TY - JOUR
T1 - Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression
AU - Shi, Hangchuan
AU - Sun, Yin
AU - He, Miao
AU - Yang, Xiong
AU - Hamada, Michiaki
AU - Fukunaga, Tsukasa
AU - Zhang, Xiaoping
AU - Chang, Chawnshang
N1 - Funding Information:
Acknowledgements We thank Karen Wolf for help with manuscript preparation. This work was supported by NIH grant (CA156700), George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002) to China Medical University, Taichung, Taiwan). Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/1/16
Y1 - 2020/1/16
N2 - Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.
AB - Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.
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U2 - 10.1038/s41388-019-0962-8
DO - 10.1038/s41388-019-0962-8
M3 - Article
C2 - 31501521
AN - SCOPUS:85072013778
SN - 0950-9232
VL - 39
SP - 530
EP - 545
JO - Oncogene
JF - Oncogene
IS - 3
ER -
