Abstract
Simple SummaryOvarian 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.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.
Highlights
Ovarian cancer is the second most common gynecological malignancy in the USA, with 90% of cancers being epithelial ovarian cancers [1,2]
We demonstrate that let-7i up-regulation results in decreased stemness and self-renewal, reduced anchorage-independent growth, decreased functional phenotypes associated with cancer metastasis, increased apoptosis, and increased chemosensitivity to olaparib in BRCA wild-type (WT) samples
We focused on the influence of miRNA let-7i on the homologous recombination repair (HRR) pathway and showed that let-7i overexpression contributes to the BRCAness phenotype, and targeted therapy sensitivity
Summary
Ovarian cancer is the second most common gynecological malignancy in the USA, with 90% of cancers being epithelial ovarian cancers [1,2]. Most cases of epithelial ovarian cancer are of high-grade serous ovarian carcinoma (HGSOC) with a long-term survival rate of 30%. The majority (85%) of ovarian cancer patients respond well to initial therapy; about 75% relapse, and this results in poor prognosis and survival [3,4]. Tumor recurrence/progression after initial therapy is due to the existence of a population of cancer stem-like cells within the tumor present at the inception of treatment. Cancer stem cells (CSCs) are partially responsible for the maintenance and growth of tumors [5]. The first-line treatment of ovarian cancer involves primary surgical debulking treatment followed by six to eight cycles of combination chemotherapy, typically of platinumbased and taxane agents, sometimes with the addition of VEGF inhibitor bevacizumab [6]
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