miR-148a inhibits self-renewal of thyroid cancer stem cells via repressing INO80 expression

Abstract

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.

Microrna-136 promotes proliferation and invasion ingastric cancer cells through Pten/Akt/P-Akt signaling pathway

“…Previously, miRNAs have been demonstrated to be functionally involved in the regulation of a series of physiological and pathological processes, including cell proliferation, apoptosis, differentiation and invasion (9). Alterations in the expression of miRNAs have been widely reported in almost all types of cancer, including hepatocellular carcinoma (10), cervical (11), thyroid (12), colorectal (13) and gastric cancer (14). Previous studies have demonstrated that expression levels of miRNAs are associated with cancer initiation and progression (15)(16)(17).…”

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

“…Oct4, Nanog and ALDH [78] miR-23a PTEN/PI3K/Akt [79] miR-494-3p NOTCH1-PI3K [80] miR-19a/19b Wnt/β-catenin [81] Mir-21 Nanog-Stat-3 [113] miR-145 ADAM17, SOX9 [114] miR-200c ALDH1, Nanog, Oct4, SOX2. [115] Ovarian miR-328 ERK [116] miR-20a miR-200c PI3K/AKT [117] miRNA-34c-5p EGFR-ERK [118] miR-92a Wnt [119] miR-1207 Wnt/β-catenin [120] miR-17 LKB1-p53-p21/WAF1 [121] miR-136 NOTCH3, NF-kB, Cyclin D1, Survivin, BCL-XL, BCL2 [122] Thyroid miR-21 ABCG2, Oct4 [123] miR-148a ATC-CSCs [124] Further, we have also elaborated how miRNAs modulate signaling pathways associated with CSCs and highlighted that exclusive targeting of the dysregulated miRNAs can be of great therapeutic significance in human cancers ( Figure 3).…”

“…Anaplastic thyroid carcinoma (ATC) accounts for 14-39% of all reported deaths due to thyroid cancer. ATC is the most aggressive type of thyroid cancer and is more metastatic, invasive, and resistant to therapies [124]. The relation between miRNAs and thyroid CSCs is not yet well-known and needs more exploring, and only a few studies have reported the role of miRNAs in thyroid CSC regulation and development.…”

“…As a result, the differentiation of SW1735 and C643 cell lines is more induced and it is thought to enhance their sensitivity to chemotherapies [123]. Another study showed that suppressed miR-148a expression in ATC-CSCs is critical for the stemness features and tumor formation as the re-expression of miR-148a promoted G2/M cell cycle arrest and inhibited stemness of ATC-CSCs [124].…”

The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer

“…Several studies have been done to characterize its oncogenic role in cancer and maintenance of stem cells; however, studies in PDAC are missing. INO80 is upregulated in cancer cell lines and human cancer tissues, including lung cancer, colon cancer, and melanoma [67][68][69]218]. Functional studies demonstrated that INO80 is required for proliferation, viability, clonogenicity, and anchorage-independent growth of cancer cells in vitro and tumor formation in vivo [67,68,218].…”