Abstract
The pro-oncogene ETS-1 (E26 transformation-specific sequence 1) is a key regulator of the proliferation and invasion of cancer cells. The present work examined the correlation of the aberrant expression of ETS-1 with histological or clinical classification of astrocytoma: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma multiforme). MicroRNA, miR-338-5p, was predicted by an online tool (miRDB) to potentially target the 3’ untranslated region of ETS-1; this was confirmed by multi-assays, including western blot experiments or the point mutation of the targeting sites of miR-338-5p in ETS-1’s 3’untralation region (3’UTR). The expression of miR-338-5p was negatively associated with that of ETS-1 in astrocytoma, and deficiency of miR-338-5p would mediate aberrant expression of ETS-1 in astrocytoma. Mechanistically, hypermethylation of miR-338-5p by DNA methyltransferase 1 (DNMT1) resulted in repression of miR-338-5p expression and the aberrant expression of ETS-1. Knockdown or deactivation of DNMT1 decreased the methylation rate of the miR-338-5p promoter, increased the expression of miR-338-5p, and repressed the expression of ETS-1 in astrocytoma cell lines U251 and U87. These results indicate that hypermethylation of the miR-338-5p promoter by DNMT1 mediates the aberrant expression of ETS-1 related to disease severity of patients with astrocytoma.
Highlights
Astrocytoma, which originates from astrocytes in the brain, is the most common and fatal type of brain tumor [1,2,3,4,5]
Our results were consistent with those of Ren et al and would reveal the potential mechanism underlying the high expression of MMPs, that is, the high expression of ETS-1 in astrocytoma tissue may eventually participate in the high expression of MMPs
The highly aggressive characteristics of malignant tumor cells are closely related to disease progression; the main mechanism of this process is that malignant tumor cells destroy extracellular matrix (ECM) through MMPs and so on to reshape the basic structure of tissues, thereby promoting both the growth of tumor cells and their transfer to other locations [44,45,46,47,48]
Summary
Astrocytoma, which originates from astrocytes in the brain, is the most common and fatal type of brain tumor (glioma) [1,2,3,4,5]. There are four histological or clinical grades of the disease: grade I (pilocytic astrocytoma) [6], grade II (diffuse astrocytoma) [7], grade III (anaplastic astrocytoma) [8], and grade IV (glioblastoma multiforme, GBM) [9]. More severe astrocytoma (i.e., grades III and IV) [10,11,12] is associated with worse prognosis and more aggressive disease. Patients with grade II astrocytoma have a survival of approximately 7–8 years [13,14,15]. Patients with grade III astrocytoma have an average/median 2–3 year survival, and the median survival of patients with GBM (grade IV astrocytoma) is only 9–14 months [13,14,15]. Detection of protein factors related to the occurrence and progression of the disease in clinical specimens of different grades is helpful for diagnosis, and can help to clarify the molecular mechanisms underlying disease progression
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