MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma
机构：[1]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China[2]School of Public Health, University of South China, Hengyang, China[3]Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China[4]Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou MedicalUniversity, Guangzhou, China[5]Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China中山大学附属第三医院[6]Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China广东省人民医院[7]The People's Hospital of Gaozhou, Gaozhou, China[8]Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital, Shenzhen, Guangdong, China深圳市康宁医院深圳医学信息中心
Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR-2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR-2110 can be regulated by cinobufotalin (CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT-PCR, and in situ hybridization were used to observe the expression of miR-2110 in NPC tissues and cells. Scratch, Boyden, and tail vein metastasis model of nude mouse were used to detect the effect of miR-2110 on NPC metastasis. Western blot, Co-IP, luciferase activity, colocalization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR-2110 affecting NPC metastasis. Finally, miR-2110 induced by CB participates in CB-stimulated inhibition of NPC metastasis was explored. The data showed that increased miR-2110 significantly suppresses NPC cell migration, invasion, and metastasis. Suppressing miR-2110 markedly restored NPC cell migration and invasion. Mechanistically, miR-2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4-induced phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT-stimulated epithelial-mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, CB, a potential new inhibitory drug for NPC metastasis, significantly induced miR-2110 expression by suppressing PI3K/AKT/c-Jun-mediated transcription inhibition. Suppression of miR-2110 significantly restored cell migration and invasion in CB-treated NPC cells. Finally, a clinical sample assay indicated that reduced miR-2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival prognosis. In summary, miR-2110 is a metastatic suppressor involving in CB-induced suppression of NPC metastasis.
基金：
National Natural Science Foundation of China,
Grant/Award Number: 81872198; Science and
Technology Program of Guangzhou,
Grant/Award Number: 202206010068;
GuangDong Basic and Applied Basic Research
Foundation, Grant/Award Numbers:
2021A151 5012430, 2020A1515110108;Natural Science Foundation of Guangdong
Province, Grant/Award Number:
2019A1515110022; Shenzhen Key Medical
Discipline Construction Fund, Grant/Award
Number: SZXK039; Shenzhen Science and
Technology Plan Projects, Grant/Award
Number: JCYJ20220530154200002
第一作者机构：[1]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China[2]School of Public Health, University of South China, Hengyang, China
共同第一作者：
通讯作者：
通讯机构：[1]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China[4]Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou MedicalUniversity, Guangzhou, China[7]The People's Hospital of Gaozhou, Gaozhou, China[8]Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital, Shenzhen, Guangdong, China[*1]Cancer Center,Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.[*2]Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China[*3]The People's Hospital of Gaozhou, Gaozhou 525200, China
推荐引用方式(GB/T 7714)：
Shiyi Fang,Lanzhu Peng,Mengmin Zhang,et al.MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma[J].ENVIRONMENTAL TOXICOLOGY.2024,doi:10.1002/tox.24197.
APA：
Shiyi Fang,Lanzhu Peng,Mengmin Zhang,Rentao Hou,Xing Deng...&Chao Cheng.(2024).MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma.ENVIRONMENTAL TOXICOLOGY,,
MLA：
Shiyi Fang,et al."MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma".ENVIRONMENTAL TOXICOLOGY .(2024)
