A Feedback Loop Involving Exosomal miR-146a and NG2 to Propel the Development and Progression of Hypothyroidism

Sui，Fang1,2; Chen，Pu1; Feng，Chao1; Yang，Qi1; Zhang，Shaoqiang2; Ji，Meiju3; Wang，Yinan4; Guan，Haixia5; Xing，Mingzhao6; Hou，Peng1

2023

10.1089/thy.2022.0676

Thyroid   Impact Factor & Quartile

1050-7256

1557-9077

Background: Thyrotropin receptor (TSHR) plays a central role in maintaining thyroid function and TSHR impairment causes hypothyroidism, which is often associated with metabolic disarrangement. The most common type of hypothyroidism is autoimmune disease-related and the mechanism, particularly with respect to the role of microRNAs (miRNAs), has not been delineated. Methods: Serum from 30 patients with subclinical hypothyroidism (SCH) and 30 healthy individuals were collected and exosomal miR-146a (exo-miR-146a) was examined, followed by extensive mechanistic investigation using various molecular and cellular experimental approaches and genetic-knockout mouse models. Results: Our clinical investigation showed that exo-miR-146a was systemically elevated in the serum of patients with SCH (p = 0.04) compared with healthy individuals, prompting us to investigate the biological effects of miR-146a in cells. We found that miR-146a could target and down-regulate neuron-glial antigen 2 (Ng2), with consequent down-regulation of TSHR. We next generated a thyroid-specific Ng2 knockout (Thy-Ng2) mouse model and found a significant down-regulation of TSHR in Thy-Ng2 mice, accompanied by the development of hypothyroidism and metabolic disorders. We further found that a decrease in NG2 resulted in decreased receptor tyrosine kinase-linked downstream signaling and down-regulation of c-Myc, consequently resulting in up-regulation of miR-142 and miR-146a in thyroid cells. Up-regulated miR-142 targeted the 3′-untranslated region (UTR) of TSHR messenger RNA (mRNA) and post-transcriptionally down-regulated TSHR, explaining the development of hypothyroidism above. Local up-regulation of miR-146a in thyroid cells augments the earlier cited processes initiated by systemically elevated miR-146a, thereby forming a feedback loop to propel the development and progression of hypothyroidism. Conclusions: This study has uncovered a self-augmenting molecular loop initiated by elevated exo-miR-146a to suppress TSHR through targeting and down-regulating NG2, thereby initiating and propelling the development and progression of hypothyroidism.

exosomal miR-146a (exo-miR-146a) hypothyroidism miR-142 NG2 TSH receptor (TSHR)

SCI

English

Corresponding

Endocrinology & Metabolism

Endocrinology & Metabolism

WOS:001048335700001

MARY ANN LIEBERT, INC

BIOLOGY & BIOCHEMISTRY

2-s2.0-85168737268

Scopus

1.Department of Endocrinology,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,China
2.Department of Otorhinolaryngology-Head and Neck Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,China
3.Center for Translational Medicine,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,China
4.Department of Obstetrics and Gynecology,Peking University Shenzhen Hospital,Shenzhen,China
5.Department of Endocrinology,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,China
6.Thyroid Research Institute,School of Medicine,Southern University of Science and Technology,Shenzhen,China

Sui，Fang,Chen，Pu,Feng，Chao,et al. A Feedback Loop Involving Exosomal miR-146a and NG2 to Propel the Development and Progression of Hypothyroidism[J]. Thyroid,2023,33(9).

Sui，Fang.,Chen，Pu.,Feng，Chao.,Yang，Qi.,Zhang，Shaoqiang.,...&Hou，Peng.(2023).A Feedback Loop Involving Exosomal miR-146a and NG2 to Propel the Development and Progression of Hypothyroidism.Thyroid,33(9).

Sui，Fang,et al."A Feedback Loop Involving Exosomal miR-146a and NG2 to Propel the Development and Progression of Hypothyroidism".Thyroid 33.9(2023).