Abstract | BACKGROUND: MATERIALS AND METHODS: Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a "sensitive" and "resistant" cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. RESULTS: microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with Zinc Finger E-Box Binding Homeobox 1 implicated as the molecular target of miR-431 in ACC. CONCLUSION: This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings. IMPLICATIONS FOR PRACTICE:
|
Authors | Grace T Y Kwok, Jing Ting Zhao, Anthony R Glover, Anthony J Gill, Roderick Clifton-Bligh, Bruce G Robinson, Julian C Y Ip, Stan B Sidhu |
Journal | The oncologist
(Oncologist)
Vol. 24
Issue 6
Pg. e241-e250
(06 2019)
ISSN: 1549-490X [Electronic] England |
PMID | 30918109
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © AlphaMed Press 2019. |
Chemical References |
- MIRN431 microRNA, human
- MicroRNAs
- ZEB1 protein, human
- Zinc Finger E-box-Binding Homeobox 1
- Doxorubicin
|
Topics |
- Adolescent
- Adrenal Cortex
(pathology, surgery)
- Adrenal Cortex Neoplasms
(genetics, pathology, therapy)
- Adrenalectomy
- Adrenocortical Carcinoma
(genetics, pathology, therapy)
- Adult
- Aged
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Apoptosis
(drug effects, genetics)
- Biopsy
- Cell Line, Tumor
- Chemotherapy, Adjuvant
(methods)
- Doxorubicin
(pharmacology, therapeutic use)
- Drug Resistance, Neoplasm
(genetics)
- Epithelial-Mesenchymal Transition
(drug effects, genetics)
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- MicroRNAs
(agonists, genetics, metabolism)
- Middle Aged
- Treatment Outcome
- Young Adult
- Zinc Finger E-box-Binding Homeobox 1
(genetics)
|