Formononetin inhibits osteosarcoma cell proliferation and promotes apoptosis by regulating the miR-214-3p/phosphatase and tensin homolog pathway

Abstract

Background: Phytoestrogens have a similar molecular structure to estrogens which can produce either estrogenic or anti-estrogenic effects. It is generally believed that phytoestrogens combine with the estrogen receptor of osteosarcoma cells, affecting a variety of signal transduction pathways and cell metabolism, resulting in altered cell proliferation, differentiation, apoptosis, invasion and migration ability. Formononetin (FN) is the active ingredient of traditional Chinese medicine astragalus, angelica, and Pueraria lobate. Our study aims to detect the role of FN on MG-63 cell viability and apoptosis through regulating phosphatase and tensin homolog (PTEN) expression via MicroRNA-214-3p (miR-214-3p). Methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Caspase 3 assay evaluated cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction (qRT-PCR) and western blot evaluated the mRNA and protein expressions, respectively. The binding site of miR-214-3p/PTEN was detected via dual luciferase assay. Results: FN suppressed cell viability and induced apoptosis, and decreased miR-214-3p level and promoted PTEN expression. PTEN was then regarded as a target of miR-214-3p, and FN improved PTEN level via inhibiting miR-214-3p. Further analysis showed that overexpressed miR-214-3p improved cell viability and suppressed apoptosis of MG-63 cells by inhibiting PTEN expression. Conclusions: Finally, our results revealed that FN inhibited cell viability and induced apoptosis by regulating miR-214-3p. FN acted as a new treatment for MG-63 cells via increasing PTEN level by inhibiting the miR-214-3p level.

Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma

“…It promoted the apoptosis of human bone cancer in vitro and in vivo in nude mice that had undergone orthotopic tumor implants by modulating the expression levels of the apoptosisrelated factors ERK, Akt [176], Bcl-2, Bax, and caspase-3 and decreasing the level of miR-375, an ER signaling-related miRNA, in ER-positive U2OS cells [175]. Further evidence showed that in MG-63 cells, the anti-proliferative function of formononetin is related to the upregulation of the expression of the tumor suppressor PTEN gene, via miR-214-3p [177], which is one of the miRs with oncogene properties that is considerably increased in OS [210]. Recently, bioinformatic-based network pharmacology has been used to disclose other therapeutic targets and bio-mechanisms of anti-OS formononetin activity [178].…”

The interplay of sex steroid hormones and microRNAs in endometrial cancer: current understanding and future directions

“…Exosomes derived from various sources, such as cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating CD8 + T cells, hold the potential for EC diagnosis and treatment. Exosomes have unique miRNA expression profiles, with certain miRNAs, such as miR-148b and miR-320a, playing a role in cancer progression and others, such as miR-15a-5p and miR-192-5p, having the ability to distinguish EC patients from healthy subjects (104,127,165,187). The role of miRNA in stem cell growth has been demonstrated through in vitro analysis of human endometrial carcinoma stem cells (HuECSCs).…”

Functional role of MicroRNA/PI3K/AKT axis in osteosarcoma

“…miR-196a overexpression affected MG63 and U-2OS by regulating the PTEN/PI3K/AKT pathway cell apoptosis, cell cycle, and proliferation ( 222 ). In osteosarcoma, there are many other microRNAs with similar mechanisms of action to the above microRNAs, including miR-19a-3p ( 214 ), miR-216 ( 215 ), miR-208a-3p ( 216 ), miR-214 ( 58 ), miR-9-5p ( 218 ), miR-620 ( 219 ), miR-130a ( 56 ), miR-21 ( 166 ), miR-21 ( 223 ), miR-221 ( 94 ), miR-214 ( 224 ), miR-92a ( 170 ), miR-214-3p ( 226 ), miR-93 ( 227 ), miR-1908 ( 60 ), miR-21 ( 228 ), miR-17 ( 95 ), miR-148a ( 171 ), miR-181b ( 230 ), miR-21 ( 231 ), miR-214 ( 232 ), miR-532-5p ( 176 ), miR-21 ( 236 ), miR-744 ( 237 ), which were found to be highly expressed in osteosarcoma tissues and osteosarcoma cell lines, all of which can target PTEN, bind to the 3,URT of PTEN and reduce its protein expression. Therefore, the aberrant activation of the PI3K/AKT pathway ultimately results in the facilitation of malignant biological processes such as proliferation, migration, invasion, cell cycle regulation, autophagy and apoptosis in osteosarcoma.…”

“…One is to design drugs for new targets. For example, Formononetin (FN) can induce apoptosis of osteosarcoma cells by targeting miR-214-3 p and inhibit proliferation of osteosarcoma cells ( 226 ). The second is to conduct research on existing anti-osteosarcoma drugs to find miRNAs that can promote the effect of existing anti-osteosarcoma drugs, improve the sensitivity of existing drugs and toxicity against tumor cells.…”