Anti-miR182 Reduces Ovarian Cancer Burden, Invasion, and Metastasis: An In Vivo Study in Orthotopic Xenografts of Nude Mice

Abstract

High-grade serous ovarian carcinoma (HGSOC) is a fatal disease, and its grave outcome is largely due to widespread metastasis at the time of diagnosis. Current chemotherapies reduce tumor burden, but they do not provide long term benefits for cancer patients. The aggressive tumor growth and metastatic behavior characteristic of these tumors demand novel treatment options such as anti-microRNA treatment which is emerging as a potential modality for cancer therapy. MicroRNA-182 miR-182 overexpression contributes to aggressive ovarian cancer, largely by its negative regulation of multiple tumor suppressor genes involved in tumor growth, invasion, metastasis, and DNA instability. In this study, we examined the therapeutic potential of anti-miR-182 utilizing the animal orthotopic model to mimic human ovarian cancer using ovarian cancer cells SKOV3 (intrabursal xenografts) and OVCAR3 (IP injection). These models provide a valuable model system for the investigation of ovarian cancer therapy in vivo. Through a combination of imaging, histological, and molecular analyses, we found that anti-miR-182 treatment can significantly reduce tumor burden (size), local invasion, and distant metastasis compared to its control in both models. The bases of anti-miR-182 treatment are mainly through the restoration of miR-182 target expression, including but not limited to BRCA1, FOXO3a, HMGA2 and MTSS1. Overall, our results strongly suggest that anti-miR-182 can potentially be used as a therapeutic modality in treating HGSOC.

Small RNA sequencing reveals a comprehensive miRNA signature ofBRCA1-associated high-grade serous ovarian cancer

“…miR-182-5p is also overexpressed in STIC, the precursor of HGSOC, suggesting a potential role in early carcinogenesis 15. This is further confirmed by the efficient reduction in tumour burden of antisense oligo's complementary to miR-182-5p in HGSOC mice models 23. We showed enhanced miR-205-5p expression levels in HGSOC tissue.…”

MicroRNAs in gynecological cancers: Small molecules with big implications

“…Other miRNAs that regulate invasion of GCs are miR-124 [191], miR-335 [192], miR-339 [193], miR-130b [194] and miR-181 [195]. miR-182 seems to be important for OC metastasis because its inhibition was shown to result in significantly reduced tumor burden, local invasion and distant metastasis in an in vivo orthotopic model of serous ovarian carcinoma [196]. miR-22 is a potential metastasis-suppressing miRNA in OC cells with putative regulation of several pro-metastatic genes [197].…”

“…miR-182 overexpression is known to promote the aggressiveness of OC. Xu et al examined the delivery of anti-miR-182 to an animal model mimicking human OC [196]. It was reported that anti-miR-182 treatment is potent enough to inhibit tumor growth and metastasis.…”

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

“…Anti-miR-182 treatment inhibits invasion, proliferation and anchorage-independent cell growth of EOC cell lines SKOV-3, HEY and OVCAR3, as well as the growth and size of tumors resulting from i.p. injected OVCAR3 cells (38). The impact of miR-182 on EOC cell metastasis was investigated by intrabursal implantation of pellets derived from OVCAR3 cells, where anti miR-182 treatment resulted in a five-fold reduction of nodules in peritoneal organs compared to controls (38).…”

“…injected OVCAR3 cells (38). The impact of miR-182 on EOC cell metastasis was investigated by intrabursal implantation of pellets derived from OVCAR3 cells, where anti miR-182 treatment resulted in a five-fold reduction of nodules in peritoneal organs compared to controls (38). Another study investigated the role of miR-182 in T29 and T80 (surface epithelium), FTE 187 (fallopian tube) and HEY, SKOV3 and OVCAR3 (EOC) cell lines, and showed that miR-182 increased transformation and invasiveness, but had no impact on proliferation.…”