Abstract
Background: Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). Despite initial benefits, many patients ultimately develop progesterone resistance. Circular RNA (circRNA) is a kind of noncoding RNA, contributing greatly to the development of human tumor. However, the role of circular RNA in MPA resistance is unknown. Methods: We explored the expression profile of circRNAs in Ishikawa cells treated with (ISK/MPA) or without MPA (ISK) by RNA sequencing, and identified a key circRNA, hsa_circ_0001860. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify its expression in MPA-resistant cell lines and tissues. CCK8, Transwell, and flow cytometry were used to evaluate the functional roles of hsa_circ_0001860 in MPA resistance. The interaction between hsa_circ_0001860 and miR-520 h was confirmed by bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay. Results: The expression of hsa_circ_0001860 was significantly downregulated in MPA-resistant cell lines and tissues, and negatively correlated with lymph node metastasis and histological grade of EC. Functional analysis showed that hsa_circ_0001860 knockdown by short hairpin RNA (shRNA) promoted the proliferation, inhibited the apoptosis of Ishikawa cells, and promoted the migration and invasion of Ishikawa cells treated with MPA. Mechanistically, hsa_circ_0001860 promoted Smad7 expression by sponging miR-520 h. Conclusion: Hsa_circ_0001860 plays an important role in the development of MPA resistance in EC through miR-520h/Smad7 axis, and it could be targeted to reverse the MPA resistance in endometrial cancer.
Highlights
Endometrial cancer is one of the most common gynecological tumors in the United States (Siegel et al, 2020)
high-throughput RNA sequencing (RNA-seq) analysis showed that a total of 4,814 Circular RNA (circRNA) were detected
The results showed 87 differentially expressed circRNAs in MPAtreated ISK cells compared with control cells (|fold change| ≥ 2.0, p < 0.05), and among them, 46 were upregulated and 41 were downregulated
Summary
Endometrial cancer is one of the most common gynecological tumors in the United States (Siegel et al, 2020). In order to preserve the fertility of young patients, progesterone such as medroxyprogesterone acetate (MPA) and megestrol acetate (MA) is regarded as the first-line drug for conservative treatment (Rodolakis et al, 2015; La Russa et al, 2018). Using a constructed stable MPA-resistant Ishikawa cell, it has been shown that SIRT1/FoxO1/ SREBP-1, as a pathway targeting PR, is involved in the development of progesterone resistance in endometrial cancer cells (Wang et al, 2018), but the molecular mechanism still remains unclear. It is of great significance to elucidate the mechanism and therapeutic target of MPA resistance in EC for individualized treatment of patients. Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). The role of circular RNA in MPA resistance is unknown
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