Abstract
Studies have demonstrated that miR-335-5p exhibits an essential role in the progress of multiple tumors, including thyroid cancer, pancreatic cancer, and non-small-cell lung cancer. However, the possible expression, the detailed role, and the underlying mechanisms of miR-335-5p in uterine leiomyoma (UL) still remained unclear. Therefore, the present study was designed to investigate the mechanism and function of miR-335-5p in UL. In our study, microRNA-335-5p (miR-335-5p) is significantly downregulated in UL tissues and UL cell lines, especially in HCC1688 and SK-UT-1 cells. Functionally, overexpression of miR-335-5p notably inhibits the viability of UL cell lines by CCK-8 assay. Besides, upregulation of miR-335-5p inhibits proliferation of UL cell lines by colony formation assay and decreases the protein levels of PCNA and Ki-67 detected by western blot assay. In addition, overexpression of miR-335-5p induces UL cell cycle arrest at G1 phase. Upregulation of miR-335-5p decreases the levels of Cyclin A1, Cyclin B1, and Cyclin D2 and upregulates the expression of p27 protein. Additionally, upregulation of miR-335-5p promotes the apoptosis of UL cell lines, increases the protein levels of Bax, Cleaved caspase-3, and Cleaved caspase-9, and decreases the protein expression of Bcl-2. Moreover, Arginine and Glutamate-Rich protein 1 (ARGLU1) is predicted as a target of miR-335-5p by ENCORI and miRDB and confirmed by dual-luciferase reporter assay. ARGLU1 is negatively associated with miR-335-5p. Furthermore, overexpression of ARGLU1 partly restores the effects of miR-335-5p mimic on the viability, proliferation, cell cycle, and apoptosis of UL cell lines. To conclude, miR-335-5p may play a repressive role in UL by targeting ARGLU1 and serve as a potential therapeutic target for the treatment of UL.
Highlights
Uterine leiomyoma (UL) is the most common benign tumor in women of childbearing age [1]
Identification and diagnosis of UL are the key to reduce infertility caused by uterine factors [20]
In our present study, miR-335-5p was obviously downregulated in clinical UL tissues and cell lines, which was highly consistent with previous studies. miR-335-5p is significantly downregulated in colorectal cancer, thyroid cancer, and NSCLC [25,26,27]
Summary
Uterine leiomyoma (UL) is the most common benign tumor in women of childbearing age [1]. Flake et al finds that nearly 40% of UL has simple and nonrandom chromosomal abnormalities [4] Such a high incidence rate can be explained by genetic mechanisms that had not been recognized by academics and the lack of targeted gene therapy of UL. A lot of research results have been achieved in the fields of malignant tumors, cardiovascular diseases, neuromuscular tissues, and stem cells [10,11,12]. Upregulation of miR-335-5p notably inhibited viability and proliferation, promoted apoptosis, and induced cell cycle arrest at the G1 phase of UL cells, which might be achieved by targeting Arginine and Glutamate-Rich protein 1 (ARGLU1), previously known as FLJ10154, and was a gene with poorly defined cellular function(s). Our findings implied that miR-335-5p functioned as a tumor suppressor and might serve as a new biomarker for therapeutic target for UL
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