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

Abstract

Background: The incidence and mortality of papillary thyroid cancer (PTC) have steadily increased. Although conventional therapies are very effective towards differentiated PTC patients, very limited therapeutic options are applicable to those patients with distant metastases. Therefore, better understanding of the molecular biology of metastatic PTC helps identify novel targets and facilitates the development of new therapies.Methods: Western blot assay was used to check relative gene protein expression. Transwell invasion assay was used to check the invasion capacity of the PTC cells. Wound healing assay was conducted to check the migration capacity of the PTC cells. qRT-PCR assay was used to check relative RNA expression of the cells. IHC assay was used to check TR4 and MMP9 expression in clinical samples or mouse tumor samples. Results: In this study, we first found that testicular orphan receptor 4 (TR4) was significantly increased in PTC tumors spreading to lymph node compared to the paired primary tumors. Experimental evidence suggested that TR4 drove PTC progression via promoting its cell invasion and cell migration. Mechanistically, TR4 transcriptionally regulated the expression level of circ-FLNA, which competed with MMP9 for miR-149-5p binding and led to increased protein level of MMP9. Interruption assays with various gene manipulations verified that TR4/circ-FLNA/miR-149-5p/MMP9 signaling axis played central role in cell invasion and cell migration of PTC cells. Moreover, xenografted mouse model also confirmed that TR4/circ-FLNA signal promoted PTC tumor growth.Conclusions: Overall, our study pinpoints the oncogenic role of TR4 in PTC development and targeting TR4/circ-FLNA/miR-149-5p/MMP9 signaling may be an alternative option for metastatic PTC patients.

Hsa_circ_0003602 Contributes to the Progression of Colorectal Cancer by Mediating the miR-149-5p/SLC38A1 Axis

“…As reported, miR-149-5p exerted a pivotal anti-cancer factor in diverse malignancy, such as cervical cancer, 26 gastric cancer 27 and papillary thyroid cancer. 28 Likewise, miR-149-5p expression was lower in CRC, and forced miR-149-5p expression played a suppressive role in CRC progression. 29 In keeping with this study, we confirmed that miR-149-5p abundance was decreased in CRC tissues and cells.…”

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition

“…Eighteen TF binding sites specific to LM7 were identified for TEAD, TR4, MYOG, SOX2, and E2F7, which support mesenchymal gene expression to disrupt ECM and cell-cell adhesions to promote cell migration (Fig. 4B) [74][75][76] . Of note, E2F7, in contrast to E2F6, is an atypical E2F factor that promotes both cell-cycle progression and metastasis 76 .…”

Mechanism of Hepatocellular Carcinoma Exosome-Derived Circular RNA Circ_0001649 in Regulating Release of Matrix Metalloproteinase 9 in Fibroblasts and Promoting Metastasis of Hepatocellular Carcinoma

“…MMP9, found in the extracellular matrix, is a protein with type IV collagen degradation properties and contains three fibronectin type II, repeats in its catalytic site, which binds denatured type IV and type V collagen to elastin. Studies have shown that MMP9 expression is associated with the progression of various cancers including HCC, lung cancer, papillary thyroid cancer, adult neuroblastoma and bladder cancer [22][23][24] .…”