miR-148a inhibits self-renewal of thyroid cancer stem cells via repressing INO80 expression
| Autor: | Wei-Zhong Sheng, Tian-Geng Dong, Yu-Sheng Chen, Yuda Gong, Wei-Dong Gao, Bo Zhang |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Population Thyroid Gland Gene Expression Antineoplastic Agents Mice SCID Biology Stem cell marker medicine.disease_cause Thyroid Carcinoma Anaplastic 03 medical and health sciences Cancer stem cell Mice Inbred NOD microRNA medicine Tumor Cells Cultured Animals Humans Thyroid Neoplasms Cell Self Renewal education Aged education.field_of_study Binding Sites Oncogene Base Sequence DNA Helicases General Medicine Cell cycle Middle Aged Xenograft Model Antitumor Assays DNA-Binding Proteins Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology Oncology Cancer research Neoplastic Stem Cells ATPases Associated with Diverse Cellular Activities Female RNA Interference Stem cell Cisplatin Carcinogenesis |
| Zdroj: | Oncology reports. 36(6) |
| ISSN: | 1791-2431 |
| Popis: | Anaplastic thyroid carcinoma (ATC) is aggressive and lethal with extrathyroidal invasion, distant metastasis, and resistance to conventional therapies. Cancer stem cells (CSCs) are proposed to be responsible for high recurrence rate in ATC. MicroRNAs (miRNAs) have recently been found as an important class of cellular regulators of ATC carcinogenesis. Identification of CSC-related miRNAs and targets is therefore a priority for the development of new therapeutic paradigms. Patient-derived ATC cells were cultured in conditional media on poly-hema-treated dish. ATC CSCs were isolated and enriched through as a series of steps including initial isolation of sphere-forming CSC population, subsequent amplification of this CSC population in a xenograft model treated with cisplatin, and purification of CSCs from xenograft tumors followed by final enrichment using sphere-forming assays. Expression of CSC markers was measured by flow cytometry, immunofluorescence staining, qPCR and western blot analyses. Expression of miRNAs in ATC-CSCs was profiled by microarray analysis. Proliferation and differentiation rates were determined based on the size of spheres formed in vitro and tumors formed in vivo. We successfully isolated and enriched an ATC-CSC population. We identified 17 miRNAs differentially expressed in primary ATC cells vs. ATC-CSCs, among which miRNA-148a was significantly downregulated in ATC-CSCs. Overexpression of miRNA148a in ATC-CSCs induced cell cycle arrest and loss of stem cell characteristics. In addition, we identified INO80 as a target gene of miR-148a. The expression of INO80 was upregulated in ATC-CSCs and downregulated upon miRNA-148 overexpression. Overexpression of miRNA-148a and knockdown of INO80 acted synergistically to decrease the expression of stem cell marker genes as well as to attenuate stem cell-specific properties including the ability to form tumors. This study identified novel contrasting roles for miR-148a and INO80 in the regulation of the stemness of ATC-CSCs and their capacity to initiate tumor formation. Our findings may open a new avenue for therapeutic development against ATC that targets INO80 in the CSCs through enhancing miRNA-148a levels. |
| Databáze: | OpenAIRE |
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