TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals

Abstract

While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3' UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis.

Vasculogenic mimicry in carcinogenesis and clinical applications

“…There are several potential mechanisms of VM formation, such as epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) [22,23], and various signaling pathways that promote VM formation, including vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular receptor A2 (EphA2), phosphatidyl inositol 3-kinase (PI3K), matrix metalloproteinases (MMPs), vascular endothelial growth factor receptor (VEGFR1), cyclic adenosine monophosphate (cAMP), focal adhesion kinase (FAK), and hypoxia inducible factor (HIF)-1a [24,25]. Moreover, noncoding RNAs such as lncRNAs and miRNAs play critical roles in VM formation in malignant tumors [16,[26][27][28]. In this review, we provide new insights into the complexity of vasculogenic mimicry and summarize the latest findings of VM formation in malignant tumors.…”

Testicular Orphan Receptor 4 (TR4) Promotes Papillary Thyroid Cancer Invasion via Activating Circ-FNLA/miR-149-5p/MMP9 Signaling

“…The tumor promoting role of TR4 has been documented in various cancers [9][10][11][12][13], promoting scientists to identify TR4 inhibitor for better treatment of cancers. Therefore, it is of importance and interest to develop small molecules which can speci cally inhibit TR4 activity.…”

“…As a transcription factor, activated TR4 is translocated to the nucleus where it binds its recognized DNA element and regulates a bundle of genes. Now increasing evidence suggest that TR4 may also contribute to cancer development [9][10][11][12][13]. For instance, TR4 played a tumor promoting role in RCC by promoting vasculogenic mimicry formation and tumor metastasis [9].…”

“…Now increasing evidence suggest that TR4 may also contribute to cancer development [9][10][11][12][13]. For instance, TR4 played a tumor promoting role in RCC by promoting vasculogenic mimicry formation and tumor metastasis [9]. Mechanistically, TR4 could increase the expression level of vimentin via downregulating its associated miRNA, miR490-3p.…”

Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM)viaaltering TWIST1 nonsense-mediated decay through lncRNA-TANAR

“…Due to its ability to circulate blood from vessels to tumor tissues and to facilitate tumor cells into the extracellular matrix, VM plays a significant role in boosting tumor growth as well as promoting metastasis, which contributes to poor prognosis and aggressiveness in many cancers (11)(12)(13)(14)(15)(16). On the other hand, as an alternative nutrient supplement, VM complements the cancer vasculature theory and provides a mechanistic alternative for the inherently or acquired resistance to anti-angiogenesis therapy (18).…”