Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis.
Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis.
复制标题
Yap-Sox9信号决定肝细胞可塑性和谱系特异性肝癌发生。
DOI：
10.1016/j.jhep.2021.11.010
复制
发表时间：
2022-03
影响因子：
25.7
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Liu Y;Zhuo S;Zhou Y;Ma L;Sun Z;Wu X;Wang XW;Gao B;Yang Y
原发性肝肿瘤包含不同的亚型。 iCCAs 的一个子集可以由小鼠模型中成熟肝细胞的细胞命运重编程产生。然而，肝癌发生过程中细胞命运可塑性的基础仍然知之甚少，这阻碍了 HCC 和 iCCA 的治疗开发。由于 YAP 激活会诱导肝脏肿瘤形成和细胞命运可塑性，因此我们研究了 Sox9（Yap 激活下游的转录因子并在胆管上皮细胞 (BEC) 中表达）在肝癌发生过程中 Yap 诱导的细胞命运可塑性中的作用。为了评估 Sox9 在 YAP 诱导的体内肝癌发生中的功能，我们在几种小鼠遗传模型中进行了诱导型肝细胞特异性 YAP 激活，同时去除了 Sox9。通过谱系追踪和免疫组织化学确定细胞命运重编程。通过对小鼠和人类肝脏肿瘤的转录和转录组分析，研究了 Yap 和 Sox9 在肝细胞可塑性中发挥作用的分子机制。 Sox9 是肝祖细胞 (LPC) 和 BEC 的标记物，在 YAP 诱导的逐步肝细胞编程中存在差异。虽然 Sox9 在肝细胞去分化为 LPC 方面的功能有限，但它是 BEC 从 LPC 分化所需的。 Sox9 缺陷肝细胞中的 YAP 激活导致更具侵袭性的 HCC，且 Yap 活性增强，但牺牲了 iCCA 样肿瘤。此外，我们发现 20% 的原发性人类肝脏肿瘤与 YAP 激活特征相关，并且肿瘤可塑性与 YAP 激活和 SOX9 表达高度相关。我们的数据表明，Yap-Sox9 信号传导决定小鼠和人类肝脏肿瘤肝癌发生中的肝细胞可塑性和肿瘤异质性。我们确定 Sox9 是肝癌发生过程中 Yap 诱导的肝细胞命运重编程所需的关键转录因子。 Sox9 是肝祖细胞和胆管内壁细胞的标记物，是 YAP 蛋白激活的下游靶标。在这里，我们发现肝细胞中的 YAP 激活导致从成熟肝细胞向第一个肝祖细胞的转变，然后在小鼠肝癌发生的第二步中需要胆管内壁细胞和 Sox9 的形成。我们还发现人类 YAP 和 SOX9 可能在肝癌中发挥相似的作用。
Primary liver tumors contain distinct subtypes. A subset of iCCAs can arise from cell fate reprogramming of mature hepatocytes in mouse models. However, the underpinning of cell fate plasticity during hepatocarcinogenesis is still poorly understood, hampering therapeutic development to treat HCC and iCCA. As YAP activation induces liver tumor formation and cell fate plasticity, we investigated the role of Sox9, a transcription factor downstream of Yap activation and expressed in biliary epithelial cells (BECs), in Yap-induced cell fate plasticity during hepatocarcinogenesis. To evaluate the function of Sox9 in YAP-induced hepatocarcinogenesis in vivo, we performed inducible hepatocyte-specific YAP activation with simultaneous Sox9 removal in several mouse genetic models. Cell fate reprogramming was determined by lineage tracing and immunohistochemistry. The molecular mechanism underlying Yap and Sox9 function in hepatocyte plasticity was investigated by transcription and transcriptomic analyses of mouse and human liver tumors. Sox9, a marker of liver progenitor cells (LPCs) and BECs, is differentially required in YAP-induced stepwise hepatocyte programming. While Sox9 has limited function in hepatocyte dedifferentiation to LPCs, it is required for BEC differentiation from LPCs. YAP activation in Sox9-deficient hepatocytes resulted in more aggressive HCC with enhanced Yap activity at the expense of iCCA-like tumors. Furthermore, we showed that 20% of primary human liver tumors were associated with a YAP activation signature, and tumor plasticity is highly correlated with YAP activation and SOX9 expression. Our data demonstrated that Yap-Sox9 signaling determines hepatocyte plasticity and tumor heterogeneity in hepatocarcinogenesis in both mouse and human liver tumors. We identified Sox9 as a critical transcription factor required for Yap-induced hepatocyte cell fate reprogramming during hepatocarcinogenesis. Sox9, a marker of liver progenitor cells and bile duct lining cells, is a downstream target of YAP protein activation. Here we found that YAP activation in hepatocytes leads to a transition from mature hepatocytes to first liver progenitor cells and then the formation of the bile duct lining cells and Sox9 is required in the second step during mouse hepatocarcinogenesis. We also found that human YAP and SOX9 may play similar roles in liver cancers.
登录
查看更多内容
影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
23.9
作者：
Planas-Paz, Lara;Sun, Tianliang;Tchorz, Jan S.
通讯作者：
Tchorz, Jan S.
影响因子：
15.9
作者：
Mu, Xueru;Espanol-Suner, Regina;Schwabe, Robert F.
通讯作者：
Schwabe, Robert F.
影响因子：
5.5
作者：
Lange, Alexander W.;Sridharan, Anusha;Whitsett, Jeffrey A.
通讯作者：
Whitsett, Jeffrey A.
影响因子：
15.9
作者：
Sekiya, Sayaka;Suzuki, Atsushi
通讯作者：
Suzuki, Atsushi