The epigenetic effect of microRNA in BCR-ABL1-positive microvesicles during the transformation of normal hematopoietic transplants

Abstract

Epigenetics have been demonstrated to play a pivotal role in the progression of multiple cancers. Our previous study has demonstrated that microvesicles (MVs) derived from K562 cells could malignantly transform normal hematopoietic cells. The aim of this section was to elucidate the epigenetic effects of RNA in K562-MVs. We altered some epigenetic RNAs (miR-106a-5p, miR-106b-5p and lincPOU3F3) in K562-MVs and followed the process of transformation. Global DNA methylation and DNA methyltransferase (DNMT) levels were observed respectively. Our findings revealed that increased miR-106a/b in K562-MVs accelerated the transformation process (8.33±0.94 vs. 13.29±1.28 days; P<0.01) whereas decreased lincPOU3F3 delayed the transformation (17.83±0.29 days; P<0.05). The targets of miR-106a/b and lincPOU3F3 in the recipient cells were DNMT3a and DNMT3b. We found that lincPOU3F3 directly increased the DNMT3a/b while miR-106a/b only in part by targeting RB. However, global DNA methylation and special gene methylation was altered due to the concurrent regulation of DNMT3a and DNMT3b. Consequently, we demonstrated that tumor-derived MVs represent a notable intercellular epigenetic communication between cancer cells and recipient cells.

Exosomal and Ectosomal Noncoding RNAs in Cancer–More Than Diagnostic and Prognostic Markers

“…In a study on malignant mammary epithelial cells, numerous exosomal miRNAs were shown to influence various oncogenic networks [17]. microvesicular miR-106a/b was reported to promote malign transformation of hematopoietic cells [18]. Similar results on leukemic transformation were obtained with miR-146b-5p in microvesicle from chronic myelogenous leukemia cells [19].…”

“…As shown above, exosomes and ectosomes carrying ncRNA cargos can spread pathological messages from cancer to other cells and even seem to participate in processes of transformation [18,19]. Obviously, they also influence cell types different from those from which the tumor cells originated.…”

“…shown to be strongly reduced in cancer-associated fibroblasts, which release tumor-promoting exosomes [23]. Other cytosine-5-methyltransferases, DNMT3a and 3b, were upregulated by an lncRNA, lincPOU3F3 (linc = long intergenic noncoding), perhaps by sequestering the procarcinogenic miR-106a/b [18]. By virtue of this property, lincPOU3F3 delayed the malign transformation of hematopoietic cells [18].…”

“…Other cytosine-5-methyltransferases, DNMT3a and 3b, were upregulated by an lncRNA, lincPOU3F3 (linc = long intergenic noncoding), perhaps by sequestering the procarcinogenic miR-106a/b [18]. By virtue of this property, lincPOU3F3 delayed the malign transformation of hematopoietic cells [18]. Moreover, numerous miRNAs with tumor suppressing properties have been identified, as summarized elsewhere [5].…”