Knockdown of circ_NEK6 Decreased ¹³¹I Resistance of Differentiated Thyroid Carcinoma via Regulating miR-370-3p/MYH9 Axis

Abstract

Radioresistance is a crucial factor for the failure of iodine 131 (131I)-based radiotherapy for differentiated thyroid carcinoma (DTC). This study aimed to explore the effect of circ_NEK6 on the development of 131I resistance in DTC and its potential mechanism. In this study, we demonstrated that circ_NEK6 expression was significantly elevated in 131I-resistant DTC tissues and cell lines. Knockdown of circ_NEK6 significantly repressed 131I resistance via inhibiting cell proliferation, migration, invasion abilities, and inducing cell apoptosis and DNA damage in 131I-resistant DTC cells. Mechanistically, knockdown of circ_NEK6 suppressed 131I resistance in DTC by upregulating the inhibitory effect of miR-370-3p on the expression of myosin heavy chain 9 (MYH9). In vivo experiments showed that circ_NEK6 inhibition aggravated 131I radiation-induced inhibition of xenograft tumor growth. Taken together, knockdown of circ_NEK6 repressed 131I resistance in DTC cells by regulating the miR-370-3p/MYH9 axis, indicating that circ_NEK6 may act as a potential biomarker and therapeutic target for DTC patients with 131I resistance.

Recent findings on miR‑370 expression, regulation and functions in cancer (Review)

“…Myosin heavy chain 9 (MYH9) serves as an oncogene in multiple types of cancer, and MYH9 inhibition markedly inhibits the malignant phenotypes and chemoresistance of cancer cells (76). Notably, miR-370-3p can inhibit cell proliferation and induce cell apoptosis by decreasing MYH9 in 131I-resistant differentiated thyroid carcinoma cells (77).…”

“…In OSCC, miR-370 can regulate IRS-1 expression and restrain the tumor phenotype (28). In thyroid cancer, miR-370-3p has been shown to suppress cell migration and invasion by targeting FZD8 (30), LMO4 (75) and MYH9 (77). In addition, miR-370-3p suppresses NSCLC cell migration and invasion through regulating TRIM44 (81) and p21 (17).…”

“…Furthermore, miR-370 enhances the radiosensitivity of NSCLC cells by downregulating EGFR and hypoxia-inducible factor 1α (107). miR-370-3p inhibits 131I resistance in thyroid cancer cells through downregulating MYH9 expression (77). Furthermore, it has been reported that miR-370-3p facilitates the therapeutic effect of anti-PD-1 treatment in melanoma through downregulating the CXCL12 (95).…”

“…In thyroid carcinoma, circNEK6 (30,77), circ_0058124 (75), and circUBAP2 (23) have been identified to regulate miR-370 expression via direct sponging and ultimately promote cancer progression by modulating the expression of targets of miR-370. Furthermore, circFBXW8 promotes NSCLC progression by elevating TRIM44, through acting as a sponge of miR-370-3p (81).…”

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

“…Downregulation of miR-370-3p activates the Wnt signaling pathway [ 193 ], which plays a critical role in regulating cell fate [ 194 ]. Knockdown of Nek6 circRNA has been observed to cause inhibition of the expression of myosin heavy chain 9 (MYH9), allowing differentiated thyroid cancers to become more susceptible to iodine 121-based radiotherapy [ 195 ]. circNek6 has also been discovered to be overexpressed in non-small-cell lung cancer and is believed to sequester miR-832-5p, preventing its regulation of Breast Carcinoma Amplified Sequence 2 [ 196 ].…”