Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Autor: Linda Sanderman, Nozomi Hojo, Yevgeniya Ioffe, Tise Suzuki, Evgeny Chirshev, Hanmin Wang, Juli Unternaehrer, Anthony L. Nguyen, Saied Mirshahidi
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Cancers
Volume 13
Issue 18
Cancers, Vol 13, Iss 4617, p 4617 (2021)
ISSN: 2072-6694
Popis: Simple Summary Ovarian cancer has a dismal prognosis and innovative treatment options are necessary to improve survival. Because the microRNA let-7 is often lost in this and other cancers, and its loss is associated with poor prognosis, we focused on therapeutic strategies to replace it. We report that let-7 overexpression in patient-derived cells resulted in a loss of aggressiveness: inhibition of migration and invasion (associated with metastasis), repression of cancer stem cell attributes (necessary for tumor maintenance and recurrence), and promotion of cell death (required for sensitivity to chemotherapy drugs). Further, cells in which let-7 is overexpressed were more sensitive to PARP inhibitors, even in patients who otherwise could not benefit from these drugs. We show that let-7 reduces the expression of several genes that may contribute to these effects. These actions of let-7 add to the rationale for use of this miRNA as a treatment for selected ovarian cancer patients. 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.
Databáze: OpenAIRE
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