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Direct in Vivo RNAi Screen Unveils Myosin IIa as a Tumor Suppressor of Squamous Cell Carcinomas

Science  17 Jan 2014:
Vol. 343, Issue 6168, pp. 309-313
DOI: 10.1126/science.1248627

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Identifying Drivers and Passengers

Modern genomics is unearthing hundreds of genetic and epigenetic alterations associated with human cancers. It is important to delineate which of these alterations participate actively in tumor progression and/or metastases (driver mutations) and which are inconsequential (passenger mutations). To this end, Schramek et al. (p. 309) conducted an in vivo RNA interference screen in mice to test simultaneously the functionality of putative cancer genes and down-regulated messenger RNAs associated with tumor-initiating cells of squamous cell carcinomas (SCCs). Several candidates, including nonmuscle myosin-IIa, not previously viewed as tumor suppressors were uncovered.

Abstract

Mining modern genomics for cancer therapies is predicated on weeding out “bystander” alterations (nonconsequential mutations) and identifying “driver” mutations responsible for tumorigenesis and/or metastasis. We used a direct in vivo RNA interference (RNAi) strategy to screen for genes that upon repression predispose mice to squamous cell carcinomas (SCCs). Seven of our top hits—including Myh9, which encodes nonmuscle myosin IIa—have not been linked to tumor development, yet tissue-specific Myh9 RNAi and Myh9 knockout trigger invasive SCC formation on tumor-susceptible backgrounds. In human and mouse keratinocytes, myosin IIa’s function is manifested not only in conventional actin-related processes but also in regulating posttranscriptional p53 stabilization. Myosin IIa is diminished in human SCCs with poor survival, which suggests that in vivo RNAi technology might be useful for identifying potent but low-penetrance tumor suppressors.

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