MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer

Peter Olson, Jun Lu, Hao Zhang, Anny Shai, Matthew G. Chun, Yucheng Wang, Steven K. Libutti, Eric K. Nakakura, Todd R. Golub, Douglas Hanahan

Research output: Contribution to journalArticle

217 Scopus citations

Abstract

While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.

Original languageEnglish (US)
Pages (from-to)2152-2165
Number of pages14
JournalGenes and Development
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2009
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Cancer
  • MicroRNA
  • Mouse model of human cancer
  • Pancreatic neuroendocrine tumor (PNET)
  • Transgenic mouse
  • miR-200

Cite this

Olson, P., Lu, J., Zhang, H., Shai, A., Chun, M. G., Wang, Y., Libutti, S. K., Nakakura, E. K., Golub, T. R., & Hanahan, D. (2009). MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes and Development, 23(18), 2152-2165. https://doi.org/10.1101/gad.1820109