Circular RNA circZFR contributes to papillary thyroid cancer cell proliferation and invasion by sponging miR-1261 and facilitating C8orf4 expression

Abstract

In recent years, more and more circular RNAs (circRNAs) have been identified in multiple tissues and cells. Increasing evidences show circRNAs play important roles in human cancers. However, the role of circRNAs in papillary thyroid carcinoma (PTC) remains largely unknown. In this study, we identified a new circRNA circZFR that was significantly upregulated in PTC tissues compared to adjacent normal tissues. Furthermore, circZFR expression level was negatively correlated with clinical severity. We found that circZFR knockdown dramatically inhibited the proliferation, migration and invasion of PTC cells in vitro. Mechanistically, we found circZFR could promote C8orf4 expression via serving as a competing endogenous RNA (ceRNA) of miR-1261 in PTC cells. Rescue assays indicated that restoration of C8orf4 significantly attenuated the inhibitory effects of circZFR knockdown on PTC cell proliferation, migration and invasion. In summary, our findings demonstrated that circRNA circZFR exerted oncogenic roles via regulating miR-1261/C8orf4 axis in PTC, which suggested circZFR might be a potential therapeutic target.

Introduction

Thyroid cancer is one of the most frequent cancers in endocrine system and contributes to a large proportion of cancer-related death in the world [1,2]. Notably, the incidence of thyroid cancer is still increasing rapidly [3]. Among all thyroid cancer cases, papillary thyroid cancer (PTC) accounts for over 80% [4]. Although most PTC patients show a good prognosis, about 20% of PTC patients display aggressive behaviors and poor outcomes [5]. Thus, it is very critical to understand the underlying molecular mechanism of PTC progression and develop novel therapeutic targets.

More than 90% of human genomic transcripts are noncoding RNAs (ncRNA), such as long noncoding RNA (lncRNA), microRNAs (miRNAs) and circular RNAs (circRNA) [[6], [7], [8]]. miRNAs and lncRNAs have been widely investigated while the study on circRNA function is just emerging. circRNA is characterized with a covalently closed loop lacking 5′-3′ ends and a poly A tail [9]. More and more studies suggest that circRNAs exert very essential roles and involved in human cancers, such as glioma [8], hepatocellular carcinoma [10], lung cancer [11], breast cancer [12] and bladder cancer [13]. CircRNAs could regulate cancer cell proliferation, migration, invasion and survival to participate in tumor progression. For example, circHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7 [14]. circMAN2B2 facilitates lung cancer cell proliferation and invasion via miR-1275/FOXK1 axis [15]. Although several cancer-related circRNAs have been identified, the function of circRNAs in PTC has not been reported until now.

In the present study, we identified a new circRNA circZFR (circBase ID: hsa_circ_0072088) located at chromosome 5p13.3. circZFR was highly expressed in PTC tissues compared to adjacent normal tissues. The expression level of circZFR was positively correlated with clinical severity. We also showed circZFR promoted the proliferation, migration and invasion of PTC cells via upregulating C8orf4 by sponging miR-1261, which suggested the circZFR/miR-1261/C8orf4 axis might be a therapeutic target.