Naslov
Upregulation of miRNA-200 family members in human paclitaxel resistant OVCAR-3/TP cells alters the sensitivity to carboplatin, but not paclitaxel

Autori
Brozovic, Anamaria ; Duran, George E. ; Moisan, François ; Francisco, E. Brian ; Wang, Yan C. ; Sikic, Branimir I.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
Stanford Oncology and Hematology Annual Research Retreat

Mjesto i datum
Pacific Grove (CA), Sjedinjene Američke Države, 23.10.2013. - 25.10.2013

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
miRNA-200 family; paclitaxel; carboplatin; drug resistance; EMT

Sažetak
Several miRNA-200 family members (miR-200a, 200b, 200c, 429, and 141) have been associated with the regulation of epithelial-mesenchymal transition (EMT). EMT is involved in cancer cell invasion and metastasis, and has been implicated in cellular resistance to taxane drugs. We have generated a series of taxane resistant models of ovarian cancer cells that demonstrate a strong EMT phenotype associated with the downregulation of miRNA-200 family members. OVCAR-3/TP variants are five-fold resistant to paclitaxel compared to parental OVCAR-3 cells, and manifest marked decreases in miR-200c and 141 content, modest decreases in miR-200a, 200b, and 429, upregulation of the mesenchymal markers vimentin and fibronectin, and downregulation of E-cadherin. In order to examine the role of miRNA-200 family members in paclitaxel resistance, OVCAR-3/TP cells were infected with retroviral particles carrying either an empty mCherry-retroviral construct, the miR-200ab429 (OVCAR-3/TPab429) cluster or the miR-200c141 (OVCAR-3/TPc141) cluster. The introduction of miRNA-200 family members to mesenchymal OVCAR-3/TP cells resulted in downregulation of the EMT transcriptional regulators, ZEB1 and ZEB2, and partial reversion of vimentin, fibronectin and E-cadherin to the levels in epithelial OVCAR-3 parental cells. Despite the increased miR-200ab429 and miR-200c141 expression and the reversal of the EMT phenotype in the OVCAR-3/TP cells, paclitaxel resistance was not altered. In contrast, the miRNA-200 expressing cell lines are two to four-fold resistant to carboplatin under identical experimental conditions. This finding is observed more in OVCAR-3/TPc141 compared to OVCAR-3/TPab429, which implies a different role of these two miRNA clusters in determining cellular responses to carboplatin. These data were confirmed by transfecting OVCAR-3/TP cells with 50 and 100 nM mirVana miRNA mimics (Life Technologies, Grand Island, NY) specific for miR-200c and 141, resulting in no change in paclitaxel sensitivity but three-fold resistance to carboplatin. Similar data were obtained for two additional ovarian cancer cell lines (MES-OV and Hey). We conclude that increased expression of miR-200c and 141 and their mimics in paclitaxel resistant OVCAR-3/TP cells does not affect cellular sensitivity to paclitaxel, but it does result in resistance to carboplatin.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

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