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FAXC 在线粒体中与 ANXA2 和 SRC 相互作用，并促进胆管癌的肿瘤发生。

FAXC interacts with ANXA2 and SRC in mitochondria and promotes tumorigenesis in cholangiocarcinoma.

机构信息

Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.

IDAC Fellow Research Group for DNA Repair and Dynamic Proteome Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.

出版信息

Cancer Sci. 2024 Jun;115(6):1896-1909. doi: 10.1111/cas.16140. Epub 2024 Mar 13.

DOI:10.1111/cas.16140
PMID:38480477
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11145136/
Abstract

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.

摘要

胆管癌 (CCA) 是最难治疗的恶性肿瘤之一，因为治疗选择有限。尽管已经确定了几个驱动基因，但大多数仍未知。在这项研究中，我们通过分析连续传代的 CCA 异种移植模型，鉴定出了一个失败的轴突连接同源物 (FAXC)，其在哺乳动物中的功能未知。FAXC 的敲低降低了小鼠的皮下肿瘤生成能力。FAXC 与促进肿瘤的基因 annexin A2 (ANXA2) 和 c-SRC 结合。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，并且 FAXC 的 C 末端氨基酸残基 (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，FAXC 与上皮-间充质转化、缺氧和 KRAS 信号基因相关。总之，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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/00bccb73e2eb/CAS-115-1896-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/00bccb73e2eb/CAS-115-1896-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/5ba682c4d734/CAS-115-1896-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/722651a78877/CAS-115-1896-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/3393e33b6a99/CAS-115-1896-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/a1ff3ba788bf/CAS-115-1896-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bece/11145136/00bccb73e2eb/CAS-115-1896-g001.jpg

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