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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
MicroRNA-379-5p attenuates cancer stem cells and reduces cisplatin resistance in ovarian cancer by regulating
Devendra Shukla1,2, Sanjay Mishra3, Tanima Mandal1,2
1Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Abstract:
Ovarian cancer (OC) is an aggressive malignancy of the female reproductive organs, associated with a low 5-year survival rate. Emerging evidence suggests the pivotal role of microRNAs (miRNAs) in regulating chemoresistance and metastasis in OC, primarily through cancer stem cells (CSCs), also known as cancer stem-like cells (CSLCs). Herein, we demonstrate that miR-379-5p is downregulated in several OC cell populations including both cell lines and patient tumor samples. Furthermore, overexpression of miR-379-5p effectively inhibits CSCs and counteracts cisplatin-induced expansion of CSCs. Further mechanistic investigations identify RAD18, a DNA repair protein involved in translesion DNA synthesis (TLS), as a direct target of miR-379-5p. Moreover, a negative correlation between miR-379-5p and RAD18 expression is observed in ovarian CSCs isolated from OC patients. The downregulation of RAD18 inhibits stem-like phenotypes and enhances the sensitivity of ovarian CSCs to cisplatin treatment. Importantly, miR-379-5p-mediated inhibition of RAD18 prevents the repair synthesis in CSCs by promoting the accumulation of DNA damage. In vivo studies further reveal that miR-379-5p enhances DNA damage, which, in turn, inhibits tumor cell proliferation in athymic nude mice. Remarkably, targeting of RAD18 by miR-379-5p prevents monoubiquitination of proliferating cell nuclear antigen (PCNA), resulting in reduced DNA Polymerase η (a TLS polymerase that helps to bypass DNA lesions) recruitment to lesion sites. In the absence of Polη, the persisting DNA lesions cause activation of cell cycle arrest and apoptosis pathway in CSCs. Therefore, our findings unveil a novel mechanism whereby miR-379-5p overexpression curtails CSCs by modulating the RAD18/Polη axis.
Insights
MicroRNA-379-5p targets RAD18, inhibiting ovarian cancer stem cells and enhancing cisplatin sensitivity. This discovery offers new therapeutic strategies for ovarian cancer by targeting the RAD18/Polη pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ovarian cancer (OC) is a deadly malignancy with poor survival rates.
- MicroRNAs (miRNAs) are increasingly recognized for their role in OC chemoresistance and metastasis via cancer stem cells (CSCs).
- miR-379-5p is notably downregulated in OC, suggesting a potential tumor-suppressive function.
Purpose of the Study:
- To investigate the role of miR-379-5p in ovarian cancer, focusing on its regulation of cancer stem cells (CSCs) and chemoresistance.
- To identify the molecular targets and mechanisms through which miR-379-5p exerts its effects in OC.
Main Methods:
- Expression analysis of miR-379-5p in OC cell lines and patient samples.
- Overexpression of miR-379-5p in OC cells and assessment of CSC phenotypes and cisplatin sensitivity.
- Identification of RAD18 as a direct target of miR-379-5p using mechanistic studies.
- Analysis of the correlation between miR-379-5p and RAD18 in patient-derived CSCs.
- In vivo studies in athymic nude mice to evaluate the anti-tumor effects of miR-379-5p.
- Investigation of the impact on DNA repair pathways, including PCNA monoubiquitination and Polη recruitment.
Main Results:
- miR-379-5p was found to be downregulated in OC, and its overexpression inhibited CSCs and sensitized them to cisplatin.
- RAD18, a DNA repair protein, was identified as a direct target of miR-379-5p, with an inverse correlation observed in patient CSCs.
- Downregulation of RAD18 by miR-379-5p reduced stem-like properties, enhanced cisplatin sensitivity, and promoted DNA damage accumulation in CSCs.
- In vivo, miR-379-5p inhibited tumor growth by increasing DNA damage.
- miR-379-5p targeting of RAD18 disrupted PCNA ubiquitination, reduced Polη recruitment, and induced cell cycle arrest and apoptosis in CSCs.
Conclusions:
- miR-379-5p acts as a tumor suppressor in ovarian cancer by targeting RAD18.
- Overexpression of miR-379-5p effectively curtails CSCs and enhances chemosensitivity through the RAD18/Polη axis.
- This study reveals a novel mechanism for controlling ovarian cancer progression and chemoresistance by modulating DNA repair pathways in CSCs.
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