miR-125a-5p Functions as Tumor Suppressor microRNA And Is a Marker of Locoregional Recurrence And Poor prognosis in Head And Neck Cancer

Abstract

MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer. However, the role of miR-125a-5p has not been fully investigated in head and neck squamous cell carcinoma (HNSCC). We performed microRNA microarray profiling of HNSCC tumor samples obtained from a prospective clinical trial evaluating the role of postoperative radiotherapy in head and neck cancer. We also mined through The Cancer Genome Atlas to evaluate expression and survival data. Biological experiments, including cell proliferation, flow cytometry, cell migration and invasion, clonogenic survival, and fluorescent microscopy, were conducted using HN5 and UM-SCC-22B cell lines. miR-125a-5p downregulation was associated with recurrent disease in a panel of high-risk HNSCC and then confirmed poor survival associated with low expression in HNSCC via the Cancer Genome Atlas, suggesting that miR-125a-5p acts as a tumor suppressor miRNA. We then demonstrated that miR-125a-5p regulates cell proliferation through cell cycle regulation at the G 1 /S transition. We also show that miR-125a-5p can alter cell migration and modulate sensitivity to ionizing radiation. Finally, we identified putative mRNA targets of miR-125a-5p, including ERBB2 , EIF4EBP1 , and TXNRD1 , which support the tumor suppressive mechanism of miR-125a-5p. Functional validation of ERBB2 suggests that miR-125a-5p affects cell proliferation and sensitivity to ionizing radiation, in part, through ERBB2. Our data suggests that miR-125a-5p acts as a tumor suppressor miRNA, has potential as a diagnostic tool and may be a potential therapeutic target for the management and treatment of squamous cell carcinoma of the head and neck.

Epigenetic Modifications in Head and Neck Cancer

“…Other studies and meta-analyses show that in HNSCC patients some miRNAs are upregulated, such as miR-126 and miR-223 in OSCC (Tachibana et al 2016), miR-196b (Luo et al 2019, miR-31 (Kao et al 2019), miR-1275 in HNSCC (Liu et al 2018), miR-212 and miR-129 in OSCC (Scapoli et al 2010), and miR-130b in HNSCC (Chen et al 2012), while others are down-regulated, such as miR-145-5p in LSCC (Gao et al 2019), miR-29a in OSCC (Huang et al 2019), miR-200b in HNSCC (Kumarasamy et al 2019), miR-125a-5p in HNSCC (Vo et al 2019), miR-486-3p and miR-337-3p in OSCC (Chou et al 2019), miR-224 in OSCC (Lu et al 2019), miR-135b, miR-197, miR-378, miR224, and miR-34a in OSCC (Scapoli et al 2010), miR-100 and miR-375 in HNSCC (Chen et al 2012). lncRNAs lncRNAs are transcribed RNA molecules, which have a length of more than 200 nucleotides, do not encode proteins, and participate in positive and negative regulation of gene expression in the transcriptional, as well as the post-transcriptional level (Wang and Chang 2011;Chen 2016;Wei et al 2017).…”

Circular RNA hsa_circ_0014130 Inhibits Apoptosis in Non–Small Cell Lung Cancer by Sponging miR-136-5p and Upregulating BCL2

“…MicroRNAs (miRNA) are another group of endogenous non-coding RNA, approximately 21 to 23 nucleotides in length (11). MiRNAs negatively regulate gene expression via binding to the complementary sequence in the 3'-untranslated region (3'-UTR) of target genes (12).…”

Hypoxia‐induced miR‐3677‐3p promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by suppressing SIRT5

“…Therefore, there is great potential for identifying an underlying miRNA that can be used to develop treatments for HCC and assist in early detection of HCC and the control of metastasis. [25][26][27] miRNAs play an independent role in the pathogenesis and progression of almost all types of cancers, such as non-small cell lung cancer, 28,29 breast cancer, [30][31][32] gastric carcinoma [33][34][35] and bladder tumours. 36,37 They are responsible for modulation of their cellular differentiation, as well as in regulating the transcription of their downstream targets.…”