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

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.

MicroRNA Let-7d-3p Contributes to Cardiac Protection via Targeting HMGA2

“…Thus far, there has been no such report to show the protective effect of Let-7d-3p in this context and it has not even been characterized in any cardiovascular diseases. In ovarian cancer, the inhibition of Let-7d-3p using antagomiRs showed a significant decreased in cell proliferation and activated apoptosis in ovarian cancer cells [32]. These results seem in line with our finding that Let-7d-3p mimic enhanced cell viability and reduced apoptosis.…”

The Construction and Analysis of the Aberrant lncRNA-miRNA-mRNA Network in Adipose Tissue from Type 2 Diabetes Individuals with Obesity

“…Studies have shown that one-third of the human genome can be regulated by miRNAs [55], which play an important regulatory role in cancers and metabolic diseases. Most miRNAs in the ceRNA network have been found to be closely related Journal of Diabetes Research to cancers [56][57][58][59]. In addition, Rohm et al [60] found that the expression of hsa-let-7d-5p was increased in the experimental group compared with the undifferentiated control group during adipogenesis.…”

Therapeutic Inducers of Apoptosis in Ovarian Cancer

“…The increased expression of let-7d-3p was correlated with a positive response to platinum/paclitaxel treatment in ovarian cancer patients. Additionally, let-7d-5p miRNA was reported to rescue ovarian cancer cells apoptosis and chemosensitivity by modulating the p53 pathway via high a mobility group 1 (HMGA1) [119].…”