miR-154-3p and miR-487-3p synergistically modulate RHOA signaling in the carcinogenesis of thyroid cancer

Abstract

Correspondence: Ning An (anning gpch@tom.com) Background: miRs family members are often thought to have extensively overlapping targets and synergistically to modulate target gene expression via post-transcriptional repression. The present study was to determine whether miR-154-3p and miR-487-3p synergistically collaborated to regulate RHOA signaling in the carcinogenesis of thyroid cancer. Materials and methods: Candidate miRs were filtrated using miR microarray assays. Gene and protein expression levels were analyzed using RT-qPCR and Western blotting, respectively. Cell growth was evaluated using CCK8 assays and nude-mouse transplanted tumor experiments. Cell apoptosis was detected using Annexin V-FITC double staining. Results: miR-154-3p and miR-487-3p were significantly decreased in 63 thyroid cancer tissues and cell lines compared with those in paired non-tumor tissues and normal thyroid follicular epithelial cells. Low expression levels of miR-154-3p and miR-487-3p significantly correlated with tumor size, TNM stage, histological grade, lymph node metastasis and shorter overall survival in patients with thyroid cancer. Furthermore, the protein expression of RHOA was significantly inversely correlated with miR-154-3p (r = −0.404; P = 0.001) and miR-487-3p (r = −0.456; P < 0.001) expression in thyroid cancer tissues. We experimentally validated that miR-154-3p and miR-487-3p synergistically blocked thyroid cancer cell growth in vitro and in vivo. However, the anti-proliferative and pro-apoptotic activities of miR-154-3p/487-3p were neutralized by RHOA overexpressed vectors. Conclusions: Our present findings expounded a novel signal cascade employing miR-154-3p/487-3p and RHOA to fine-tune thyroid cancer cell proliferation and apoptosis. We corroborated that suppression of RHOA by miR-154-3p/487-3p may be a valuable therapeutic target for impeding thyroid cancer progression.Ras homolog family member A (RHOA) as a representative protein of RHO subfamily primarily participates in actin cytoskeleton rearrangement, which is implicated in various physiological functions, including cell proliferation, differentiation, migration, polarity and gene transcription [6]. Rho-associated protein kinase (ROCK) is a downstream effector of RHOA and has the ability to modulate cytoskeleton dynamics [6]. Over-activation of RHOA/ROCK signaling pathway may be associated with a decrease in cell-cell junctions and a promotion of cell motility [7]. Previous studies have validated that high expression of RHOA and ROCK is frequently reported in various cancer-types, such as breast cancer, ovarian cancer and colon cancer [6,8,9]. In thyroid cancer, RHOA/ROCK signaling has a profound stimulative impact to facilitate the invasiveness of anaplastic thyroid cancer cells [10]. microRNAs (miRs) are a class of non-coding RNAs and have widely been elaborated in the pathogenesis of various diseases, including carcinogenesis [11]. miRs function as post-transcriptional regulators to repress target genes translation via binding with their 3 -un...

Circular RNA circ_0008274 enhances the malignant progression of papillary thyroid carcinoma <i>via</i> modulating solute carrier family 7 member 11 by sponging miR-154-3p

“…Here, we first confirmed that circ_0008274 mediated SLC7A11 expression by sponging miR-154-3p. MiR-154-3p has been demonstrated to be involved in the pathogenesis of lung cancer, breast cancer and PTC [16,29,30]. Here, we first identified that SLC7A11 was a functional target of miR-154-3p in regulating PTC progression in vitro.…”

“…Growing evidence has highlighted the association between miRNAs and PTC progression [14,15]. It was reported that miR-154-3p was down-regulated in thyroid cancer and correlated with the outcome of the disease [16]. The study also unraveled the involvement of miR-154-3p in thyroid cancer development through targeting ras homolog family member A (RHOA).…”

miR-544-3p mediates arthritis pain through regulation of FcγRI

“…However, we did not observe any significant changes in stat3 mRNA expression in the DRG in the context of arthritis, suggesting that STAT3 may not be a direct of target of miR-554-3p in the DRG under arthritis conditions. In cancer tissues, miR-544-3p functions as a tumor suppressor by directly targeting a variety of genes, such as ras homolog family member A (RHOA) and Toll-like receptor 2 (TLR2) 36,37,47 . Further investigation is required to explore whether any of these potential targets mediate analgesic effects of miR-544-3p in the setting of arthritis.…”

“…Taken together, these results suggest that miR-544-3p downregulation contributes to the maintenance of arthritis pain, at least in part, through the regulation of FcγRI expression in the DRG. However, we cannot exclude the possibility that miR-544-3p regulates the expression of other genes [35][36][37] .…”

MiR-1301-3p Inhibits Epithelial to Mesenchymal Transition via Targeting RhoA in Pancreatic Cancer

“…Previous studies also pointed out that miRNAs regulated RhoA expression in multiple cancers [21,22] . For example, Fan et al demonstrated that miR-154-3p and miR-487-3p speci cally repressed RhoA expression at the post-transcriptional level in thyroid cancer [23] . Furthermore, miR-101 negatively regulated EMT and migration capacity of cancer cells by directly reducing the RhoA level [24] .…”