Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

Gerard J. Nuovo, Michela Garofalo, Nicola Valeri, Vicki Roulstone, Stefano Volinia, David E. Cohn, Mitch Phelps, Kevin J. Harrington, Richard Vile, Alan Melcher, Evanthia Galanis, Sarah Sehl, Rob Adair, Karen Scott, Ailsa Rose, Giles Toogood, Matthew C. Coffey

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

We analyzed the in situ molecular correlates of infection from cancer patients treated with reovirus. Melanoma, colorectal, and ovarian cancer samples from such patients showed variable infection of the cancer cells but not the intermingled benign cells. RT in situ PCR showed most cancer cells contained the viral genome with threefold less having productive viral infection as documented by either tubulin or reoviral protein co-expression. Productive infection in the cancer cells was strongly correlated with co-expression of p38 and caspase-3 as well as apoptosis-related death (P=0.001). The cancer cell apoptotic death was due to a marked viral-induced inhibition of microRNA-let-7d that, in turn, upregulated caspase-3 activity. In summary, reovirus shows a striking tropism to cancer cells in clinical samples. A rate-limiting factor of reovirus-induced cancer cell death is productive viral infection that operates via the marked reduction of microRNA-let-7d and concomitant elevated caspase-3 expression.

Original languageEnglish (US)
Pages (from-to)1333-1344
Number of pages12
JournalModern Pathology
Volume25
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • PKR
  • Ras
  • apoptosis
  • caspase-3
  • microRNA-let-7d
  • reovirus

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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