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Published on: August 2, 2024
CircSERPINE2 Induces Platinum Resistance in Ovarian Cancer via the miR-513a-5p/miR-526b-3p/SEMA7A Axis
Zhiyuan Niu1,2, Yuqing Mo1,2, Bikang Yang3
1The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, 410078, China.
Introduction:
Ovarian cancer (OC) is the third most aggressive gynecological malignancy worldwide, and platinum resistance is a common malignant feature of OC associated with poor clinical prognosis. Circular RNA (circRNA) has been reported in many tumor progressions, including drug resistance. In this study, a new circRNA that mediates OC progression by acting as a ceRNA was identified.
Methods:
Through high-throughput transcriptome sequencing and bioinformatic analyses, the CircSERPINE2/miR-513a-5p/miR-526b-3p/SEMA7A axis was identified as a potential key factor in the development of platinum resistance in OC. CCK-8, colony formation assay, and flow cytometry confirmed the role of CircSERPINE2 in regulating platinum resistance in OC. Relevant patents were cited by the China National Intellectual Property Administration (CNIPA).
Results:
In OC cells and subcutaneous xenograft tumors, downregulation of CircSERPINE2 was associated with elevated expression of miR-513a-5p/miR-526b-3p, inactivation of the SEMA7A/ IL-6 pathway, and reduced tumor size following platinum treatment. Furthermore, the CircSERPINE2/SEMA7A axis mediated IL-6 autocrine in OC cells and significantly decreased platinum-induced apoptosis. Moreover, the CircSERPINE2/SEMA7A axis promoted M2 polarization of macrophages in the tumor microenvironment, which in turn impaired platinum sensitivity in ovarian cancer cells.
Discussion:
Given that circRNAs can act as promising clinical diagnostic biomarkers and therapeutic targets, the development of circRNA vaccine nanocomposites represents a novel and promising therapeutic strategy to potentiate tumor-killing efficacy when combined with chemotherapy regimens. On this basis, our subsequent research will focus on the rational design and development of a tailored nano-drug delivery system for this application.
Conclusion:
CircSERPINE2 promotes platinum resistance in OC cells and induces an immunosuppressive environment through the miR-513a-5p/miR-526b-3p/SEMA7A axis, highlighting its potential as a target for overcoming platinum resistance in OC.
Insights
Circular RNA SERPINE2 (CircSERPINE2) promotes platinum resistance in ovarian cancer (OC) by regulating the miR-513a-5p/miR-526b-3p/SEMA7A axis. Targeting CircSERPINE2 offers a novel strategy to overcome platinum resistance in OC.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Ovarian cancer (OC) is a highly aggressive gynecological malignancy.
- Platinum resistance is a major challenge in OC treatment, leading to poor prognosis.
- Circular RNAs (circRNAs) are implicated in tumor progression and drug resistance.
Purpose of the Study:
- To identify novel circRNAs involved in platinum resistance in OC.
- To elucidate the mechanism by which circRNAs mediate platinum resistance.
- To explore potential therapeutic targets for overcoming platinum resistance in OC.
Main Methods:
- High-throughput transcriptome sequencing and bioinformatic analyses to identify the CircSERPINE2/miR-513a-5p/miR-526b-3p/SEMA7A axis.
- Cell viability assays (CCK-8), colony formation assays, and flow cytometry to confirm the role of CircSERPINE2.
- Analysis of SEMA7A/IL-6 pathway and macrophage polarization in OC cells and xenograft tumors.
Main Results:
- Downregulation of CircSERPINE2 correlated with increased miR-513a-5p/miR-526b-3p expression, decreased SEMA7A/IL-6 pathway activity, and reduced tumor size post-platinum treatment.
- The CircSERPINE2/SEMA7A axis mediated IL-6 autocrine signaling, reduced platinum-induced apoptosis, and promoted M2 macrophage polarization.
- M2 macrophage polarization impaired platinum sensitivity in OC cells.
Conclusions:
- CircSERPINE2 promotes platinum resistance in OC by modulating the miR-513a-5p/miR-526b-3p/SEMA7A axis and creating an immunosuppressive tumor microenvironment.
- CircSERPINE2 represents a potential therapeutic target for overcoming platinum resistance in OC.
- Development of circRNA-based therapies, such as circRNA vaccine nanocomposites, holds promise for enhancing chemotherapy efficacy in OC.
