Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.
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DOI：
10.1038/s41368-021-00118-4
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发表时间：
2021-03-22
影响因子：
14.9
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Chen W;Wu C;Chen Y;Guo Y;Qiu L;Liu Z;Sun H;Chen S;An Z;Zhang Z;Li Y;Li L
C18神经酰胺在口腔鳞状细胞癌的发生发展中起重要作用。然而，C18神经酰胺合成的关键酶神经酰胺合成酶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成酶1与口腔癌的关系。在本研究中，我们发现神经酰胺合成酶1在口腔癌组织和细胞系中表达下调。在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基因敲除与口腔恶性转化的严重程度相关。免疫组化结果显示，PCNA、MMP 2、MMP 9和BCL 2在病理增生区表达明显上调，而BAX表达明显下调。此外，神经酰胺合成酶1敲低促进细胞增殖，迁移和体外侵袭。CERS 1的过表达获得了相反的效果。神经酰胺合酶1敲低引起内质网应激并诱导VEGFA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，神经酰胺合成酶1基因敲低引起的轻度内质网应激可诱导顺铂耐药。总之，我们的研究表明，神经酰胺合成酶1在口腔癌中下调，并促进口腔鳞状细胞癌的侵袭性和化疗药物耐药性。
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.
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影响因子：
--
作者：
Chan OTM;Furuya H;Pagano I;Shimizu Y;Hokutan K;Dyrskjøt L;Jensen JB;Malmstrom PU;Segersten U;Janku F;Rosser CJ
通讯作者：
Rosser CJ
影响因子：
3.7
作者：
Andersen S;Donnem T;Al-Shibli K;Al-Saad S;Stenvold H;Busund LT;Bremnes RM
通讯作者：
Bremnes RM
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
DOI：
10.1002/hed.24714
发表时间：
2017-05-01
影响因子：
2.9
作者：
Lin, Chin Shien;de Oliveira Santos, Andre Bandiera;Cernea, Claudio Roberto
通讯作者：
Cernea, Claudio Roberto
DOI：
10.1016/j.bbrc.2017.06.190
发表时间：
2018-05-27
影响因子：
3.1
作者：
Edlich, Frank
通讯作者：
Edlich, Frank