Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Abstract

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.

Enhanced YB1/EphA2 axis signaling promotes acquired resistance to sunitinib and metastatic potential in renal cell carcinoma

“…Therefore, drug resistance studies have always been a hot spot for oncologists. Our previous results indicated that TR4 nuclear receptor-mediated lncTASR/AXL signaling promoted RCC SUN resistance, and this effect could be reversed by tretinoin [ 28 ]. YB1 transcriptionally regulates the expression of multiple-drug resistance-associated genes to mediate multidrug resistance in a variety of tumors [ 29 ].…”

Androgen receptor decreases renal cell carcinoma bone metastases via suppressing the osteolytic formation through altering a novel circEXOC7 regulatory axis

“…15 Our studies also substantiate early findings that noncoding RNAs play a crucial role in the initiation and progression of multiple cancers. [46][47][48][49][50] Compared to their linear counterparts, the circRNAs are widely and highly expressed in a variety of human cells 51 and are less prone to be degraded by RNA exo-enzymes due to their unique closed-loop structure 52 and may function by regulating the oncogenic or suppressor genes to intervene with tumor progressions. 20,53 Previous studies demonstrated that DHX9 inhibits the synthesis of circRNAs through binding to their flanking inverted complementary sequences and inhibiting the pairing of these sequences.…”

Testicular orphan receptor 4 (TR4) promotes papillary thyroid cancer invasion via activating circ-FNLA/miR-149-5p/MMP9 signaling

“…In addition, a small molecule, tretinoin, was also reported to suppress RCC progression and affect sunitinib sensitivity via directly inhibiting the function of TR4. 21 As fact, the potential anti-cancer role of tretinoin in TC has been recognized many decades ago. It is possible that the anti-cancer effect of tretinoin on TC relies on its inhibition on the function of TR4.…”