miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor and the third most common cancer that occurs during childhood and adolescence. Increasing evidence has suggested that microRNA (miR)-23b-3p has an important role in OS tumorigenesis; however, the underlying molecular mechanisms remain unknown. The aim of the present study was to investigate the expression levels of miR-23b-3p and sine oculis homeobox homolog 1 (SIX1) in OS tissues and cell lines (MG-63, SaOS-2 and U2OS), as well as to observe the effects of miR-23b-3p on U2OS cell viability, cell cycle, apoptosis and invasive ability. The results revealed that the expression levels of miR-23b-3p were significantly decreased in OS tissues and cell lines compared with tumor-adjacent normal tissues and a non-cancerous human fetal osteoblastic cell line (hFOB1.19). To investigate the underlying mechanisms of miR-23b-3p in OS tumorigenesis and progression, human U2OS cell lines over-or under expressing miR-23b-3p were established. The effects of miR-23b-3p on U2OS cell viability, cell cycle, apoptosis and invasion properties were determined by performing Cell Counting Kit-8, flow cytometry and Transwell invasion assays. miR-23b-3p was revealed to suppress cell viability, proliferation and invasion, and to enhance the levels of cell apoptosis. Furthermore, SIX1 mRNA and protein expression levels in OS tissues and cell lines were significantly upregulated when compared with tumor-adjacent normal tissues and hFOB 1.19 cells, which suggested that SIX1 expression levels may be inversely associated with miR-23b-3p levels in OS. Luciferase reporter system analysis demonstrated that miR-23b-3p binds to the SIX1 3'-untranslated region. miR-23b-3p downregulation contributed to SIX1 upregulation, which facilitated the potentiation of cyclin D1 and vascular endothelial growth factor-C expression levels, as well as the inhibition of caspase-3 expression. Collectively, these results suggested that miR-23b-3p is downregulated and SIX1 is upregulated in OS cells, and that miR-23b-3p inhibition may suppress the proliferation and invasion of OS cells, and contribute to cell apoptosis via negative regulation of SIX1. miR-23b-3p/SIX1 may therefore represent a potential target for the treatment of OS.

miR-23b-3p suppressing PGC1α promotes proliferation through reprogramming metabolism in osteosarcoma

“…Here we demonstrated that miR-23b-3p was upregulated in OS cell lines and promoted the growth of OS cell lines (MNNG-HOS and MG63). Different from our findings, Liu et al 22 reported that miR-23b-3p inhibited the proliferation of OS cell line (U-2OS) through targeting SIX1 and inhibiting its expression, as it is well acknowledged that OS have multiple rearrangements across the genome, kataegis, and a high degree of intra- and intertumor heterogeneity 23–25 . The study of Christopher et al 26 also highlighted heterogeneity in growth rates and genetics among OS cell lines.…”

MicroRNA miR-23b-3p promotes osteosarcoma by targeting ventricular zone expressed PH domain-containing 1 (VEPH1)/phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway

“…Similar results were obtained in vitro in this study: the addition of an exogenous miR-23b-3p mimic significantly improved cell viability, proliferation, and migration of OS cells. Compared with previous studies on miR-23b-3p in OS [ 28 , 51 , 52 ], our study confirmed the promoting effect of miR-23b-3p on the viability and proliferation in OS. In addition, we showed using a wound-healing assay that miR-23b-3p promoted the migration of two OS cell lines, which is novel and different from the findings of previous studies.…”

Long noncoding RNA FAM66C promotes tumor progression and glycolysis in intrahepatic cholangiocarcinoma by regulating hsa‐miR‐23b‐3p/KCND2 axis

“…LncRNA TUG1 can promote the growth and metastasis of ICC cells by miR‐145/SIRT3/GDH 31 . Besides, miR‐23b‐3p was revealed to suppress cell viability, proliferation and invasion and to enhance the levels of osteosarcoma cell apoptosis by targeting SIX1 19 . miR‐23b inhibited cell proliferation of lung cancer by targeting CCNG1, 32 and miR‐23b‐3p regulated apoptosis and autophagy by inhibiting SIRT1 in lens epithelial cells under oxidative stress 33 .…”

“…Recently, lncRNA UCA1 was shown to facilitate the Colorectal Carcinoma (CRC) cell 5‐FU resistance by inducing autophagy and suppressing apoptotic cell death through the miR‐23b‐3p/ZNF281 axis in vivo and in vitro 18 . Also, miR‐23b‐3p / SIX1 may represent a viable target for osteosarcoma treatment 19 . Furthermore, miR‐23b‐3p reportedly functions as a tumor suppressor that inhibits c‐Met expression and thereby alters cervical cancer progression 20 .…”