European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
Hepatology. 2020 Oct;72(4):1430-1443. doi: 10.1002/hep.31120. Epub 2020 Jul 29.
Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.
We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.
Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
在肝癌中，MYC 和连环蛋白β-1（CTNNB1，编码β-连环蛋白）的激活可能同时发生，但这些癌基因如何在肿瘤发生中协同作用尚不清楚。
我们构建了一种小鼠模型，允许在肝脏中表达 CRE 重组酶时，条件性激活 MYC 和 WNT/β-连环蛋白信号（通过β-连环蛋白激活或 APC-腺瘤性结肠息肉丢失），并监测它们对肝细胞增殖、凋亡、基因表达谱和肿瘤发生的影响。WNT/β-连环蛋白信号的激活强烈加速了 MYC 驱动的肝癌发生。这两种途径也在体外协同促进细胞转化，证明了它们的细胞自主作用。在肝细胞中短期诱导 MYC 和β-连环蛋白，然后进行 RNA-seq 分析，允许鉴定出一个“MYC/β-连环蛋白特征”，由一组离散的 MYC 激活基因组成，其表达在存在活性β-连环蛋白时增加。值得注意的是，该特征富集了 Yes 相关蛋白（Yap）和 PDZ 结合基序转录共激活因子（Taz）的靶标，这两种转录共激活因子已知被 WNT/β-连环蛋白信号激活，并与 MYC 一起在有丝分裂激活和肝转化中合作。与这些调节连接一致，在 MYC/β-连环蛋白激活时，Yap/Taz 积累，不仅需要随后的增殖反应，还需要肿瘤细胞的生长和存活。最后，在一组具有相对较差预后的人类肝细胞癌中富集了 MYC/β-连环蛋白特征。
MYC 和β-连环蛋白在肝癌发生中表现出强烈的协同作用，Yap 和 Taz 是这种作用的介导物。这些发现值得努力针对 Yap/Taz 在以 MYC/β-连环蛋白活性升高为特征的侵袭性肝肿瘤中进行治疗靶向。
