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Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

Research output: Contribution to journalArticle

  • Martin Munoz-Lopez
  • Daniel J. Gerhardt
  • [No Value] Thu Nguyen
  • Agnese Collino
  • Serena Ghisletti
  • Shruti Sinha
  • Fabio Iannelli
  • Enrico Radaelli
  • Alexandre Dos Santos
  • Delphine Rapoud
  • Catherine Guettier
  • Didier Samuel
  • Gioacchino Natoli
  • Piero Carninci
  • Francesca D. Ciccarelli
  • Jamila Faivre
  • Geoffrey J. Faulkner

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http://www.sciencedirect.com/science/article/pii/S0092867413002213
Original languageEnglish
Pages (from-to)101-111
Number of pages11
JournalCell
Volume153
Issue number1
DOIs
Publication statusPublished - 28 Mar 2013

Abstract

LINE-1 (L1) retrotransposons are mobile genetic elements comprising similar to 17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic beta-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

    Research areas

  • GENE, HEPATITIS-B-VIRUS, TUMOR-SUPPRESSOR, LINE-1 RETROTRANSPOSITION, SOMATIC RETROTRANSPOSITION, IDENTIFICATION, HUMAN GENOME, L1 RETROTRANSPOSITION, MAMMALIAN-CELLS, COLORECTAL-CANCER

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