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下调神经酰胺合酶 1 通过内质网应激促进口腔癌。

Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.

机构信息

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Department of Oral and Maxillofacial-Head and Neck Oncology, Capital Medical University School of Stomatology, Beijing, China.

出版信息

Int J Oral Sci. 2021 Mar 22;13(1):10. doi: 10.1038/s41368-021-00118-4.

DOI:10.1038/s41368-021-00118-4
PMID:33753723
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7985500/
Abstract

C18 ceramide plays an important role in the occurrence and development of oral squamous cell carcinoma. However, the function of ceramide synthase 1, a key enzyme in C18 ceramide synthesis, in oral squamous cell carcinoma is still unclear. The aim of our study was to investigate the relationship between ceramide synthase 1 and oral cancer. In this study, we found that the expression of ceramide synthase 1 was downregulated in oral cancer tissues and cell lines. In a mouse oral squamous cell carcinoma model induced by 4-nitroquinolin-1-oxide, ceramide synthase 1 knockout was associated with the severity of oral malignant transformation. Immunohistochemical studies showed significant upregulation of PCNA, MMP2, MMP9, and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area. In addition, ceramide synthase 1 knockdown promoted cell proliferation, migration, and invasion in vitro. Overexpression of CERS1 obtained the opposite effect. Ceramide synthase 1 knockdown caused endoplasmic reticulum stress and induced the VEGFA upregulation. Activating transcription factor 4 is responsible for ceramide synthase 1 knockdown caused VEGFA transcriptional upregulation. In addition, mild endoplasmic reticulum stress caused by ceramide synthase 1 knockdown could induce cisplatin resistance. Taken together, our study suggests that ceramide synthase 1 is downregulated in oral cancer and promotes the aggressiveness of oral squamous cell carcinoma and chemotherapeutic drug resistance.

摘要

C18 神经酰胺在口腔鳞状细胞癌的发生和发展中起着重要作用。然而，C18 神经酰胺合成的关键酶——神经酰胺合酶 1 在口腔鳞状细胞癌中的作用尚不清楚。本研究旨在探讨神经酰胺合酶 1与口腔癌的关系。在本研究中，我们发现神经酰胺合酶 1在口腔癌组织和细胞系中的表达下调。在由 4-硝基喹啉-1-氧化物诱导的小鼠口腔鳞状细胞癌模型中，神经酰胺合酶 1 敲除与口腔恶性转化的严重程度相关。免疫组织化学研究显示，在病理性增生区域，PCNA、MMP2、MMP9 和 BCL2 的表达显著上调，BAX 的表达下调。此外，神经酰胺合酶 1 敲低在体外促进细胞增殖、迁移和侵袭。CERS1 的过表达获得了相反的效果。神经酰胺合酶 1 敲低导致内质网应激，并诱导 VEGFA 的上调。激活转录因子 4 负责神经酰胺合酶 1 敲低引起的 VEGFA 转录上调。此外，神经酰胺合酶 1 敲低引起的轻度内质网应激可诱导顺铂耐药。综上所述，本研究表明神经酰胺合酶 1在口腔癌中下调，促进口腔鳞状细胞癌的侵袭性和化疗药物耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e11e/7985500/91dc9330a0ae/41368_2021_118_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e11e/7985500/bb7921155099/41368_2021_118_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e11e/7985500/a03d5c28563d/41368_2021_118_Fig2_HTML.jpg
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