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LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization.

ABSTRACT: Coronary atherosclerosis (CAS) is a major cause of cardiovascular disease. Long non-coding RNAs (lncRNAs) have been implicated as novel biomarkers in coronary artery disease (CAD). APOA1 antisense RNA (APOA1-AS) was proven to show high expression during atherosclerotic development, but no report has uncovered the detailed mechanism of APOA1-AS in CAS. Thus, this paper aims to explore the role of APOA1-AS in CAS. Vascular smooth muscle cells (VSMCs) were treated with oxidized low-density lipoprotein (ox-LDL) to mimic atherosclerosis-like injury. Quantitative real-time PCR (RT-qPCR) and western blot analysis analyzed gene expression. Cell counting kit-8 (CCK-8), wound healing assay, and flow cytometry were implemented to assess the function of APOA1-AS in modulating pathological phenotype of VSMCs. Results demonstrated that APOA1-AS was notably up-regulated in ox-LDL treated VSMCs (ox-LDL-VSMCs). The deficiency of APOA1-AS hindered proliferation and migration and stimulated apoptosis in ox-LDL-VSMCs. Mechanistically, APOA1-AS recruited TATA-box binding protein associated factor 15 (TAF15) protein to stabilized SMAD family member 3 (SMAD3) mRNA and activate the TGF-β/SMAD3 signaling pathway. In conclusion, APOA1-AS contributed to proliferation and migration and repressed apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization, indicating that APOA1-AS could be a promising target for CAS.

SUBMITTER: Wang J

PROVIDER: S-EPMC8489913 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization.

Wang Jixiang J Cai Ying Y Lu Hui H Zhang Fugeng F Zheng Junyi J

Cell cycle (Georgetown, Tex.) 20210812 17

Coronary atherosclerosis (CAS) is a major cause of cardiovascular disease. Long non-coding RNAs (lncRNAs) have been implicated as novel biomarkers in coronary artery disease (CAD). APOA1 antisense RNA (APOA1-AS) was proven to show high expression during atherosclerotic development, but no report has uncovered the detailed mechanism of APOA1-AS in CAS. Thus, this paper aims to explore the role of APOA1-AS in CAS. Vascular smooth muscle cells (VSMCs) were treated with oxidized low-density lipoprot ...[more]

PMID: 34382908

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Project description:BackgroundEpithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown.MethodsThe correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining.ResultsThe expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance.ConclusionsMIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

Dataset Information

LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization.

Publications

LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization.

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