Section of Pathology, Department of Morphological Biology, Division of Biomedical Sciences, Fukuoka Dental College, Fukuoka, Japan.
Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, Japan.
Lab Invest. 2021 Jan;101(1):38-50. doi: 10.1038/s41374-020-00486-1. Epub 2020 Sep 8.
Epidermal growth factor receptor (EGFR) is highly expressed in several types of cancer cells including oral squamous cell carcinoma (OSCC). EGF/EGFR signaling is recognized as an important molecular target in cancer therapy. However, cancer cells often become tolerant to EGF/EGFR signaling-targeted therapies. In the tumor microenvironment, the tumor incites inflammation and the inflammation-derived cytokines make a considerable impact on cancer development. In addition, hyperosmolarity is also induced, but the role of osmotic stress in cancer development has not been fully understood. This study demonstrates molecular insights into hyperosmolarity effect on OSCC development and shows that NFAT5 transcription factor plays an important functional role in enhancing the oral cancer cell proliferation by inducing the EGFR translocation from the endoplasmic reticulum to the plasma membrane through increase the expression of DPAGT1, an essential enzyme for catalyzing the first committed step of N-linked protein glycosylation. These results suggest that hyperosmolarity-induced intra-nuclear translocation of NFAT5 essential for DPAGT1 activation and EGFR subcellular translocation responsible for OSCC tumor progression.
表皮生长因子受体 (EGFR) 在包括口腔鳞状细胞癌 (OSCC) 在内的几种癌细胞中高度表达。EGF/EGFR 信号被认为是癌症治疗的重要分子靶点。然而，癌细胞通常对 EGF/EGFR 信号靶向治疗产生耐受性。在肿瘤微环境中，肿瘤引发炎症，炎症衍生的细胞因子对癌症的发展产生重大影响。此外，还会引起高渗胁迫，但渗透压胁迫在癌症发展中的作用尚未完全了解。本研究深入了解了高渗胁迫对 OSCC 发展的影响，并表明 NFAT5 转录因子通过增加 DPAGT1 的表达，在促进口腔癌细胞增殖方面发挥重要功能作用，DPAGT1 是催化 N-连接蛋白糖基化第一步的必需酶。这些结果表明，NFAT5 的核内易位对于 DPAGT1 的激活以及 EGFR 的亚细胞易位是必需的，这负责 OSCC 肿瘤的进展。
