MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5’ end, leading to mRNA cleavage and/or translation repression. Here, we demonstrated a miRNA-induced dual regulation of heme oxygenase-1 (HO-1) via seed region and non-seed region, consequently inhibited tumor growth of NSCLC. We identified miR-1254 as a negative regulator inhibiting HO-1 translation by directly targeting HO-1 3’UTR via its seed region, and suppressing HO-1 transcription via non-seed region-dependent inhibition of transcriptional factor AP-2 alpha (TFAP2A), a transcriptional activator of HO-1. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Consistently with the in vitro studies, mouse xenograft studies validated that miR-1254 suppressed NSCLC tumor growth in vivo. Moreover, we found that HO-1 expression was inversely correlated with miR-1254 level in human NSCLC tumor samples and cell lines. Overall, these findings identify the dual inhibition of HO-1 by miR-1254 as a novel functional mechanism of miRNA, which results in a more effective inhibition of oncogenic mRNA, and leads to a tumor suppressive effect.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells

“…TFAP2A has been implicated in cancer proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) [ 33 , 34 ]. However, it remains unclear whether TFAP2A is involved in tumor-induced angiogenesis.…”

“…Previous studies reported that TFAP2A promotes EMT procession by regulating TGF-β signaling in cancer cells [ 33 ] and TFAP2A regulates tumor growth via hypoxia inducible factor-1a (HIF-1a) signaling in nasopharyngeal carcinoma and NSCLC [ 34 , 41 ], whereas the HIF-1a pathway has been confirmed to promote angiogenesis [ 42 ]. To validate the role of TFAP2A in anlotinib resistance, we performed TFAP2A knockdown in AR cells and found that tumor-induced angiogenesis was decreased in AR cells by TFAP2A knockdown.…”

MiR-1254 inhibits proliferation, migration and invasion of human brain tumour cell lines

“…The results of the present study showed that ectopic expression of miR-1254 caused G2/M cell arrest in the SW 1088 astrocytoma cells. Earlier investigations carried out on miR-1254 have revealed that it inhibited cell migration and invasion of cancer cells [14]. For instance, miR-1254 has been reported to inhibit the migration and invasion of colorectal cancer by inhibiting PSMD10 [15].…”

Circulating miR-1254 predicts ventricular remodeling in patients with ST-Segment-Elevation Myocardial Infarction: A cardiovascular magnetic resonance study

“…Studies regarding the function of miR-1254 in myocardium are lacking. miR-1254 has been linked to cell apoptosis and cell cycle arrest 33 . miR-1254-1 resides within the 15 th intron of the gene cell cycle and apoptosis regulator 1 (CCAR1) on 10q21.3.…”