title: Inflammatory Adipokines Decrease Expression of Two High Molecular Weight Isoforms of Tropomyosin Similar to the Change in Type 2 Diabetic Patients.
abstract: Cardiovascular disease and cancer are increased in Type 2 diabetes. TPM1 and TPM4 genes encode proteins associated with cardiovascular and neoplastic disease. High (HMW) and low (LMW) molecular weight isoforms from TPM1 and TPM4 are altered in several cancer cells and the 3'UTR of TPM1 mRNA is tumour suppressive. Leukocytes influence cardiovascular and neoplastic disease by immunosurveillance for cancer and by chronic inflammation in Type 2 diabetes and cardiovascular disease. The aim was to determine changes in expression of isoforms from TPM1 and TPM4 genes in leukocytes from Type 2 diabetic patients and to use the leukocyte cell line THP1 to identify possible mediators of changes in the patients. Gene expression was determined by RT-qPCR. In diabetes, expression of HMW isoforms from TPM1 were markedly decreased (0.55 v 1.00; p = 0.019) but HMW isoforms from TPM4 were not significantly different (0.76 v 1.00; p = 0.205). Within individual variance in expression of HMW isoforms was very high. The change in expression in HMW isoforms from TPM1 and TPM4 was replicated in THP1 cells treated with 1 ng/ml TNFα (0.10 and 0.12 v 1.00 respectively) or 10 ng/ml IL-1α (0.17 and 0.14 v 1.00 respectively). Increased insulin or glucose concentrations had no substantial effects on TPM1 or TPM4 expression. Decreased TPM1 mRNA resulted in decreases in HMW protein levels. Expression of HMW isoforms from TPM1 is decreased in Type 2 diabetes. This is probably due to increased levels of inflammatory cytokines TNFα and IL-1α in Type 2 diabetes. Lower levels of TPM1 mRNA reduce tumour suppression and could contribute to increased cancer risk in Type 2 diabetes. Decreased HMW tropomyosin isoforms are associated with cancer. Decreased HMW isoforms give rise to cells that are more plastic, motile, invasive and prone to dedifferentiation resulting in leukocytes that are more invasive but less functionally effective.
authors.affiliation: Betsi Cadwaladr University Health Board, Croesnewydd Road, Wrexham, United Kingdom.
authors.forename: Stuart A
authors.identifier: http://orcid.org/0000-0002-6264-7868
authors.initials: SA
authors.lastname: Savill
authors.affiliation: Betsi Cadwaladr University Health Board, Croesnewydd Road, Wrexham, United Kingdom.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Leitch
authors.affiliation: Betsi Cadwaladr University Health Board, Croesnewydd Road, Wrexham, United Kingdom.|School of Medical Sciences, Wrexham Academic Unit, Bangor University, Bangor, United Kingdom.
authors.forename: John N
authors.initials: JN
authors.lastname: Harvey
authors.affiliation: Betsi Cadwaladr University Health Board, Croesnewydd Road, Wrexham, United Kingdom.
authors.forename: Trevor H
authors.initials: TH
authors.lastname: Thomas
mesh_terms: D054392:Adipokines / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D054392:Adipokines; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D053582:Interleukin-1alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; C490775:TPM1 protein, human; C501213:TPM4 protein, human; D014335:Tropomyosin; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose