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NUF2 通过抑制 TFR1 的自噬降解来驱动胆管癌的进展和迁移。

NUF2 Drives Cholangiocarcinoma Progression and Migration via Inhibiting Autophagic Degradation of TFR1.

机构信息

Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University.

出版信息

Int J Biol Sci. 2023 Feb 21;19(5):1336-1351. doi: 10.7150/ijbs.80737. eCollection 2023.

DOI:10.7150/ijbs.80737
PMID:37056930
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10086752/
Abstract

Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy and associated with poor prognosis. Lack of therapeutic methods for CCA and insensitivity of targeted therapy and immunotherapy make its treatment challenging. NUF2, a component of Ndc80 kinetochore complex, is implicated in the initiation and development of multiple cancers. However, the role and mechanism of NUF2 in CCA is still unclear. In this research, we investigated the biological processes and underlying mechanisms of NUF2 in CCA. We discovered that the expression of NUF2 was upregulated in CCA and negatively correlated with prognosis. Changes in NUF2 levels had an impact on cell proliferation and migration. Moreover, NUF2 functioned as an oncogene to promote the progression of CCA through p38/MAPK signaling by inhibiting p62 binding of TFR1 and affecting its autophagic degradation. In addition, TFR1 promoted CCA progression and Kaplan-Meier analyses uncovered patients with high expression of TFR1 was associated with the poor survival. In conclusion, our study demonstrated that NUF2 promoted CCA progression by regulating TFR1 protein degradation, and the NUF2/TFR1/MAPK axis could be an excellent therapeutic target for CCA.

摘要

胆管癌（CCA）是第二常见的原发性肝恶性肿瘤，预后不良。缺乏针对 CCA 的治疗方法以及靶向治疗和免疫治疗的不敏感使得其治疗具有挑战性。NUF2 是 Ndc80 动粒复合物的一个组成部分，与多种癌症的发生和发展有关。然而，NUF2 在 CCA 中的作用和机制尚不清楚。在这项研究中，我们研究了 NUF2 在 CCA 中的生物学过程和潜在机制。我们发现，NUF2 在 CCA 中表达上调，与预后呈负相关。NUF2 水平的变化对细胞增殖和迁移有影响。此外，NUF2 通过抑制 TFR1 与 p62 的结合并影响其自噬降解，作为癌基因通过 p38/MAPK 信号通路促进 CCA 的进展。此外，TFR1 促进了 CCA 的进展，Kaplan-Meier 分析发现 TFR1 高表达的患者与生存率降低有关。总之，我们的研究表明，NUF2 通过调节 TFR1 蛋白降解促进 CCA 的进展，NUF2/TFR1/MAPK 轴可能是 CCA 的一个极好的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cbe/10086752/36d484e371c9/ijbsv19p1336g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cbe/10086752/36d484e371c9/ijbsv19p1336g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cbe/10086752/36d484e371c9/ijbsv19p1336g009.jpg

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