let-7d-3p is associated with apoptosis and response to neoadjuvant chemotherapy in ovarian cancer

García-Vázquez,Raúl; Gallardo Rincón,Dolores; Ruiz-García,Erika; Meneses García,Abelardo; Hernández De La Cruz,Olga  N.; Astudillo-De La Vega,Horacio; Isla-Ortiz,David; Marchat,Laurence  A.; Salinas-Vera,Yarely  M.; Carlos-Reyes,Ángeles; López-González,Sullivan; Ramos-Payan,Rosalio; López-Camarillo,César

doi:10.3892/or.2018.6366

let-7d-3p is associated with apoptosis and response to neoadjuvant chemotherapy in ovarian cancer

Authors:
- Raúl García-Vázquez
- Dolores Gallardo Rincón
- Erika Ruiz-García
- Abelardo Meneses García
- Olga N. Hernández De La Cruz
- Horacio Astudillo-De La Vega
- David Isla-Ortiz
- Laurence A. Marchat
- Yarely M. Salinas-Vera
- Ángeles Carlos-Reyes
- Sullivan López-González
- Rosalio Ramos-Payan
- César López-Camarillo
View Affiliations

Affiliations: Molecular Biomedicine Program and Biotechnology Network, Instituto Politecnico Nacional, México City 07320, Mexico, Translational Medicine Laboratory, National Institute of Cancerology, México City 14080, Mexico, Translational Medicine Laboratory, National Institute of Cancerology, México City 14080, Mexico, Genomics Sciences Program, Autonomous University of Mexico City, México City 03100, Mexico, Laboratory of Translational Cancer Research and Cellular Therapy, National Medical Center ‘Century XXI’, México City 06720, Mexico, Department of Oncologic Surgery, National Institute of Cancerology, México City 14080, Mexico, Laboratory of Lung Cancer, National Institute of Respiratory Diseases ‘Ismael Cosio Villegas’, Mexico City 14080, Mexico, Sciences Faculty, Autonomous University of Culiacan, Culiacan Sinaloa 80040, Mexico
Published online on: April 12, 2018 https://doi.org/10.3892/or.2018.6366
Pages: 3086-3094

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Abstract

Altered expression of microRNAs contributes to the heterogeneous biological behavior of human malignancies and it may correlate with the clinical pathological features of patients. The let-7 microRNA family is frequently downregulated in human cancers and its aberrant expression may be a useful marker for prediction of the clinical response to therapy in patients. In the present study, we analyzed the expression of three members of the let-7 family (let-7a-3p, let-7d-3p and let-7f), which remains largely uncharacterized in ovarian cancer tissues. We also investigated the function of let-7d-3p in the apoptosis and sensitization to chemotherapy in ovarian cancer cells. Our data from stem-loop quantitative RT-PCR showed that expression of let-7a-3p and let-7d-3p, but not let-7f, was significantly (P<0.04) upregulated in ovarian tumors relative to that noted in normal ovarian tissues. Markedly, an increased expression of let‑7d-3p (also known as let-7d-3*) was associated with positive response to carboplatin/paclitaxel treatment in ovarian cancer patients. To investigate the biological relevance of let‑7d-3p, we knocked down its expression in SKOV-3 ovarian cancer cell line using antagomiRs. Loss of function analysis showed that inhibition of let-7d-3p significantly (P<0.05) impaired cell proliferation and activated apoptosis. In contrast, scratch/wound healing and Transwell chamber assays showed that migration and invasion abilities were not affected in the let-7d-3p-deficient SKOV-3 cancer cells. Notably, Annexin V assays showed a significant (P<0.05) increase in cell death of cancer cells treated with the let-7d-3p inhibitor plus carboplatin indicating a synergistic effect of the drug with antagomiR therapy. Gene ontology classification of predicted targets of let-7d-3p identified a number of genes involved in cellular pathways associated with therapy resistance such as ABC transporters, HIF-1, RAS and ErbB signaling. In summary, our findings showed that inhibition of let-7d-3 activates apoptosis and that its upregulation is associated with a positive response of ovarian cancer patients to carboplatin/paclitaxel chemotherapy.

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