Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c‐SRC, which are tumor‐promoting genes. The FAXC/ANXA2/c‐SRC complex forms in the mitochondria. FAXC enhances SRC‐dependent ANXA2 phosphorylation at tyrosine‐24, and the C‐terminal amino acid residues (351–375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial–mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.

中文翻译：

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FAXC 与线粒体中的 ANXA2 和 SRC 相互作用并促进胆管癌的肿瘤发生

胆管癌（CCA）是最难治疗的恶性肿瘤之一，因为治疗选择有限。尽管已经确定了一些驱动基因，但大多数仍然未知。在这项研究中，我们确定了一个轴突连接同系物失败（传真通讯），其功能在哺乳动物中是未知的，通过分析连续传代的CCA异种移植模型。击倒传真通讯降低小鼠皮下致瘤性。FAXC 与膜联蛋白 A2 (ANXA2) 和 c-SRC 结合，它们是肿瘤促进基因。FAXC/ANXA2/c-SRC 复合物在线粒体中形成。FAXC 增强 SRC 依赖性 ANXA2 在酪氨酸 24 处的磷酸化，FAXC 的 C 端氨基酸残基 (351-375) 是 ANXA2 磷酸化所必需的。来自异种移植 CCA 细胞系的转录组数据表明传真通讯与上皮-间质转化、缺氧和 KRAS 信号基因相关。总的来说，这些发现增进了我们对 CCA 肿瘤发生的理解并提供了候选治疗靶点。