Tumor suppressor miR-215 counteracts hypoxia-induced colon cancer stem cell activity

Pit Ullmann, Martin Nurmik, Martine Schmitz, Fabien Rodriguez, Jil Weiler, Komal Qureshi-Baig, Paul Felten, Petr V. Nazarov, Nathalie Nicot, Nikolaus Zuegel, Serge Haan, Elisabeth Letellier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

37 Citations (Scopus)

Abstract

Cancer stem cells, also known as tumor-initiating cells (TICs), are a population of aggressive and self-renewing cells that are responsible for the initiation and progression of many cancers, including colorectal carcinoma. Intratumoral hypoxia, i.e. reduced oxygen supply following uncontrolled proliferation of cancer cells, is thought to support TIC activity by inducing specific hypoxia-responsive mechanisms that are not yet entirely understood. Using previously established and fully characterized patient-derived TIC cultures, we could observe increased sphere and colony formation under hypoxic conditions. Mechanistically, microRNA (miRNA)-profiling experiments allowed us to identify miR-215 as one of the main hypoxia-induced miRNAs in primary colon TICs. Through stable overexpression of miR-215, followed by a set of functional in vitro and in vivo investigations, miR-215 was pinpointed as a negative feedback regulator, working against the TIC-promoting effects of hypoxia. Furthermore, we could single out LGR5, a bona fide marker of non-neoplastic intestinal stem cells, as a downstream target of hypoxia/miR-215 signaling. The strong tumor- and TIC-suppressor potential of miR-215 and the regulatory role of the hypoxia/miR-215/LGR5 axis may thus represent interesting points of attack for the development of innovative anti-CSC therapy approaches.

Original languageEnglish
Pages (from-to)32-41
Number of pages10
JournalCancer Letters
Volume450
DOIs
Publication statusPublished - 28 May 2019

Keywords

  • Colon cancer stem cell
  • Hypoxia
  • LGR5
  • miR-215
  • microRNA

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