Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples.
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.
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. gnuovomd@pol.net
Gerard J
GJ
Nuovo
Michela
M
Garofalo
Nicola
N
Valeri
Vicki
V
Roulstone
Stefano
S
Volinia
David E
DE
Cohn
Mitch
M
Phelps
Kevin J
KJ
Harrington
Richard
R
Vile
Alan
A
Melcher
Evanthia
E
Galanis
Sarah
S
Sehl
Rob
R
Adair
Karen
K
Scott
Ailsa
A
Rose
Giles
G
Toogood
Matthew C
MC
Coffey
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005260:Female; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000379:methods*; D030102:Orthoreovirus, Mammalian / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012088:Reoviridae Infections / Q000821:virology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3