Gene expression and pathway bioinformatics analysis detect a potential predictive value of MAP3K8 in thyroid cancer progression

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cellsComment: 5 page

Machine Learning and Bioinformatics Models to Identify Pathways that Mediate Influences of Welding Fumes on Cancer Progression

Abstract: Welding generates and releases fumes that are hazardous to human health. Welding fumes (WFs) are a complex mix of metallic oxides, fluorides and silicates that can cause or exacerbate health problems in exposed individuals. In particular, WF inhalation over an extended period carries an increased risk of cancer, but how WFs may influence cancer behaviour or growth is unclear. To address this issue we employed a quantitative analytical framework to identify the gene expression effects of WFs that may affect the subsequent behaviour of the cancers. We examined datasets of transcript analyses made using microarray studies of WF-exposed tissues and of cancers, including datasets from colorectal cancer (CC), prostate cancer (PC), lung cancer (LC) and gastric cancer (GC). We constructed gene-disease association networks, identified signaling and ontological pathways, clustered protein-protein interaction network using multilayer network topology, and analyzed survival function of the significant genes using Cox proportional hazards (Cox PH) model and product-limit (PL) estimator. We observed that WF exposure causes altered expression of many genes (36, 13, 25 and 17 respectively) whose expression are also altered in CC, PC, LC and GC. Gene-disease association networks, signaling and ontological pathways, protein-protein interaction network, and survival functions of the significant genes suggest ways that WFs may influence the progression of CC, PC, LC and GC. This quantitative analytical framework has identified potentially novel mechanisms by which tissue WF exposure may lead to gene expression changes in tissue gene expression that affect cancer behaviour and, thus, cancer progression, growth or establishment

Machine Learning and Bioinformatics Models to Identify Pathways that Mediate Influences of Welding Fumes on Cancer Progression

Abstract: Welding generates and releases fumes that are hazardous to human health. Welding fumes (WFs) are a complex mix of metallic oxides, fluorides and silicates that can cause or exacerbate health problems in exposed individuals. In particular, WF inhalation over an extended period carries an increased risk of cancer, but how WFs may influence cancer behaviour or growth is unclear. To address this issue we employed a quantitative analytical framework to identify the gene expression effects of WFs that may affect the subsequent behaviour of the cancers. We examined datasets of transcript analyses made using microarray studies of WF-exposed tissues and of cancers, including datasets from colorectal cancer (CC), prostate cancer (PC), lung cancer (LC) and gastric cancer (GC). We constructed gene-disease association networks, identified signaling and ontological pathways, clustered protein-protein interaction network using multilayer network topology, and analyzed survival function of the significant genes using Cox proportional hazards (Cox PH) model and product-limit (PL) estimator. We observed that WF exposure causes altered expression of many genes (36, 13, 25 and 17 respectively) whose expression are also altered in CC, PC, LC and GC. Gene-disease association networks, signaling and ontological pathways, protein-protein interaction network, and survival functions of the significant genes suggest ways that WFs may influence the progression of CC, PC, LC and GC. This quantitative analytical framework has identified potentially novel mechanisms by which tissue WF exposure may lead to gene expression changes in tissue gene expression that affect cancer behaviour and, thus, cancer progression, growth or establishment

MiR-144: A new possible therapeutic target and diagnostic/prognostic tool in cancers

MicroRNAs (miRNAs) are small and non-coding RNAs that display aberrant expression in the tissue and plasma of cancer patients when tested in comparison to healthy individuals. In past decades, research data proposed that miRNAs could be diagnostic and prognostic biomarkers in cancer patients. It has been confirmed that miRNAs can act either as oncogenes by silencing tumor inhibitors or as tumor suppressors by targeting oncoproteins. MiR-144s are located in the chromosomal region 17q11.2, which is subject to significant damage in many types of cancers. In this review, we assess the involvement of miR-144s in several cancer types by illustrating the possible target genes that are related to each cancer, and we also briefly describe the clinical applications of miR-144s as a diagnostic and prognostic tool in cancers

A Comprehensive Model and Modulation of Cellular Signaling Involved in Early Mammary Development and Aggressive Cancer Using a Novel Recombinant Protein of the G3 Domain of Laminin-5

The mammary gland is a unique and specialized epidermal organ; mammary organogenesis begins in the embryo but is not fully complete until puberty. As such, formation of the mammary gland depends on temporally and spatially regulated developmental steps that require coordination of multiple biological and cell signaling processes; many of which have parallels with cancer development. Research describing the events that occur between birth and puberty is lacking and little is known about human breast development of youth. Since mammary gland development requires a coordinated balance between cell growth, proliferation, and apoptosis, it is critical to understand which signaling pathways are utilized to relay developmental signals, and how these pathways and their targets interact and cooperate with age. Additionally, interactions between integrin molecules and their laminin ligands, especially Laminin-5 (Ln-5; also known as Laminin-332), regulate multiple facets of both embryonic development and tumor growth, invasion, and metastasis. α6β4 integrin serves as a marker to detect distant metastases in the early stages of specific malignancies and β4 integrin overexpression has been found in basal-like breast cancers, correlating with aggressiveness to institute a prognostic β4 signature that increases with tumor grade. The mechanism α6β4 integrin utilizes to modulate oncogenic signaling through association with Ln-5 molecules in the ECM is the basis for the recombinant protein (rG3, the third of five G domains of Ln-5) produced for the work reported in this dissertation. Here, it is shown there are specific transcriptional differences and a unique interaction of a gene set over time that contributes to postnatal mammary gland development, and this model clearly shares similarities and signaling pathways with oncogenic development. Especially important are pathways of the adaptive and innate immunities, ECM remodeling and integrin interactions, and extrinsic and intrinsic TP53-mediated apoptosis, greater understanding of which could lead to early detection of potential tumorigenic growth and identification of potential treatment avenues. Presented is a comprehensive model of early mammary development along with several panels of biomarkers that possess a role in normal mammary development, are involved in aggressive cancers, and are affected by apoptosis induced by rG3 treatment. rG3 has proven to be a valuable tool to study apoptotic pathways and the crosstalk among those pathways

investigating integrin ανβ6 activation status in breast cancer

PhDbackground The extracellular matrix receptor integrin ανβ6 is known to potentiate breast cancer (BrCa) cell invasion, metastasis and tumour-trophic growth factor receptor crosstalk during tumourigenesis. Monoclonal antibody blockade of ανβ6 diminishes invasion in vitro and arrests BrCa tumour growth and metastasis in vivo. Aberrant integrin activation status has been implicated in progression to metastatic disease in BrCa; with differential internalisation and endocytic trafficking kinetics reported for active versus inactive integrin species in malignant disease. Despite its emerging potential for targeted therapy, little is known regarding regulation of integrin ανβ6–mediated activation and signalling during progression to an invasive, metastatic state. It is hypothesised that the aetiopathological significance of integrin ανβ6 during neoplastic transformation and malignant progression in BrCa is dependent specifically upon its activation status and associated conformation, since this active state will permit establishment of known integrin–mediated oncogenic signalling underpinning acquisition of a malignant phenotype, including activation of invasion and metastasis. results Canonical integrin activation studies using divalent cations and cognate ligand stimulation indicated antibodies 6.2E5 and 6.2G2 recognise activation-associated epitopes, which are also ligand-induced binding sites (LIBS) in live-labelled cells by FCM and IMF. However, their utility to discriminate the active fraction distinct from the total or inactive fractions of ανβ6 by IHC in primary BrCa samples could not be robustly established. Evaluation of the 6.2E5 and 6.2G2 epitopes in the MCF10 isogenic model revealed that relative surface abundance of these active epitopes determined by FCM was not significantly altered; but their subcellular redistribution upon neoplastic transformation and malignant progression was observed by IMF, implicating derailed internalisation and trafficking of active ανβ6 during breast tumourigenesis and metastatic disease progression. Proteomic interrogation and network analysis of the 2D-enriched adhesion assays identified 7 novel putative molecular regulators of a ligand-engaged, activated ανβ6–mediated adhesion environment (DMBT-1, MARCKS, MXRA5, SEPT6, SEPT9, MYH9, MYH10) in the BT-20 TNBC cell line. Functional validation of these candidate mediators of the “β6 adhesome” by siRNA strategies was not achieved due to inconsistent stable knockdown. Phosphoproteomic definition of LAP ligand-engaged, active ανβ6–mediated signalling (“β6 kinome”) during receptor-ligand internalisation revealed EGFR-dependency for downstream ERK1/2 signal activation in BT-20 and SUM159, but not MDA-MB-468 TNBC cells. Kinase substrate enrichment analysis (KSEA) identified 5 novel putative mediators of downstream ανβ6 signalling (COT, MAPKAPK2, PDPK1, Nuak1, TBK1) and implicated Akt1 isoform-specific activation downstream of ανβ6–LAP internalisation. Following LAP-induced ανβ6 activation and internalisation, EGFR underwent phosphorylation at multiple known activation sites, including a residue (Thr693) critical for EGFR receptor internalisation; suggesting integrin ανβ6–EGFR reciprocity during respective receptor activation and internalisation. conclusion The active conformer of integrin ανβ6 may be studied using antibodies 6.2E5 and 6.2G2 in live-labelled cells by FCM and IMF. Subcellular redistribution of activation-associated epitopes during BrCa progression implicates derailed internalisation and intracellular trafficking kinetics of active ανβ6 during tumourigenesis, while protein expression studies identified 7 putative molecular regulators of ligand-engaged, active ανβ6–mediated adhesion. Integrin ανβ6-mediated signalling during internalisation revealed an ανβ6–EGFRAkt1 signalling axis during breast tumourigenesis and disease progression, while further understanding of integrin biology and growth factor receptor crosstalk may provide additional rationale for potential combination therapies in breast cancer.Cancer Research UK