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.