MicroRNA-181c Suppresses the Biological Progression of Osteosarcoma via Targeting SMAD7 and Regulating Transforming Growth Factor-β (TGF-β) Signaling Pathway

Abstract

Background Osteosarcoma is a primary bone aggressive cancer, affecting adolescents worldwide. Increasing evidence suggests that dysfunction of microRNAs (miRNAs) plays a pivotal role in malignancies. The aim of this study was to evaluate the potential functions of miR-181c and verifying its regulatory effects on SMAD7 in osteosarcoma. Material/Methods The expressions of miR-181c and SMAD7 in osteosarcoma were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, invasion and migration abilities were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and Transwell assay. Bioinformatics analysis and luciferase reporter assay were used to explore the interaction between miR-181c and SMAD7. Western blot was performed to determine the functions of miR-181c on osteosarcoma cell epithelial-to-mesenchymal transition (EMT) and transforming growth factor-β (TGF-β) signaling pathway. Results Decreased expression levels of miR-181c and SMAD7 were identified in osteosarcoma using qRT-PCR. The downregulated miR-181c and SMAD7 expressions indicated poor prognosis of osteosarcoma patients. Moreover, miR-181c overexpression prominently repressed osteosarcoma cell proliferation, invasion, and migration abilities via modulating EMT and TGF-β signaling pathway. SMAD7 functioned as an important target for miR-181c in osteosarcoma cells. Furthermore, upregulation of miR-181c dramatically suppressed osteosarcoma tumorigenesis in vivo. Conclusions These findings indicated that miR-181c suppressed osteosarcoma progression, providing new insight into the pathogenesis and representing a potential therapeutic target for osteosarcoma.

MiR-581/SMAD7 Axis Contributes to Colorectal Cancer Metastasis: A Bioinformatic and Experimental Validation-Based Study

“…SMAD7, a member of SMAD family, is reported to be associated with the development of a variety of cancers. Recent studies have shown that SMAD7 is present in common malignancies and acts as a tumor suppressor, including lung cancer, liver cancer, gastric cancer, bladder cancer, triple negative breast cancer, and osteosarcoma [11,[23][24][25][26][27][28]. In CRC, reduced level of SMAD7 is found to be involved in the process of cancer growth as well as the process of EMT and invasion [29].…”

miRNAs expression signature potentially associated with lymphatic dissemination in locally advanced prostate cancer

“…In a study of osteosarcoma, it was found that a decrease in miR-181c expression level was associated with a poor prognosis and malignant clinical and pathological features. As a result of functional studies, it was shown that activation of miR-181c dramatically inhibited the proliferation, invasion and migration of osteosarcoma cells [77]. It was also revealed that the SMAD7 gene was a direct functional target for miR-181c in osteosarcoma cells and that overexpression of miR-181c suppresses the signaling pathway of EMT and TGF-β in osteosarcoma cells through regulation of SMAD7 [77].…”

“…As a result of functional studies, it was shown that activation of miR-181c dramatically inhibited the proliferation, invasion and migration of osteosarcoma cells [77]. It was also revealed that the SMAD7 gene was a direct functional target for miR-181c in osteosarcoma cells and that overexpression of miR-181c suppresses the signaling pathway of EMT and TGF-β in osteosarcoma cells through regulation of SMAD7 [77]. Significant downregulation of miR-181c was also detected in the case of hepatocellular carcinoma when compared with normal tissues.…”

Current perspectives on inhibitory SMAD7 in health and disease

“…Interestingly, distinct miRNA variants derived from the same precursor can affect SMAD7 gene expression in different cell types. For example, from the miR-181 precursor four mature miRNAs can be produced: miR-181a, miR-181b, miR-181c or miR-181d, of which MiR-181a was found to induce repression of its functional target SMAD7 in ovarian cancer cells to promote TGFb-mediated epithelial-to-mesenchymal transition (EMT) (Parikh et al 2014), whereas MiR-181c downregulated SMAD7 expression in neuroblastoma and osteosarcoma (Li et al 2014;Fu et al 2019). Additionally, miR-181 variants have been shown to regulate T cell phenotype in autoimmune neuroinflammation by directly targeting SMAD7 mRNA (Ghorbani et al 2017;.…”

“…MiRNAs regulating SMAD7 expression in the context of disease a . ,miR-15a, miR-18a, miR-20a, miR-21, miR-25, miR-32, miR-92a/b, miR-93, miR-106a, miR-106b $25, miR-130b, miR-132, miR-181, miR-182, miR-185, miR-195, miR-216a, miR- 324, miR-367, miR-424, miR-452, miR-497, miR-503, MiR-519d, miR-520g/h, miR-543, miR-663b, miR-1269, miR-2909, miR-4775 (Smith et al 2012Chen et al 2013;Li et al 2013;Xia et al 2013;Chang et al 2013;Li et al 2014;Parikh et al 2014;Yu et al 2014;Kan et al 2015;Liu et al 2015;Tang et al 2015;Bu et al 2015;Wang et al 2015;Xu et al 2015;Hu et al 2016;Zhuang et al 2016;Liu et al 2016;Duan and Chen 2016;Dai et al 2016;Yu et al 2016;Ratz et al 2017;Tong et al 2017;Zhao et al 2017;Wang et al 2017;Wang 2017;Ayub and Kaul 2017;Hujie et al 2018;Chen et al 2018;Zhai et al 2018;Fu et al 2019;Huang et al 2019;Shen et al 2019; This table includes SMAD7-regulating miRNAs from homo sapiens, mus musculus and rattus norvegicus.…”