Dexmedetomidine inhibits cell malignancy in osteosarcoma cells via miR-520a-3p-YOD1 interactome
Introduction
Osteosarcoma (OS) is a common malignant tumor in adolescents, which derives from primitive transformed mesenchymal cells. And the 5-year survival rate among OS patients still remains unsatisfactory in the past 10 years [1]. Despite advanced progress has been applied in diagnosis and treatment for osteosarcoma patients, surgery accompanied with chemotherapy are the most common strategy for osteosarcoma patients’ treatment. Traditional techniques are difficult to solve the metastatic spread and recurrence problems and short 5-year survival rate [2]. Thus, it is important to explore more potential mechanisms in osteosarcoma progression and provide more strategy for osteosarcoma diagnosis and treatment.
Dexmedetomidine (DEX), a sedative and anesthetic, has been widely used during amputation surgery of OS patients, which can prolong sedation and analgesia for osteosarcoma patients suffering surgery [3,4]. One study has clarified that DEX inhibited OS cell proliferation and migration, but enhanced cell apoptosis by miR-520a-3p/AKT axis [5]. However, other potential mechanism remains unknown.
MicroRNAs (miRNAs), consisting of 18–25 nucleotides, can directly regulate some target genes by 3′-untranslated regions (3′-UTR) [6]. Evidences suggested that miRNAs regulated cell growth and apoptosis in most of the cancers, such as breast cancer [7], colon cancer [8], and bladder cancer [9]. MiR-520a-3p was reported as a tumor suppressor in many cancers via suppressing cell invasion, migration and epithelial-mesenchymal transition (EMT) and inducing cell apoptosis, including gastric cancer [10], breast cancer [11], thyroid carcinoma [12], and non-small cell lung cancer [13] In addition, miR-520a-3p targeted by LINC01116 could affect Interleukin 6 Receptor (IL6R) expression, and further promoted the development of OS through the Jak-stat signaling pathway [14]. However, to our knowledge, only this study demonstrated the role of miR-520a-3p in the occurrence of osteosarcoma. We suggested that miR-520a-3p may regulate osteosarcoma cell growth by targeting to other genes.
YOD1 deubiquitinase (YOD1) gene locating on chromosome 1q32.1 consists of four exons. It encodes a deubiquitinase subfamily characterized by an ovarian tumor (OTU) domain. And it controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction [15]. Several studies showed that YOD1 induced cancer progression by upregulating cell proliferation and inhibiting cell apoptosis partly via Yes Associated Protein 1 (YAP) signaling, such as liver cancer [15,16] and cervical cancer [17]. YOD1 has also been suggested as an oncogene in osteosarcoma, which enhanced cell proliferation, migration, and downregulated cell apoptosis by activating Hippo signaling pathway [18]. However, the potential mechanisms of DEX effect on miR-520a-3p and YOD1 in osteosarcoma need further exploration.
Thus, our study sought to confirm a novel interactome between miR-520a-3p and YOD1, and further explore the response of miR-520a-3p-YOD1 axis at the treatment of DEX in osteosarcoma. We hypothesized that downregulated miR-520a-3p might suppress osteosarcoma by inhibiting YOD1 under the treatment of DEX. Our study can reveal the potential mechanism of the effects of DEX on the miR-520a-3p-YOD1 axis in the progression of osteosarcoma.
Section snippets
Cell culture and cell transfection
The human osteosarcoma cell lines HOS and U2OS were purchased from ATCC (Manassas, VA, USA). HOS cell was cultured in MEM medium, and U2OS cell was cultured in RPMI-1640 containing 10% FBS at 37 °C and 5% CO2 condition. All the reagents for cell culture were provided by Thermo Fisher Scientific, Inc. (Gibco, Waltham, MA, USA). For DEX treatment, DEX (Cat#: SML0956, Sigma, USA) was dissolved in ddH2O at a concentration of 1 mg/mL in store. And the 1 mg/mL DEX solution was diluted to three final
DEX inhibited cell growth and promoted apoptosis in osteosarcoma
To investigate whether DEX affected cell growth in osteosarcoma, we performed cell viability at 1h, 12h, and 24h with concentration at 0, 1, 10, and 100 ng/mL using CCK8 kit. The results showed that cell viability in OS cells decreased with the increase of DEX concentration, and significantly increased at the concentration of 100 ng/mL at 24h of DEX treatment (Fig. 1A). Thus, we chose 100 ng/mL and 24h treatment conditions of DEX for subsequent studies. Next, we confirmed that HOS and U2OS
Discussion
In our study, we found that DEX treatment inhibited cell viability, proliferation and adhesion, while it promoted cell apoptosis in OS cells. Moreover, upregulation of miR-520a-3p targeting to YOD1 showed the negative effect on osteosarcoma cells. Notably, DEX treatment could downregulate YOD1 expression via increasing miR-520a-3p expression, thereby suppressing cell proliferation and cell adhesion, and elevating cell apoptosis in osteosarcoma cells. Thus, DEX treatment inhibited malignancy of
Funding
The study was supported by Joint Fund Project of Hubei Health Commission (Grant number: WJ2019H284).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors’ contributions
Rongrong Yan performed the experiments and data analysis. Shuangfen Jin conceived and designed the study. Hongchao Liu formed the methodology. Chengjin Le did investigation. Jie Gao find resources required. Jing Cheng and Shuangfen Jin wrote the paper. Rongrong Yan reviewed and edited the manuscript. All authors read and approved the manuscript.
Ethics approval and consent to participate
No patient specimens and animal specimens were involved in this study.
Consent for publication
The authors consent for the publication of this paper.
Declaration of competing interest
The authors declare that they have no conflict of interests.
Acknowledgements
None.
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The authors contribute equally to this work.