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拮抗Sec62在细胞内钙稳态中的功能代表了一种治疗头颈癌的新策略。

Antagonizing Sec62 function in intracellular Ca homeostasis represents a novel therapeutic strategy for head and neck cancer.

作者信息

Körner Sandrina, Pick Tillman, Bochen Florian, Wemmert Silke, Körbel Christina, Menger Michael D, Cavalié Adolfo, Kühn Jan-Philipp, Schick Bernhard, Linxweiler Maximilian

机构信息

Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany.

Experimental and Clinical Pharmacology and Toxicology, Pre-Clinical Center for Molecular Signalling (PSMZ), Saarland University, Homburg, Germany.

出版信息

Front Physiol. 2022 Aug 15;13:880004. doi: 10.3389/fphys.2022.880004. eCollection 2022.

DOI:10.3389/fphys.2022.880004
PMID:36045752
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9421371/
Abstract

Various cancer types including head and neck squamous cell carcinomas (HNSCC) show a frequent amplification of chromosomal region 3q26 that encodes, among others, for the gene. Located in the ER membrane, this translocation protein is known to play a critical role as a potential driver oncogene in cancer development. High expression levels were observed in various cancer entities and were associated with a poor outcome and increased metastatic burden. Because of its intracellular localization the SEC62 protein is poorly accessible for therapeutic antibodies, therefore a functional knockdown represents the most promising mechanism of a potential antineoplastic targeted therapy. By stimulating the Ca efflux from the ER lumen and thereby increasing cellular stress levels, a functional inhibition of SEC62 bears the potential to limit tumor growth and metastasis formation. In this study, two potential anti-metastatic and -proliferative agents that counteract SEC62 function were investigated in functional assays by utilizing an immortalized human hypopharyngeal cancer cell line as well as a newly established orthotopic murine model. Additionally, a CRISPR/Cas9 based knockout HNSCC cell line was generated and functionally characterized for its relevance in HNSCC cell proliferation and migration as well as sensitivity to SEC62 targeted therapy .

摘要

包括头颈部鳞状细胞癌（HNSCC）在内的多种癌症类型，均显示出染色体区域3q26的频繁扩增，该区域编码多种基因，其中包括 基因。这种易位蛋白位于内质网（ER）膜中，已知作为癌症发展中潜在的驱动癌基因发挥关键作用。在各种癌症实体中均观察到高表达水平，且与不良预后和转移负担增加相关。由于SEC62蛋白的细胞内定位，治疗性抗体难以作用于它，因此功能性敲低是潜在抗肿瘤靶向治疗最有前景的机制。通过刺激内质网腔中的钙离子外流，从而增加细胞应激水平，对SEC62的功能性抑制具有限制肿瘤生长和转移形成的潜力。在本研究中，利用永生化的人类下咽癌细胞系以及新建立的原位小鼠模型，在功能试验中研究了两种对抗SEC62功能的潜在抗转移和抗增殖剂。此外，还构建了基于CRISPR/Cas9的SEC62基因敲除HNSCC细胞系，并对其在HNSCC细胞增殖、迁移中的相关性以及对SEC62靶向治疗的敏感性进行了功能表征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/75d635a51042/fphys-13-880004-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/a2b7dab43a5e/fphys-13-880004-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/08c82a5e4e62/fphys-13-880004-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/19dbbd75990c/fphys-13-880004-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/18c146fea8b8/fphys-13-880004-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/589daddc458e/fphys-13-880004-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/6f2e3e4c2db1/fphys-13-880004-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/75d635a51042/fphys-13-880004-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/a2b7dab43a5e/fphys-13-880004-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/08c82a5e4e62/fphys-13-880004-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/19dbbd75990c/fphys-13-880004-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/18c146fea8b8/fphys-13-880004-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/589daddc458e/fphys-13-880004-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/6f2e3e4c2db1/fphys-13-880004-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc16/9421371/75d635a51042/fphys-13-880004-g007.jpg

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