癌蛋白YAP1的研究进展

Yes相关蛋白1(Yes-associated protein 1,YAP1)是Hippo信号通路(Hippo pathway)中的一个分子.早期研究人员发现,在Hippo信号通路正常的情况下,YAP1处于非激活状态;当Hippo信号通路中的某些分子出现突变时,YAP1处于超激活状态.此时,超激活状态下的YAP1可以促进细胞增殖、转移、生存(survival)以及维持干细胞活性.由于YAP1的超激活可以促进肿瘤的发生与发展,因此,YAP1被定义为一个癌蛋白.近期,研究者发现,YAP1的突变体与小细胞肺癌病人的存活率有一定关系,YAP1与链蛋白(catenin)、Kras相互作用,调节肿瘤细胞的转移侵袭能力,此外,部分micro RNA也与YAP1有相互作用.基于YAP1的功能,可以制定一些抗癌策略,寻找一些抗癌靶点.本文对当前YAP1的研究进行综述,为肿瘤治疗的基础及临床研究提供一些依据.     

YAP1 increases organ size and expands undifferentiated progenitor cells

The mechanisms that regulate mammalian organ size are poorly understood. It is unclear whether the pathways that control organ size also impinge on stem/progenitor cells. A highly expressed gene in stem cells is YAP1, the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador, merlin, LATS, and YAP1, have been implicated in tumorigenesis. We report here that YAP1 increases organ size and causes aberrant tissue expansion in mice. YAP1 activation reversibly increases liver size more than 4-fold. In the intestine, expression of endogenous YAP1 is restricted to the progenitor/stem cell compartment, and activation of YAP1 expands multipotent undifferentiated progenitor cells, which differentiate upon cessation of YAP1 expression. YAP1 stimulates Notch signaling, and administration of gamma-secretase inhibitors suppressed the intestinal dysplasia caused by YAP1. Human colorectal cancers expressing higher levels of YAP1 share molecular aspects with YAP1-induced dysplastic growth in the mouse. Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer.     

Hippo信号对卵巢生殖干细胞增殖及卵巢功能的影响

已有研究表明,Hippo信号通路对干细胞的自我更新和分化至关重要,且Hippo信号通路在调控卵泡生长中起重要作用,然而,目前关于Hippo通路对卵巢生殖干细胞的增殖和分化以及卵巢功能重塑的影响相关的研究较少。为了明确Hippo信号通路效应因子YAP1与卵巢生殖干细胞体外增殖分化的关系,以及Hippo信号通路对卵巢癌的主要功能。我们采用两步法酶促分离和磁性分离技术分别鉴定卵巢生殖干细胞,通过测定MVH和OCT4标记物的表达,然后选择YAP1作为Hippo信号通路的主要效应分子,作为研究的靶基因。将含有过表达的YAP1或YAP1靶向的shRNA的慢病毒转导入卵巢生殖干细胞中。通过将过表达YAP1或YAP1 shRNA的慢病毒载体微量注射到不育小鼠模型中,观察调节Hippo信号通路对卵巢的增殖、分化和内分泌功能的影响。研究结果表明,在分离的卵巢生殖干细胞中观察到YAP1和MVH的共表达。与对照组相比,过表达YAP1的卵巢生殖干细胞中MVH和OCT4表达水平显著增加。而YAP1敲低后,MVH和OCT4水平显著降低;不育小鼠模型中YAP1过表达15 d后,E2和FSH含量显著升高,而YAP1 shRNA表达后,小鼠血清E2和FSH含量显著降低。YAP1可用于调控卵巢生殖干细胞的增殖和分化以及小鼠的卵巢功能。本研究表明,Hippo信号通路可能是调控卵巢功能重建的一个新的分子靶点。     

CD44 acts through RhoA to regulate YAP signaling

The Hippo pathway plays an important role in both physical and pathogenesis processes. As crucial downstream effectors of Hippo pathway, YAP is inhibited by Lats1/2 through phosphorylation. However, upstream signals that regulate the Hippo pathway have been still poorly understood. Here, we found that knockdown of CD44 reduced YAP expression and nuclear localization, but nearly had no effect on its upstream effectors, Mst1 and Lats1. Downregulated CD44 expression also significantly decreased the expression of YAP downstream effectors CTGF, Cyr61 and EDN1 at mRNA level. Our next study showed that knockdown of CD44 inhibited RhoA expression, which was consistent with RhoA knockdown mediated YAP downregulation. Furthermore, we demonstrated that over expression of the constitutively active RhoA (RhoA-V14) could block the YAP expression decrease mediated by CD44 knockdown. Moreover, downregulation of CD44 significantly promoted cell apoptosis and inhibited cell proliferation, cell cycle progression and migration, which were consistent with the effects of RNAi-mediated YAP knockdown in both A549 and HepG2 cells. Overall, data are presented showing that CD44 could act through RhoA signaling to regulate YAP expression and this study also provide new insights into the regulatory mechanisms of the Hippo–YAP pathway.     

GABAB receptor inhibits tumor progression and epithelial-mesenchymal transition via the regulation of Hippo/YAP1 pathway in colorectal cancer

Gamma-Aminobutyric Acid Type B Receptor (GABABR) plays essential roles in tumor progression. However, the function of GABABR in colorectal cancer (CRC) needs further clarification. As the main part of GABABR, GABABR1 expression was identified significantly lower in tumor tissues than those in non-tumor normal tissues and that CRC patients with high GABABR1 expression lived longer. Further studies indicated that knockdown of GABABR1 elevated CRC cell proliferation, migration, and invasion. Furthermore, knockdown of GABABR1 activated the expression of the epithelial-mesenchymal transition (EMT)-related proteins N-cadherin and Vimentin, whereas decrease the protein level of E-cadherin. In addition, activation of Hippo/YAP1 signaling contributes to the GABABR1 down-regulation promoted proliferation, migration, invasion and EMT in CRC cells. At last, we verified the contribution of Hippo/YAP1 signaling in the GABABR1 down-regulation impaired biological phenotype of colon cancer cells in vivo. In summary, these data indicate that GABABR1 impairs the migration and invasion of CRC cells by inhibiting EMT and the Hippo/YAP1 pathway, suggesting that GABABR1 could be a potential therapeutic target for CRC.     

ANKHD1, a novel component of the Hippo signaling pathway,promotes YAP1 activation and cell cycle progression in prostate cancer cells

ANKHD1 is a multiple ankyrin repeat containing protein, recently identified as a novel member of the Hippo signaling pathway. The present study aimed to investigate the role of ANKHD1 in DU145 and LNCaP prostate cancer cells. ANKHD1 and YAP1 were found to be highly expressed in prostate cancer cells, and ANKHD1 silencing decreased cell growth, delayed cell cycle progression at the S phase, and reduced tumor xenograft growth. Moreover, ANKHD1 knockdown downregulated YAP1 expression and activation, and reduced the expression of CCNA2, a YAP1 target gene. These findings indicate that ANKHD1 is a positive regulator of YAP1 and promotes cell growth and cell cycle progression through Cyclin A upregulation.     

Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the predominant esophageal cancer type in China. The aberrant activation of glioma-associated oncogene homolog1 (Gli1), a key factor in Hedgehog (Hh) signaling pathway, has been found in esophageal carcinoma. Moreover, Yes-associated protein 1 (YAP1), the major mediator of Hippo signaling pathway, has been linked to esophageal carcinoma progression. However, the precise roles and the underlying mechanism of both Gli1 and YAP1 in ESCC are unclear. Here, we found that Gli1 and YAP1 are overexpressed in ESCC and are associated with poor prognosis. In addition, we confirmed that knockdown of Gli1 or YAP1 suppresses ESCC cell growth, migration, and invasion in ESCC TE1 and EC109 cells. Significantly, Gli1 interacts with YAP1 in ESCC cells. Both Gli1 and YAP1 proteins are closely correlated with each other in human ESCC samples. Mechanistically, Gli1 upregulates YAP1 in a LATS1-independent manner. Conversely, YAP1 induces Gli1 by regulating phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Most importantly, we demonstrated that the interaction between Gli1 and YAP1 promotes ESCC tumor growth in vitro and in vivo. Our findings established a novel signaling mechanism by which the interaction between Gli1 and YAP1 promotes ESCC cell growth. This signaling regulation of the tumorigenesis provides a new therapeutic strategy for highly lethal ESCC.     

YAP1 regulates PPARG and RXR alpha expression to affect the proliferation and differentiation of ovine preadipocyte

Adipose tissue development is regulated by a serial of developmental signaling pathways. The Hippo pathway is a novel signaling cascade closely associated with adipogenesis. While most of Hippo pathway components had been verified that have a vital role in preadipocytes proliferation and differentiation, little is known about the function of Yes-associated protein 1 (YAP1) in mammalian adipose tissue development. Therefore, we investigated the role of YAP1 in ovine adipose tissue development by in vitro and in vivo experiments. We observed that the adipocyte size in subcutaneous adipose tissue increased with development. YAP1 expression increased during adipose tissue development, while decreased during the differentiation of ovine preadipocytes in vitro. YAP1 knockdown notably promoted lipid accumulation and suppressed ovine preadipocyte proliferation. In addition, we observed that YAP1 deficiency significantly upregulated peroxisome proliferator-activated receptor gamma (PPARG) and retinoid X receptor alpha (RXR alpha) expression. By contrast, overexpression of YAP1 led to the suppression of preadipocyte differentiation, lipid droplets formation, and PPARG expression. In brief, our findings demonstrated that YAP1 regulates the proliferation and differentiation of ovine preadipocyte via altering PPARG and RXR alpha expression.     

YAP与干细胞及肿瘤

YAP蛋白作为Hippo信号通路中关键成分,在控制生物器官发育和调控细胞生长中起着十分重要的作用。鉴于YAP蛋白的促细胞生长功能以及过表达YAP或YAP上游调控基因失活将引发肿瘤,YAP因此被认为是原癌蛋白。最新的研究表明YAP在维持干细胞特性、抑制干细胞分化及促进成体细胞重编程中也起着十分重要的作用。可见YAP在干细胞和肿瘤细胞中都扮演着重要角色。因此更好地了解和研究YAP蛋白及其信号通路有助于更好地理解干细胞与肿瘤的关系,有助于干细胞治疗的安全应用以及特异性靶向肿瘤治疗药物的开发。