Diagnostic potential of miR-483 family for IGF-II producing non-islet cell tumor hypoglycemia

in European Journal of Endocrinology
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  • 1 Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
  • 2 Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
  • 3 Tokyo Women’s Medical University, Sinjuku-ku, Tokyo, Japan

Correspondence should be addressed to M Nagao or I Fukuda; Email: s8067@nms.ac.jp or i-fukuda@nms.ac.jp
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Objective

In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH.

Design

Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting.

Results

Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II.

Conclusion

The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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  • 1

    Takayama-Hasumi S, Eguchi Y, Sato A, Morita C & Hirata Y Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemic attacks in Japan. Diabetes Research and Clinical Practice 1990 10 211214. (https://doi.org/10.1016/0168-8227(9090063-y)

    • Search Google Scholar
    • Export Citation
  • 2

    Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, Danoff A, Breen TL, Kaviani N & Shanik MH et al. Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocrine Reviews 2013 34 798826. (https://doi.org/10.1210/er.2012-1033)

    • Search Google Scholar
    • Export Citation
  • 3

    Hizuka N, Fukuda I, Takano K, Asakawa-Yasumoto K, Okubo Y & Demura H Serum high molecular weight form of insulin-like growth factor II from patients with non-islet cell tumor hypoglycemia is O-glycosylated. Journal of Clinical Endocrinology and Metabolism 1998 83 28752877. (https://doi.org/10.1210/jcem.83.8.5021)

    • Search Google Scholar
    • Export Citation
  • 4

    Fukuda I, Hizuka N, Takano K, Asakawa-Yasumoto K, Shizume K & Demura H Characterization of insulin-like growth factor II (IGF-II) and IGF binding proteins in patients with non-islet-cell tumor hypoglycemia. Endocrine Journal 1993 40 111119. (https://doi.org/10.1507/endocrj.40.111)

    • Search Google Scholar
    • Export Citation
  • 5

    de Groot JW, Rikhof B, van Doorn J, Bilo HJ, Alleman MA, Honkoop AH & van der Graaf WT Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocrine-Related Cancer 2007 14 979993. (https://doi.org/10.1677/ERC-07-0161)

    • Search Google Scholar
    • Export Citation
  • 6

    Lawson EA, Zhang X, Crocker JT, Wang WL & Klibanski A Hypoglycemia from IGF2 overexpression associated with activation of fetal promoters and loss of imprinting in a metastatic hemangiopericytoma. Journal of Clinical Endocrinology and Metabolism 2009 94 22262231. (https://doi.org/10.1210/jc.2009-0153)

    • Search Google Scholar
    • Export Citation
  • 7

    Daughaday WH, Emanuele MA, Brooks MH, Barbato AL, Kapadia M & Rotwein P Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. New England Journal of Medicine 1988 319 14341440. (https://doi.org/10.1056/NEJM198812013192202)

    • Search Google Scholar
    • Export Citation
  • 8

    Fukuda I, Hizuka N, Ishikawa Y, Yasumoto K, Murakami Y, Sata A, Morita J, Kurimoto M, Okubo Y & Takano K Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia. Growth Hormone and IGF Research 2006 16 211216. (https://doi.org/10.1016/j.ghir.2006.05.003)

    • Search Google Scholar
    • Export Citation
  • 9

    Allegra A, Alonci A, Campo S, Penna G, Petrungaro A, Gerace D & Musolino C Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review). International Journal of Oncology 2012 41 18971912. (https://doi.org/10.3892/ijo.2012.1647)

    • Search Google Scholar
    • Export Citation
  • 10

    Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO & Landthaler M et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007 129 14011414. (https://doi.org/10.1016/j.cell.2007.04.040)

    • Search Google Scholar
    • Export Citation
  • 11

    Liu D, Fan J, Mei M, Ingvarsson S & Chen H Identification of miRNAs in a liver of a human fetus by a modified method. PLoS ONE 2009 4 e7594. (https://doi.org/10.1371/journal.pone.0007594)

    • Search Google Scholar
    • Export Citation
  • 12

    Ma N, Wang X, Qiao Y, Li F, Hui Y, Zou C, Jin J, Lv G, Peng Y & Wang L et al. Coexpression of an intronic microRNA and its host gene reveals a potential role for miR-483-5p as an IGF2 partner. Molecular and Cellular Endocrinology 2011 333 96101. (https://doi.org/10.1016/j.mce.2010.11.027)

    • Search Google Scholar
    • Export Citation
  • 13

    Veronese A, Lupini L, Consiglio J, Visone R, Ferracin M, Fornari F, Zanesi N, Alder H, D'Elia G & Gramantieri L et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Research 2010 70 31403149. (https://doi.org/10.1158/0008-5472.CAN-09-4456)

    • Search Google Scholar
    • Export Citation
  • 14

    Gallo W, Esguerra JLS, Eliasson L & Melander O miR-483-5p associates with obesity and insulin resistance and independently associates with new onset diabetes mellitus and cardiovascular disease. PLoS ONE 2018 13 e0206974. (https://doi.org/10.1371/journal.pone.0206974)

    • Search Google Scholar
    • Export Citation
  • 15

    Hizuka N, Fukuda I, Takano K, Okubo Y, Asakawa-Yasumoto K & Demura H Serum insulin-like growth factor II in 44 patients with non-islet cell tumor hypoglycemia. Endocrine Journal 1998 45 (Supplement) S61S 65. (https://doi.org/10.1507/endocrj.45.suppl_s61)

    • Search Google Scholar
    • Export Citation
  • 16

    Vigneron N, Meryet-Figuiere M, Guttin A, Issartel JP, Lambert B, Briand M, Louis MH, Vernon M, Lebailly P & Lecluse Y et al. Towards a new standardized method for circulating miRNAs profiling in clinical studies: interest of the exogenous normalization to improve miRNA signature accuracy. Molecular Oncology 2016 10 981992. (https://doi.org/10.1016/j.molonc.2016.03.005)

    • Search Google Scholar
    • Export Citation
  • 17

    Zhang Z, Ge S, Wang X, Yuan Q, Yan Q, Ye H, Che Y, Lin Y, Zhang J & Liu P Serum miR-483-5p as a potential biomarker to detect hepatocellular carcinoma. Hepatology International 2013 7 199207. (https://doi.org/10.1007/s12072-012-9341-z)

    • Search Google Scholar
    • Export Citation
  • 18

    Butz H & Patocs A MicroRNAs in endocrine tumors. EJIFCC 2019 30 146164.

  • 19

    Fu H, Tie Y, Xu C, Zhang Z, Zhu J, Shi Y, Jiang H, Sun Z & Zheng X Identification of human fetal liver miRNAs by a novel method. FEBS Letters 2005 579 38493854. (https://doi.org/10.1016/j.febslet.2005.05.064)

    • Search Google Scholar
    • Export Citation
  • 20

    Pepe F, Visone R & Veronese A The glucose-regulated MiR-483-3p influences key signaling pathways in cancer. Cancers 2018 10 181. (https://doi.org/10.3390/cancers10060181)

    • Search Google Scholar
    • Export Citation
  • 21

    Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J & Guo X et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Research 2008 18 9971006. (https://doi.org/10.1038/cr.2008.282)

    • Search Google Scholar
    • Export Citation
  • 22

    Iglesias P & Diez JJ Management of endocrine disease: a clinical update on tumor-induced hypoglycemia. European Journal of Endocrinology 2014 170 R147R 157. (https://doi.org/10.1530/EJE-13-1012)

    • Search Google Scholar
    • Export Citation
  • 23

    Zapf J, Futo E, Peter M & Froesch ER Can ‘big’ insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? Journal of Clinical Investigation 1992 90 25742584. (https://doi.org/10.1172/JCI116152)

    • Search Google Scholar
    • Export Citation
  • 24

    Daughaday WH & Kapadia M Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors. PNAS 1989 86 67786782. (https://doi.org/10.1073/pnas.86.17.6778)

    • Search Google Scholar
    • Export Citation
  • 25

    Rikhof B, Van Den Berg G & Van Der Graaf WT Non-islet cell tumour hypoglycaemia in a patient with a gastrointestinal stromal tumour. Acta Oncologica 2005 44 764766. (https://doi.org/10.1080/02841860500267816)

    • Search Google Scholar
    • Export Citation
  • 26

    Blum WF & Schweizer R Insulin-like growth factors and their binding proteins. In Diagnostics of Endocrine Function in Children and Adolescents, pp. 166199. Ed Ranke MBBasel: Karger, 2003.

    • Search Google Scholar
    • Export Citation
  • 27

    Suzuki HI, Katsura A, Yasuda T, Ueno T, Mano H, Sugimoto K & Miyazono K Small-RNA asymmetry is directly driven by mammalian Argonautes. Nature Structural and Molecular Biology 2015 22 512521. (https://doi.org/10.1038/nsmb.3050)

    • Search Google Scholar
    • Export Citation
  • 28

    Chiang HR, Schoenfeld LW, Ruby JG, Auyeung VC, Spies N, Baek D, Johnston WK, Russ C, Luo S & Babiarz JE et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes and Development 2010 24 9921009. (https://doi.org/10.1101/gad.1884710)

    • Search Google Scholar
    • Export Citation
  • 29

    Gallagher EJ & LeRoith D The proliferating role of insulin and insulin-like growth factors in cancer. Trends in Endocrinology and Metabolism 2010 21 610618. (https://doi.org/10.1016/j.tem.2010.06.007)

    • Search Google Scholar
    • Export Citation
  • 30

    Livingstone C IGF2 and cancer. Endocrine-Related Cancer 2013 20 R321R 339. (https://doi.org/10.1530/ERC-13-0231)

  • 31

    Zhou W, Yang W, Ma J, Zhang H, Li Z, Zhang L, Liu J, Han Z, Wang H & Hong L Role of miR-483 in digestive tract cancers: from basic research to clinical value. Journal of Cancer 2018 9 407414. (https://doi.org/10.7150/jca.21394)

    • Search Google Scholar
    • Export Citation
  • 32

    Kahn CR The riddle of tumour hypoglycaemia revisited. Clinics in Endocrinology and Metabolism 1980 9 335360. (https://doi.org/10.1016/s0300-595x(8080037-5)

    • Search Google Scholar
    • Export Citation
  • 33

    Liu M, Roth A, Yu M, Morris R, Bersani F, Rivera MN, Lu J, Shioda T, Vasudevan S & Ramaswamy S et al. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes and Development 2013 27 25432548. (https://doi.org/10.1101/gad.224170.113)

    • Search Google Scholar
    • Export Citation