MALAT1-dependent hsa_circ_0076611 regulates translation rate in triple-negative breast cancer

Abstract

Vascular Endothelial Growth Factor A (VEGFA) is the most commonly expressed angiogenic growth factor in solid tumors and is generated as multiple isoforms through alternative mRNA splicing. Here, we show that lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) protein, previously referred to as regulators of linear isoforms of VEGFA, induce back-splicing of VEGFA exon 7, producing circular RNA circ_0076611. Circ_0076611 is detectable in triple-negative breast cancer (TNBC) cells and tissues, in exosomes released from TNBC cells and in the serum of breast cancer patients. Circ_0076611 interacts with a variety of proliferation-related transcripts, included MYC and VEGFA mRNAs, and increases cell proliferation and migration of TNBC cells. Mechanistically, circ_0076611 favors the expression of its target mRNAs by facilitating their interaction with components of the translation initiation machinery. These results add further complexity to the multiple VEGFA isoforms expressed in cancer cells and highlight the relevance of post-transcriptional regulation of VEGFA expression in TNBC cells.

Therapeutic Implications of the Drug Resistance Conferred by Extracellular Vesicles Derived from Triple-Negative Breast Cancer Cells

“…They are expressed ubiquitously across species and exert their functions as transcriptional regulators, miR sponges, protein templates and protein decoys, scaffolds, and recruiters. Circ_0076611 is synthesized by the back-splicing of vascular endothelial growth factor A (VEGFA) exon 7 in TNBC cell lines and tissue samples from patients [ 87 ]. Circ_0076611 induces the expression of proliferation-related genes and proangiogenic cytokines such as MYC proto-oncogene ( MYC ), bromodomain-containing protein 4 ( BRD4 ) , GATA-binding protein 3 ( GATA3 ), VEGFA , chemokine (C-C motif) ligand 16 ( CXCL16 ), and CXCL1 .…”

“…Induces the expression of its target mRNAs, including MYC and VEGFA mRNAs by enhancing their interaction with translation initiation machinery [ 87 ]…”

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

“…lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) regulates linear isoforms of VEGFA, inducing the back-splicing of VEGFA exon 7 and producing circular RNA circ_0076611. Circ_0076611 is detectable in TNBC cells [ 491 ]. The expression of circHSDL2, targeting let-7a-2-3p during the progression of TNBC, was found to be significantly upregulated in serum SEVs and tumor tissues from TNBC patients [ 492 ].…”

Critical Review on the Different Roles of Exosomes in TNBC and Exosomal-Mediated Delivery of microRNA/siRNA/lncRNA and Drug Targeting Signalling Pathways in Triple-Negative Breast Cancer

“…The lncRNAs MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) cause an upregulation of the circular RNA circ 0076611 in exosomes released by TNBC. This circular RNA circ 0076611, released from the exosomes of TNBC cells, interacts with MYC (proto-oncogenes) and VEGFA (vascular endothelial growth factor A) mRNAs, further initiating cell proliferation and migration of TNBC cells [ 55 ]. Exosomes secreted by the TNBC cell line containing MMP-1 (Matrix Metallopeptidase 1) interact with the PAR1( protenase-activated receptor 1), a G protein receptor that initiates the EMT, which enables the breast cancer tumour to metastasize to the lungs [ 56 ].…”