Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

Abstract

MicroRNAs (miRNAs) act as crucial regulators of biological pathways/processes by reinforcing transcriptional programs and moderating transcripts. Emerging evidences have shown the involvement of dysregulated miRNAs in pathophysiology of human diseases including several cancer types. Recently, miR‐197‐3p has been reported to play different roles in different cancers; however, its role in fibrosarcoma, a highly aggressive and malignant soft tissue sarcoma originated from the mesenchymal tissues, has not yet been studied. Therefore, this study aims to investigate the possible regulatory roles of miR‐197‐3p in the oncogenicity of fibrosarcoma. For this, we initially performed qRT‐PCR of miR‐197‐3p, which we found to be downregulated in HT1080 human fibrosarcoma cells compared with IMR90‐tert normal fibroblast cells. Subsequently, we performed gain‐of‐function study by employing several methods such as MTT assay, clonogenic assay, wound healing, flow cytometry cell cycle analysis, and acridine orange staining after transfecting HT1080 cells with miR‐197‐3p mimic. From these assays, we observed that miR‐197‐3p significantly inhibits viability, colony forming, and migration ability as well as triggers G2/M phase cell cycle arrest and autophagy in fibrosarcoma cells. To understand the mechanism through which miRNA performs these functions, we predicted its targets using TargetScan and performed pathway enrichment analysis after screening them by their expression in fibrosarcoma. Among the enriched targets, we found RAN (ras‐related nuclear protein) to be a crucial target through which miR‐197‐3p represses tumorigenesis by binding to its 3´ UTR, validated by luciferase reporter assay. The tumor suppressive role of the miRNA was further confirmed by transfecting its mimic in RAN‐overexpressed cells which showed significant attenuation in tumorigenic effect of RAN in fibrosarcoma as seen in different assays. Taken together, our study unveiled that miR‐197‐3p acts as an oncosuppressor in fibrosarcoma through G2/M phase arrest and induction of autophagy, and raises the possibility to act as a novel therapeutic intervention for the malignancy.

Identification of key serum biomarkers for the diagnosis and metastatic prediction of osteosarcoma by analysis of immune cell infiltration

“…Jain et al . reported that hsa-miR-197-3p regulates fibrosarcoma carcinogenicity by targeting RAN [ 74 ]. It will be interesting to understand the unknown molecular mechanism behind the role of the RAN in OS.…”

Primary Synchronous Ipsilateral Renal Fibrosarcoma and Renal Pelvic Carcinoma: A Case Report and Literature Review

“…Recent study manifested that the soluble pattern recognition receptor long-pentraxin 3 (PTX3) may act as an oncosuppressor, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system to inhibit FGF-dependent tumor growth. 25 Jain et al 26 found that miR-197-3p can significantly inhibit the viability, colony formation, migration as well as triggers G2/M phase cell cycle arrest of fibrosarcoma cells. For the recurrent fibrosarcoma with high expression of vascular endothelial growth factor (VEGF), apatinib could effectively reduce the risk of disease progression in patient with recurrent fibrosarcoma, which highly expressed vascular endothelial growth factor (VEGF).…”

Primary synchronous ipsilateral renal fibrosarcoma and renal pelvic carcinoma: a case report and literature review

“…Recent study manifested that the soluble pattern recognition receptor long-pentraxin 3 (PTX3) may acts as an oncosuppressor, functioning as an antagonist of the broblast growth factor/ broblast growth factor receptor (FGF/FGFR) system to inhibit FGF-dependent tumor growth [16]. Jain et al [25] found that miR-197-3p can signi cantly inhibit the viability, colony formation, migration as well as triggers G2 / M phase cell cycle arrest of brosarcoma cells [17]. For the recurrent brosarcoma with high expression of vascular endothelial growth factor (VEGF), apatinib could effectively reduce the risk of disease progression in patient with recurrent brosarcoma, which highly expressed vascular endothelial growth factor (VEGF) [18].…”