Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, China; Biliary Disease Research Institute of Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China; Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2024 Jun 28;592:216923. doi: 10.1016/j.canlet.2024.216923. Epub 2024 May 1.
Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.
胆囊癌（GBC）患者常发生肝转移，这给临床管理带来了巨大挑战，并成为预后不良的指标。然而，肝转移的机制在很大程度上仍不清楚。在这里，我们报道了酪氨酸转氨酶（TAT）在 GBC 肝转移中的关键作用。TAT 在 GBC 组织中频繁上调。TAT 表达增加与 GBC 患者频繁发生肝转移和预后不良相关。TAT 的过表达促进 GBC 细胞在体外的迁移和侵袭，以及体内的肝转移。TAT 敲低则具有相反的效果。有趣的是，TAT 通过增强依赖心磷脂的线粒体自噬促进 GBC 的肝转移。在机制上，TAT 直接结合心磷脂，导致心磷脂外化和随后的线粒体自噬。此外，E3 泛素连接酶 TRIM21 与 TAT 相互作用。TRIM21 的组氨酸残基 336 和 338 对于这种结合是必需的。TRIM21 主要在心磷脂上的 K136 位置优先添加赖氨酸 63（K63）连接的泛素链到 TAT 上。TRIM21 介导的 TAT 泛素化会损害其二聚化和线粒体定位，从而抑制 GBC 细胞的侵袭和迁移。因此，我们的研究确定 TAT 是 GBC 肝转移的新驱动因素，强调了其作为治疗靶点的潜力。
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