Research paperUp-regulation of microRNA-496 suppresses proliferation, invasion, migration and in vivo tumorigenicity of human osteosarcoma cells by targeting eIF4E
Introduction
Pediatric patients worldwide suffer from osteosarcoma (OS), which is known as the most common bone malignancy [1,2]. It is one of the primary osteogenic neoplasms that feature a high relapse and metastasis rate, along with an unsatisfied prognosis [3]. Patients with two age spans are prone to OS: the first being over 50 years, the second, is between 10 and 20, which is most common among patients [4]. About 2.4% of pediatric patients with malignant tumors suffer from OS, which ranks as the eighth most common childhood cancer [5]. About 80% of OS cases feature long bones including femur and tibia, where OS usually develops [6]. Patients suffering from OS typically go through multi-agent adjuvant therapy, primary tumor surgery and post-op chemotherapy; but even with successful outcome from the above treatments, patients may still face death as the metastases progresses, typically to the lung [7]. MicroRNAs (miRNAs) with differently expressed patterns have been proven to be a favorable way to help diagnose OS, as well as a promising tool to treat it [8].
MiRNAs are non-protein-coding small RNAs, and are commonly 20 to 25 nucleotides in length [9]. According to a latest study, miRNAs often manifest themselves at reduced levels in tumors due to epigenetic silencing, genetic loss, or biogenesis pathway defects [10]. Information about miR-496 still remains largely unknown, except for its low expression found in elder people [11] and its involvement in cartilage and bone formation [12]. A previous study has also confirmed that the overexpression of miR-496 led to the inhibition of the proliferation of breast cancer cells [13]. Eukaryotic translation initiation factor 4E (eIF4E) normally acts as a promoter in its translation into protein by putting more mRNAs into the ribosomes in cytoplasm [14]. A number of studies have shown that overexpression of eIF4E is related to multiple types of malignant tumors such as colon, rectal, and breast cancers and also OS [7,15,16]. Another recent study has demonstrated that down regulated eIF4E could hinder the proliferation of gastric tumor cells [17]. However, few studies have investigated whether miR-496 can target eIF4E. Nonetheless, miR-34c-3p is reported to function as a suppressor in non-small cell lung cancer by inhibiting eIF4E expression [18]. Furthermore, miR-503 could inhibit hepatocellular carcinoma (HCC) cell proliferation by targeting eIF4E [19]. Therefore this study aims to investigate the expression of miR-496 in OS and its effects on proliferation, invasion, and migration of OS cells and tumor formation in nude mice through targeting eIF4E.
Section snippets
Ethics statement
The study was approved by the ethics committee of the Fifth Hospital of Harbin. All patients signed the informed consent. The animal experiments were carried out in conformity with Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Microarray gene expression profiling
The OS-related gene expression chips (GSE63631 and GSE63639) were retrieved from the National Center for Biotechnology Information (NCBI) database. The data from the chip were downloaded from the Gene Expression Omnibus (GEO)
miR-496 is speculated to regulate eIF4E in OS
In total, 4,308 differentially expressed genes were screened from the GSE63631 chip, and 7,433 differentially expressed genes were screened from the GSE63639 chip. It had been previously suggested that eIF4E had important prognostic values in HCC [21] influenced the angiogenesis, cell growth and survival in HCC [22], and could apply its carcinogenic effect in cancer [23]. Presently, designed and screened compounds targeting eIF4E suggest a promising future direction [24,25], and eIF4E was found
Discussion
Between the age group of 15–19 years, 15% of patients with solid extracranial cancers suffer from OS [26]. Yet the overall survival rate remained the same for a period of 20 years, though the current diagnosis and treatment of it have greatly advanced [27]. In order to develop better plans to combat and inhibit the metastases of OS, identifying new therapeutic targets for OS is the most important thing to do [28]. In this present study, the microarray analysis that was conducted led to a
Conclusions
When taken together, this study revealed that the overexpression of miR-496 is a suppressive miRNA in OS cells, as it inhibits the proliferation, invasion and migration of OS cells and in vivo tumor growth. Furthermore, overexpression of miR-496 was also found to inhibit the expression of eIF4E. This experiment also exhibited evidence that miR-496 can directly target eIF4E, and further inhibit the activity of OS cells, thus presenting a new target for the treatment of OS. However, the specific
Conflicts of interest
None.
Author's contributors
Ni-Nan Qi and Fu-Li Wang designed the study. Shuo Tian, Xin Li and Bin Liu collated the data, designed and developed the database, and produced the initial draft of the manuscript. Ni-Nan Qi and Bin Liu prepared the table and figures. Shuo Tian, Xin Li and Fu-Li Wang contributed to polishing the manuscript. All authors have read and approved the final submitted manuscript.
Acknowledgment
We thank the reviewers for critical comments.
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