Abstract

NEAT1 (nuclear paraspeckle assembly transcript 1) is an oncogenic long non-coding RNA (lncRNA) that facilitates tumorigenesis in multiple cancers. In papillary thyroid cancer (PTC), the molecular mechanism by which NEAT1 affects invasion and metastasis remains elusive. RNA sequencing was used to discover differentially expressed NEAT1_2 downstream genes. Protein and RNA expression analyses and immunohistochemistry detected the expression of NEAT1_2, Transglutaminase 2 (TGM2), and microRNA-491 (miR-491) among PTC and non-cancerous tissues. Transwell and wound healing assays, and a mouse model of lung metastasis were used for further functional analyses. Bioinformatics was performed to predict miRNAs binding to both NEAT1_2 and TGM2. Rescue experiments and dual-luciferase reporter assays were performed. In PTC tissues, NEAT1_2 expression was markedly increased and regulated TGM2 expression. TGM2 was overexpressed in PTC, correlating positively with exthyroidal extension and lymph node metastasis. TGM2 knockdown significantly inhibited invasion and metastasis. NEAT1_2 sponged miR-491, acting as a competing endogenous RNA to regulate TGM2 expression. Fibronectin 1 (FN1) was predicted as a TGM2 target. TGM2 could transcriptionally activate FN1 by promoting nuclear factor kappa B (NFκb) p65 nuclear translocation, ultimately promoting PTC invasion/metastasis. These findings identify that NEAT1_2 sponges miR-491 to regulate TGM2 expression. TGM2 activates FN1 via NFκb to promote PTC invasion and metastasis.

Highlights

  • Among endocrine malignancies, thyroid cancer is the most common, representing almost 5% of new cancer cases and its incidence has increased rapidly worldwide over the past 20 years [1]

  • Eighty pairs of papillary thyroid cancer (PTC) tissues and adjacent non-cancerous was used in quantitative real-time reverse transcription PCR, 92 pairs were used for immunohistochemistry, and 12 pairs was used for western blotting

  • Among the downregulated mRNAs, Transglutaminase 2 (TGM2) was identified as a downstream target, which was downregulated by 66.67% in the NEAT1_2 knockdown group compared with that in the negative control (NC) group (p < 0.01) (Figures 1B, C)

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Summary

Introduction

Thyroid cancer is the most common, representing almost 5% of new cancer cases and its incidence has increased rapidly worldwide over the past 20 years [1]. Papillary thyroid carcinoma (PTC) accounting for 80 to 90% [2]. Despite improvement in detection and surgical management, including surgical resection, radiotherapy, and levothyroxine treatment, among patients with aggressive PTC, 30% will suffer from recurrence and distant metastasis, which can cause death [3, 4]. According to American Joint Committee on Cancer 8th stage for differentiated thyroid cancer, local invasion and distant metastasis are critical factors that affect the prognosis of thyroid cancer [5].

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