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Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells
Evgeny Chirshev1,2, Tise Suzuki1, Hanmin Wang1
1Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, CA 92354, USA.
Abstract:
High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.
Insights
Let-7i microRNA suppresses ovarian cancer stemness and metastasis. Overexpressing let-7i enhances sensitivity to PARP inhibitors, offering a new therapeutic strategy for ovarian cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Gynecologic Oncology
Background:
- High-grade serous ovarian carcinoma is a lethal gynecologic cancer with low survival rates.
- MicroRNA dysregulation contributes to cancer stem cell (CSC) formation, oncogenesis, and tumor progression.
- The let-7 microRNA family exhibits tumor-suppressive roles in various cancers, including ovarian cancer.
Purpose of the Study:
- To investigate the tumor suppressor functions of let-7i in ovarian cancer.
- To explore let-7i's impact on cancer stemness, migration, invasion, and apoptosis.
- To determine if let-7i enhances sensitivity to PARP inhibitors and elucidate potential mechanisms.
Main Methods:
- Assessed let-7i's effects on ovarian cancer cell stemness, migration, invasion, and apoptosis.
- Evaluated let-7i overexpression's impact on sensitivity to olaparib in BRCA-wildtype samples.
- Investigated let-7i's regulation of homologous recombination repair (HRR) pathway factors.
Main Results:
- Let-7i demonstrated tumor suppressor activity by repressing cancer stemness, inhibiting migration and invasion, and promoting apoptosis.
- Overexpression of let-7i increased sensitivity to the PARP inhibitor olaparib in BRCA-wildtype ovarian cancer cells.
- Let-7i was shown to inhibit key factors within the homologous recombination repair pathway.
Conclusions:
- Let-7i exhibits significant tumor suppressor functions in ovarian cancer, targeting stemness, metastasis, and apoptosis.
- Let-7i induces a BRCAness phenotype, enhancing olaparib sensitivity in non-BRCA mutated ovarian cancers.
- Let-7i's inhibition of HRR pathway factors provides a mechanistic basis for its therapeutic potential in ovarian cancer treatment.
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