机构：[1]Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China[2]Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China[3]Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China临床科室耳鼻咽喉-头颈外科首都医科大学附属北京同仁医院首都医科大学附属同仁医院[4]Key Laboratory of Otolaryngology Head and Neck Surgery (Ministry of Education of China), Beijing Institute of Otolaryngology, Beijing, China研究所耳鼻咽喉科研究所首都医科大学附属北京同仁医院首都医科大学附属同仁医院[5]Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, Guangdong, China深圳市龙岗区耳鼻咽喉医院深圳医学信息中心
BackgroundPoorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear.Methods and materialsIn this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V).ResultsThe overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V.ConclusionCollectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.
基金：
National Natural
Science Foundation of China (n. 81972493) and the Research Grants
Council of the Hong Kong Special Administrative Region CUHK
14108921.
第一作者机构：[1]Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China[2]Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
通讯作者：
通讯机构：[1]Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China[2]Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
推荐引用方式(GB/T 7714)：
Gong Z.,Xue L.,Vlantis A. C.,et al.Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2[J].JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION.2024,47(5):1271-1280.doi:10.1007/s40618-023-02248-4.
APA：
Gong, Z.,Xue, L.,Vlantis, A. C.,van Hasselt, C. A.,Chan, J. Y. K....&Chen, G. G..(2024).Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION,47,(5)
MLA：
Gong, Z.,et al."Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2".JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION 47..5(2024):1271-1280
