Dual inhibition of RNAi therapeutic miR-26a-5p targeting cMet and immunotherapy against EGFR in endometrial cancer treatment

Abstract

Background: Precise prediction of drug combination targeting tumor cells effectively is a crucial challenge for tumor therapy, especially for endometrial cancer (EC). Considering the resistance, crosstalk that occurs between the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMet) and epidermal growth factor receptor (EGFR), and their indispensable influence on the occurrence of EC, this study aimed to explore a novel therapeutic approach for EC treatment through blocking cMet and EGFR simultaneously.Methods: In the present study, the expression of miR-26a-5p in EC cell lines was detected using quantitative real-time polymerase chain reaction assay. The potential role of miR-26a-5p in the development of EC was examined using cell counting kit assay, 5-ethynyl-2'-deoxyuridine staining, wound healing assay, and cell apoptosis staining assay. Subsequently, the effect of upregulated miR-26a-5p in vivo was confirmed on a xenograft model. Luciferase reporter assay and Western blot analysis were performed to verify the relation between miR-26a-5p and cMet. Furthermore, the dual therapeutic effect of miR-26a-5p and EGFR monoclonal antibody cetuximab was confirmed in vivo and in vitro. Results:The results indicated that miR-26a-5p expression significantly reduced in EC cell lines compared with the normal endometrial cell line. Furthermore, the overexpression of miR-26a-5p inhibited the progression of EC, including cell migration, cell proliferation, and cell apoptosis in vivo and in vitro.Subsequently, mir-26a-5p regulated the expression of cMet and the downstream the hepatocyte growth factor (HGF)/cMet pathway, thus exerting an inhibitory effect on EC cells. In addition, the study also demonstrated that the upregulation of miR-26a-5p could significantly enhance the inhibitory effect of cetuximab compared with the use of cetuximab alone in vivo and in vitro.Conclusions: RNAi therapeutic miR-26a-5p suppressed the progression of EC through regulating the cMet/HGF pathway. The dual therapy using RNA interference and neutralizing antibody simultaneously blocked tumor targets, including cMet and EGFR, thus providing a novel approach for overcoming the resistance to the inhibitors against a single target in EC treatment.

Understanding How Pregnancy Protects Against Ovarian and Endometrial Cancer Development: Fetal Antigens May Be Involved

“…Our recent study (under review) found that up to 7 miRNAs (miR-519a-5p, miR-199b-3p, miR-199a-3p, miR-148a-3p, miR-26a-5p, miR-512-3p, and miR-143-3p) identified in placental EVs inhibited ovarian or endometrial cancer cell proliferation and migration, and promoted cancer cell death. Interestingly, most of these miRNAs have been reported to be downregulated in ovarian ( 66–70 ) and endometrial cancer tissues or cell lines ( 71 , 72 ). Recently, we found that treating ovarian cancer cells with placental EVs isolated from first trimester placentae significantly reduced ovarian cancer cell proliferation due to a delay in cell cycle progression ( 73 ).…”

MiR-26a-5p exerts its influence by targeting EP300, a molecule known for its role in activating the PI3K/AKT/mTOR signaling pathway in CD8+tumor-infiltrating lymphocytes of colorectal cancer

“…These miRNAs are vital for orchestrating immune control within tumor infiltrations (15). One such miRNA, miR-26a-5p, was found to target tumor cells and inhibit the progression of various carcinomas, including renal cell carcinoma, NSCLC, as well as endometrial cancer (16)(17)(18). Yet, the precise regulatory mechanism of miR-26a-5p in tumor-infiltrating T lymphocytes remains unidentified.…”

MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell

“…MiR-26a-5p promoted tumor progression by suppressing activation of PTEN signaling in the non-small cell lung cancer [ 10 ]. The expression of miR-26a-5p was significantly reduced in endometrial cancer and cell lines, and overexpression of miR-26a-5p enhanced the inhibitory effect of cetuximab by regulating cMet/HGF pathway in vivo and in vitro [ 11 ]. The miR-26a-5p/ARPP19 axis modulated nasopharyngeal carcinoma progression by sponging lncRNA SNHG6 [ 12 ].…”