PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma
PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma
复制标题
PDLIM1通过激活肝细胞癌中的Hippo信号传导抑制肿瘤转移
DOI：
10.1002/hep.30930
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发表时间：
2020-01-21
期刊：
影响因子：
13.5
通讯作者：
Peng, Yong
中科院分区：
文献类型：
--
作者：
Huang, Zhao;Zhou, Jian-Kang;Peng, Yong
背景与目的肿瘤转移是肝细胞癌（HCC）高复发率和死亡率的主要因素，但其潜在机制尚不清楚。我们报道PDZ和LIM结构域蛋白1 （PDLIM1）在转移性人HCC组织中显著下调，预示预后不良，提示PDLIM1可能在HCC转移过程中发挥重要的抑制作用。方法和结果功能研究表明，PDLIM1敲低可诱导肝癌细胞上皮-间质转化（EMT），提高其侵袭能力，促进肝癌细胞的转移，而PDLIM1过表达则表现出相反的表型。从机制上讲，PDLIM1竞争性地与细胞骨架交联蛋白α -肌动蛋白4 （ACTN4）结合，导致ACTN4与f -肌动蛋白分离，从而防止f -肌动蛋白过度生长。相反，PDLIM1缺失诱导F-actin过度形成，导致大肿瘤抑制激酶1去磷酸化，yes相关蛋白激活，从而促进HCC转移。此外，PDLIM1的Asn145 （N145）对其与ACTN4的相互作用至关重要，N145A突变使其在Hippo信号传导和HCC转移中的调节功能消失。结论PDLIM1通过调节Hippo信号传导抑制HCC转移，提示PDLIM1可能是转移性HCC的潜在预后标志物。
Background and Aims Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. We report that PDZ and LIM domain protein 1 (PDLIM1) is significantly down-regulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis. Approach and Results Functional studies indicate that PDLIM1 knockdown induces epithelial-to-mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis in vitro and in vivo, whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross-linking protein alpha-actinin 4 (ACTN4), leading to the disassociation of ACTN4 from F-actin, thus preventing F-actin overgrowth. In contrast, loss of PDLIM1 induces excessive F-actin formation, resulting in dephosphorylation of large tumor suppressor kinase 1 and activation of Yes-associated protein, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis. Conclusions Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC.