Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch

Fangmei An, Sumitaka Yamanaka, Sarah Allen, Lewis R. Roberts, Gregory J. Gores, Timothy M. Pawlik, Qing Xie, Masaharu Ishida, Esteban Mezey, Anne C. Ferguson-Smith, Yuriko Mori, Florin Selaru

Research output: Contribution to journalArticle

Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Interleukin-6 (IL-6) is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree. Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However, the precise mechanisms of IL-6 effects in CCA remain unclear. We now demonstrate that microRNA (miR)-370 is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time-dependent silencing of miR-370. In addition, demethylation of CCA cells results in upregulation of miR-370. Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR) responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment. In addition, the IG-DMR is hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation. Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments. Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism.

Original languageEnglish (US)
Article numbere45606
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 22 2012

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Cholangiocarcinoma
Loss of Heterozygosity
MicroRNAs
microRNA
interleukin-6
Interleukin-6
Switches
Mothers
Genomic Imprinting
genomic imprinting
Biliary Tract
Alleles
biliary tract
alleles
Inflammation Mediators
human MIRN370 microRNA
luciferase
Luciferases
lethal genes
Liver

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch. / An, Fangmei; Yamanaka, Sumitaka; Allen, Sarah; Roberts, Lewis R.; Gores, Gregory J.; Pawlik, Timothy M.; Xie, Qing; Ishida, Masaharu; Mezey, Esteban; Ferguson-Smith, Anne C.; Mori, Yuriko; Selaru, Florin.

In: PLoS One, Vol. 7, No. 10, e45606, 22.10.2012.

Research output: Contribution to journalArticle

An, F, Yamanaka, S, Allen, S, Roberts, LR, Gores, GJ, Pawlik, TM, Xie, Q, Ishida, M, Mezey, E, Ferguson-Smith, AC, Mori, Y & Selaru, F 2012, 'Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch', PLoS One, vol. 7, no. 10, e45606. https://doi.org/10.1371/journal.pone.0045606
An, Fangmei ; Yamanaka, Sumitaka ; Allen, Sarah ; Roberts, Lewis R. ; Gores, Gregory J. ; Pawlik, Timothy M. ; Xie, Qing ; Ishida, Masaharu ; Mezey, Esteban ; Ferguson-Smith, Anne C. ; Mori, Yuriko ; Selaru, Florin. / Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch. In: PLoS One. 2012 ; Vol. 7, No. 10.
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AU - Yamanaka, Sumitaka

AU - Allen, Sarah

AU - Roberts, Lewis R.

AU - Gores, Gregory J.

AU - Pawlik, Timothy M.

AU - Xie, Qing

AU - Ishida, Masaharu

AU - Mezey, Esteban

AU - Ferguson-Smith, Anne C.

AU - Mori, Yuriko

AU - Selaru, Florin

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