.3 (61.6%), in which the TL was slightly shorter or longer than that in normal tissue. Notably, the tumour/normal TL ratio was correlated with the likelihood of disease recurrence (P = 0.002), the 5-hydroxymethylcytosine level (P = 0.043), and expression of the ten-eleven translocation (TET) gene (P = 0.043). Our findings show that TL shortening and subsequent low levels of 5-hydroxymethylcytosine and TET expression may contribute to development of HNSCC.
| S-EPMC7974875 | biostudies-literature
Project description:PurposeHead and neck cancer (HNC) is the sixth most common cancer worldwide with a 5-year survival rate of less than 50%. The PI3K/AKT/mTOR signaling pathway is frequently implicated in HNC. Recently, IQ motif-containing GTPase-activating protein 1 (IQGAP1) was discovered to scaffold the PI3K/AKT signaling pathway. IQGAP1 gene expression is increased in HNC, raising the hypothesis that IQGAP1 contributes to HNC.Experimental designWe performed a combination of in vitro studies using human cancer cell lines treated with a cell-permeable peptide that interferes with IQGAP1's ability to bind to PI3K, and in vivo studies utilizing mice genetically knocked out for the Iqgap1 (Iqgap1 -/-). In vivo EGF stimulation assays were used to evaluate PI3K signaling. To study the role of IQGAP1 in HNC, we used a well-validated mouse model that drives HNC via a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO).ResultsIQGAP1 is necessary for efficient PI3K signaling in vitro and in vivo. Disruption of IQGAP1-scaffolded PI3K/AKT signaling reduced HNC cell survival. Iqgap1 -/- mice had significantly lower cancer incidences, lesser disease severity, and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1+/+ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1 -/- mice was significantly reduced, consistent with the hypothesis that IQGAP1 contributes to HNC at least partly through PI3K signaling. High IQGAP1 expression correlated with reduced survival, and high pS6 levels correlated with high IQGAP1 levels in patients with HNC.ConclusionsThese data demonstrate that IQGAP1 contributes to head and neck carcinogenesis.
| S-EPMC6942630 | biostudies-literature