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Int J Biol Sci 2022; 18(3):1134-1149. doi:10.7150/ijbs.68091 This issue Cite

Research Paper

TBL1X and Flot2 form a positive feedback loop to promote metastasis in nasopharyngeal carcinoma

Hongjuan Xu^1,2#, Xuejun Yan^1,2#, Hecheng Zhu³, Yuanbo Kang^1,2, Weiren Luo⁴, Jin Zhao^1,2, Kefan Zhou^1,2, Xiwu Liu^1,2, Li Ye^1,2, Quanwei Zhou⁵, Shasha Li^1,2, Ming Zhao³, Lei Wang^1,2, Bin Zhu^1,2, Weidong Liu^1,2, Jianxiong Li^6✉, Xingjun Jiang^5✉, Caiping Ren^1,2✉

1. Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, NHC Key Laboratory of Biological Nanotechnology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
2. NHC Key Laboratory of Carcinogenesis and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medical Science, Central South University, Changsha, Hunan 410008, China.
3. Changsha Kexin Cancer Hospital, Changsha, Hunan 410008, China.
4. Cancer Research Institute, Shenzhen Third People's Hospital, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong 518112, China.
5. Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
6. Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100089, China.
#Equal contributions

✉ Corresponding author: Caiping Ren: rencaipingedu.cn, Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, NHC Key Laboratory of Biological Nanotechnology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Xingjun Jiang: jiangxjedu.cn, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Jianxiong Li: 301301ljxcom, Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100089, China. More

Abstract

Metastasis is the main cause of death in patients with nasopharyngeal carcinoma (NPC). The molecular mechanisms underlying the metastasis of NPC remain to be elucidated. TBL1X has been shown abnormally expressed in diverse cancers. However, the role and mechanism of TBL1X in NPC remain unknown. Here, we showed TBL1X expression was significantly higher in metastatic NPC tissues compared to non-metastatic tissues and significantly correlated with TNM stage and metastasis of NPC patients. In addition, NPC patients with high TBL1X expression had a poor prognosis. TBL1X interacted with TCF4 to trans-activate Flot2 expression. TBL1X promoted NPC cell migration and invasion in vitro and in vivo through Flot2. Moreover, Flot2 increased the expression of TBL1X by upregulating c-myc, which was identified to be a positively regulatory transcription factor of TBL1X. TBL1X could restore the functional changes of NPC cells resulting from Flot2 alteration. TBL1X and Flot2 were positively correlated in NPC. Patients with high expression of both TBL1X and Flot2 possessed poorer overall survival (OS) and disease-free survival (DFS) compared to patients with high expression of any single one of the two proteins. Our findings demonstrate that TBL1X and Flot2 positively regulate each other to promote NPC metastasis, which provides novel potential molecular targets for NPC treatment.

Keywords: Nasopharyngeal carcinoma (NPC), metastasis, prognosis, Transducin β-like protein 1 X (TBL1X), Flotillin-2 (Flot2)

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