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

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.

Profiling and bioinformatics analyses reveal differential circular RNA expression in NK/T-cell lymphoma-associated hemophagocytic syndrome

“…This indicates that circ-APC is a new type of proliferation inhibitor. Restoring Circ-APC expression may be a promising treatment for patients with DLBCL [ 41 ]. Deng et al showed that circ-LAMP1 was overexpressed in T-cell lymphoblastic lymphoma (T-LBL) tissues and cell lines and modulated cell growth and apoptosis by regulating the miR-615-5p/DDR2 pathway in T-LBL.…”

Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics

“…Circ-APC was significantly downregulated in DLBCL (Hu et al, 2019). In cytoplasm circ-APC sponges miR-888 leading to an increase in levels of its target APC, whereas in nucleus it binds to APC promoter and recruits the DNA demethylase TET1 to transcriptionally upregulate APC (Hu et al, 2019).…”

“…Circ-APC (circ_0127621) was downregulated in diffuse large B-cell lymphoma (DLBCL) and its levels in plasma can distinguish patients from healthy controls (Hu et al, 2019). Moreover, DLBCL patients with lower circ-APC levels were more likely to exhibit an advanced Ann Arbor stage, shorter OS, resist chemotherapy and display a low International Prognostic Index (Hu et al, 2019).…”

“…In cytoplasm circ-APC sponges miR-888 leading to an increase in levels of its target APC, whereas in nucleus it binds to APC promoter and recruits the DNA demethylase TET1 to transcriptionally upregulate APC (Hu et al, 2019). Ectopically expressed circ-APC acts as a tumor-suppressor and acts by inhibiting Wnt/β-catenin signaling in DLBCL (Hu et al, 2019).…”

PCAT6 mediates cellular biological functions in gastrointestinal stromal tumor via upregulation of PRDX5 and activation of Wnt pathway

“…Circular RNA APC is a proliferation inhibitor in diffuse large B-cell lymphoma via inactivation of Wnt/β-catenin signaling through acting as a ceRNA of miR-888. 15 Also, multiple reports have indicated the importance of Wnt/β-catenin pathway in GIST. As an example, Wnt/β-catenin signaling accelerates cell cycle activity and enhances aggressiveness in GIST through collaborating with ETS variant transcription factor 4 (ETV4).…”