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We read with great interest the letter by Cheng-Maw et al., commenting on our study about the increased expression levels of Yes-associated protein (YAP) in chemically induced mouse hepatocellular carcinomas (HCCs).1 These increased expression levels were associated with down-regulation of microRNA-375 (miR-375) expression, which is known to control YAP expression,2 and with enhanced levels of alpha-fetoprotein (AFP), which, in two independent studies, was found to be a target gene of YAP.3, 4 Cheng-Maw et al. in their letter show that in 157 HCC, divided into two groups on the basis of the mean levels of miR-375 expression, serum AFP levels were significantly higher in the group showing less reduction in miR-375 than in the group showing stronger reduction of miR-375. Based on these findings, the authors suggest that AFP expression in HCCs is not solely regulated by the axis of miR-375-YAP-AFP. We totally agree with this conclusion. Indeed, as shown in our article, while an anti-correlation exists between miR-375 and YAP expression, such an inverse relation could not be observed between miR and AFP, and nowhere in the text did we imply that a YAP increase could be the main mechanism responsible for AFP regulation. AFP is a well-known marker of HCC and its increase is considered the result of a loss of differentiation of cancer cells. Thus, it seems clear that the increased levels of AFP cannot be due simply to up-regulation of YAP, but rather to a general change in the several factors regulating this protein. Interestingly, the article that originally described AFP as a target gene of YAP was based on a transgenic mouse model where YAP overexpression was induced in newborn (3-week-old) animals.3 Thus, it is possible that the increased AFP expression observed in YAP-overexpressing mice could also be due to YAP-dependent alteration of hepatocyte differentiation.

In conclusion, we agree with Cheng-Maw et al. that AFP expression in HCCs is not solely regulated by the axis of miR-375-YAP-AFP. As with most genes, many pathways and many mechanisms (both at the transcriptional, posttranscriptional, and posttranslational levels) can regulate the expression of a particular protein and this is surely true also for AFP. What we said in our article is that YAP is among the many factors that can contribute to this regulation.

Marta A. Kowalik Ph.D.*, Giovanna M. Ledda-Columbano Ph.D.*, Silvia Giordano M.D., Ph.D.†, Amedeo Columbano Ph.D.*, * Department of Toxicology, University of Cagliari, Italy, † Institute for Cancer Research and Treatment, University of Torino, Italy.

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