Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Cancer Lett. 2021 May 28;506:128-141. doi: 10.1016/j.canlet.2021.03.001. Epub 2021 Mar 8.
Metastasis remains the major obstacle of improving the survival of patients with hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is critical to cancer metastasis. Successful induction of EMT requires dramatic cytoskeleton rearrangement. However, the significance of microtubule (MT), one of the core components of cell cytoskeleton, in this process remains largely unknown. Here we revealed that STMN2, an important MT dynamics regulator, is barely expressed in normal live tissues but markedly up-regulated in HCCs, especially in those with early recurrence. High STMN2 expression correlates with aggressive clinicopathological features and predicts poor prognosis of HCC patients. STMN2 overexpression in HCC cells promotes EMT, invasion and metastasis in vitro and in vivo, whereas STMN2 knockdown has opposite results. Mechanistically, STMN2 modulates MTs disassembly, disrupts MT-Smad complex, and facilitates release from MT network, phosphorylation and nuclear translocation of Smad2/3 even independent of TGFβ stimulation, thereby enhancing TGFβ signaling. Collectively, STMN2 orchestrates MT disassembly to facilitate EMT via TGF-β signaling, providing a novel insight into the mechanisms underlying cancer metastasis. STMN2 is a promising prognostic biomarker and potential therapeutic target for HCC.
转移仍然是提高肝细胞癌 (HCC) 患者生存率的主要障碍。上皮-间充质转化 (EMT) 对癌症转移至关重要。EMT 的成功诱导需要剧烈的细胞骨架重排。然而，细胞骨架的核心成分之一微管 (MT) 在这个过程中的意义在很大程度上仍不清楚。在这里，我们揭示了 STMN2，一种重要的 MT 动力学调节剂，在正常活组织中几乎不表达，但在 HCC 中明显上调，尤其是在早期复发的 HCC 中。高 STMN2 表达与侵袭性临床病理特征相关，并预测 HCC 患者的预后不良。HCC 细胞中 STMN2 的过表达促进 EMT、体外和体内侵袭和转移，而 STMN2 的敲低则有相反的结果。在机制上，STMN2 调节 MT 的解聚，破坏 MT-Smad 复合物，并促进 Smad2/3 从 MT 网络中释放、磷酸化和核转位，即使在没有 TGFβ 刺激的情况下也是如此，从而增强 TGFβ 信号。总之，STMN2 通过 TGF-β 信号协调 MT 解聚以促进 EMT，为癌症转移的机制提供了新的见解。STMN2 是 HCC 的有前途的预后生物标志物和潜在治疗靶点。
