Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers
| Autor: | Young Hwa Soung, Jun Chung, Hyungjin Kim, Jingfang Ju, Andrew Fesler, Eok Soo Oh, Heesung Chung, Cecilia Yan |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research lcsh:RC254-282 Article law.invention Metastasis ARRDC3 03 medical and health sciences 0302 clinical medicine Breast cancer law microRNA Arrestin Medicine Metastasis suppressor Receptor triple-negative breast cancers business.industry chemoresistance miR-489 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Oncology Tumor progression 030220 oncology & carcinogenesis CMM489 Cancer research Suppressor business |
| Zdroj: | Cancers Volume 12 Issue 8 Cancers, Vol 12, Iss 2209, p 2209 (2020) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12082209 |
| Popis: | Triple-negative breast cancers (TNBCs) lack ER, PR and her2 receptors that are targets of common breast cancer therapies with poor prognosis due to their high rates of metastasis and chemoresistance. Based on our previous studies that epigenetic silencing of a potential metastasis suppressor, arrestin domain-containing 3 (ARRDC3), is linked to the aggressive nature of TNBCs, we identified a sub-group of tumor suppressing miRNAs whose expressions were significantly up-regulated by ARRDC3 over-expression in TNBC cells. Among these tumor suppressing miRs, we found that miR-489 is most anti-proliferative in TNBC cells. miR-489 also blocked DNA damaging responses (DDRs) in TNBC cells. To define the mechanism by which miR-489 inhibits TNBC cell functions, we screened the potential target genes of miR-489 and identified MDC-1 and SUZ-12 as novel target genes of miR-489 in TNBC cells. To further exploit the therapeutic potentials of miR-489 in TNBC models, we chemically modified the guide strand of miR-489 (CMM489) by replacing Uracil with 5-fluorouracil (5-FU) so that tumor suppressor (miR-489) and DNA damaging (5-FU) components are combined into a single agent as a novel drug candidate for TNBCs. Our studies demonstrated that CMM489 shows superior effects over miR-489 or 5-FU in inhibition of TNBC cell proliferation and tumor progression, suggesting its therapeutic efficacy in TNBC models. |
| Databáze: | OpenAIRE |
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