A circular RNA from APC inhibits the proliferation of diffuse large B-cell lymphoma by inactivating Wnt/β-catenin signaling via interacting with TET1 and miR-888.

Yanping Hu,Yixun Zhao,Chao Shi,Bing Wei,Pengfei Ren,Yongjun Guo,Jie Ma

doi:10.18632/aging.102122

Abstract

Circular RNA (circRNA), a type of non-coding RNA, can promote or suppress tumorigenesis. To investigate the involvement of circRNA in diffuse large B-cell lymphoma (DLBCL), we performed a circRNA microarray analysis on paired DLBCL and normal tissues. We identified a novel and highly stable circRNA originating from the back-splicing of APC exon 7 to exon 14, circ-APC (hsa_circ_0127621), which was downregulated in DLBCL tissues, cell lines and plasma. In gain-of-function experiments, ectopic expression of circ-APC inhibited DLBCL cell proliferation in vitro and tumor growth in vivo. Cytoplasmic circ-APC functioned as a sponge for miR-888, thus post-transcriptionally upregulating APC by alleviating the repressive effects of miR-888 on this gene. Further, nuclear circ-APC bound to the APC promoter and recruited the DNA demethylase TET1, thereby transcriptionally upregulating APC. Upon its upregulation, APC dampened the canonical Wnt/β-catenin signaling pathway by reducing the accumulation of β-catenin in the nucleus, thereby retarding DLBCL growth. Clinically, circ-APC was found to be an effective diagnostic and prognostic biomarker for patients with DLBCL. Our study suggests that circ-APC is a novel proliferation inhibitor, and that restoring circ-APC expression may be a promising therapeutic approach for DLBCL patients.

Highlights

Diffuse large B-cell lymphoma (DLBCL), a highly aggressive and heterogeneous type of malignant tumor, is the most common form of non-Hodgkin lymphoma, accounting for almost one-third of all cases [1]
A quantitative real-time Polymerase chain reaction (PCR) analysis demonstrated that circ-APC was significantly downregulated in DLBCL tissues compared with adjacent normal tissues, consistent with the findings of the Circular RNA (circRNA) microarray (Figure 1B)
Numerous studies have linked circRNA to cancer initiation, development and progression [17]; to the best of our knowledge, this is the first study to explore the characteristics of circRNA in DLBCL

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL), a highly aggressive and heterogeneous type of malignant tumor, is the most common form of non-Hodgkin lymphoma, accounting for almost one-third of all cases [1]. Circular RNA (circRNA) is a novel type of non-coding RNA having no 5′ cap or 3′ poly-A tail, but having a covalently closed loop structure generated by head-totail splicing. Due to this structure, circRNA is resistant to exonucleases and is more stable than linear noncoding RNAs such as microRNA (miRNA) and long non-coding RNA [4]. A circRNA may function as an oncogene or a tumor suppressor, altering tumor proliferation, migration, invasion, angiogenesis and so on It is still unknown whether circRNA participates in the malignancy of DLBCL

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Results

Conclusion