A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis

Abstract

Organ size determination is one of the most intriguing unsolved mysteries in biology. Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers. However, how robust YAP activation is achieved during organ size control remains elusive. Here we report that the YAP signaling is sustained through a novel microRNA-dependent positive feedback loop. miR-130a, which is directly induced by YAP, could effectively repress VGLL4, an inhibitor of YAP activity, thereby amplifying the YAP signals. Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis. Furthermore, the Drosophila Hippo pathway target bantam functionally mimics miR-130a by repressing the VGLL4 homolog SdBP/Tgi. These findings reveal an evolutionarily conserved positive feedback mechanism underlying robustness of the Hippo pathway in size control and tumorigenesis.

miR-285– Yki/Mask double-negative feedback loop mediates blood–brain barrier integrity in Drosophila

“…Although function and regulation of the Hippo pathway have been extensively studied, how Hippo signaling pathway is regulated remains incompletely understood in this important field. Since the first microRNA lin-4 identified in Caenorhabditis elegans, the importance of microRNAs in regulation of various aspects of life and diseases has been well recognized; however, only very few microRNAs have been reported to mediate the growth control activity of Hippo pathway in vivo (24,41). Recently, mammalian miR-130a was reported to amplify Yki signals through targeting its inhibitor VGLL4 and established a positive feedback loop (24).…”

“…Since the first microRNA lin-4 identified in Caenorhabditis elegans, the importance of microRNAs in regulation of various aspects of life and diseases has been well recognized; however, only very few microRNAs have been reported to mediate the growth control activity of Hippo pathway in vivo (24,41). Recently, mammalian miR-130a was reported to amplify Yki signals through targeting its inhibitor VGLL4 and established a positive feedback loop (24). By investigating the well-known bantam in Drosophila, it was found that bantam functionally mimics mammalian miR-130a through targeting the Yki inhibitor SdBP/Tgi (24), although they do not share a conserved seed sequence.…”

“…In Drosophila, the microRNA bantam is a downstream target of Yki and is required for Yki-regulated cell growth (22,23). bantam represses the Yki inhibitor SdBP/Tgi to establish a feedback loop, which functionally mimics its mammalian homolog miR-130a targeting VGLL4, a YAP inhibitor (24). Although the core signaling cascade of the Hippo pathway has been extensively studied, whether Hippo pathway is functional at BBB maintenance is unknown, and the regulatory mechanisms underlying Hippo signaling are key questions that remain unanswered in the Hippo research field.…”

Mechanisms of Hippo pathway regulation

“…Although earlier transgenic mouse studies have shown striking phenotypes and established a role of the Hippo pathway in development and carcinogenesis (Morin-Kensicki et al 2006;Camargo et al 2007;Dong et al 2007;Yabuta et al 2007), many more refined transgenic mouse models with tissue-specific deletion and inducible overexpression have been generated in the last few years. These mouse model studies allow for more detailed charaterizations of the physiological contribution of individual Hippo pathway components to tissue growth, cell differentiation, cell competition, and malignant transformation (Zhou et al 2009;Cai et al 2010;Barry et al 2013;Chen et al 2014Chen et al , 2015bYimlamai et al 2014;Imajo et al 2015;Mamada et al 2015;Shen et al 2015).…”

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

“…We thus set out to testify the hypothesis that miR-520d-5p may partially account for CypB upregulation in cancer and inhibit gastric cancer growth by suppressing CypB. Recently, STAT3 was found to transcriptionally target many miRNAs (25,26), which frequently form feedback loops because they are regulated by transcription factors that they may also target directly or indirectly (25,27,28).…”