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

2012; Elsevier BV; Volume: 25; Issue: 10 Linguagem: Inglês

10.1038/modpathol.2012.95

1530-0285

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

RNA Interference and Gene Delivery

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.