Long Non−Coding RNA H19 Regulates Glioma Cell Growth and Metastasis via miR-200a-Mediated CDK6 and ZEB1 Expression

Abstract

Long non-coding RNAs (lncRNAs) serve essential roles on various biological functions. Previous studies have indicated that lncRNAs are involved in the occurrence, growth and infiltration of brain tumors. LncRNA H19 is key regulator in the pathogenesis of gliomas, but the underlying mechanisms of H19-regulated tumor progression remain unknown. Therefore, we investigated the effects and mechanism of action of lncRNA H19 on the homeostasis of glioma cells. As a novel oncogenic factor, up-regulation of H19 was able to promote the proliferation of glioma cells by targeting miR-200a. Furthermore, elevated miR-200a levels could reverse H19-induced cell growth and metastasis. Overexpression of miR-200a could significantly suppress the proliferation, migration and invasion of glioma cells. These biological behavior changes in glioma cells were dependent on the binding to potential target genes including CDK6 and ZEB1. CDK6 could promote cell proliferation and its expression was remarkably increased in glioma. In addition, up-regulation of miR-200a lead to reduction of CDK6 expression and inhibit the proliferation of glioma cells. ZEB1 could be a putative target gene of miR-200a in glioma cells. Thus, miR-200a might suppress cell invasion and migration through down-regulating ZEB1. Moreover, overexpression of miR-200a resulted in down-regulation of ZEB1 and further inhibited malignant phenotype of glioma cells. In summary, our findings suggested that the expression of H19 was elevated in glioma, which could promote the growth, invasion and migration of tumor cells via H19/miR-200a/CDK6/ZEB1 axis. This novel signaling pathway may be a promising candidate for the diagnosis and targeted treatment of glioma.

HOTTIP Mediated Therapy Resistance in Glioma Cells Involves Regulation of EMT-Related miR-10b

“…The very indication that this H19 affects MET comes through the miRNA it targets as this miRNA is very well known to be involved in regulation of EMT ( 29 ), thus making this miRNA an attractive cancer biomarker ( 30 ). Similar to our findings reported here, H9 was found to regulate EMT marker ZEB1 ( 19 ) which thus appears to be important EMT gene regulated by lncRNAs. Similarly, lncRNA SUMO1P3 also seems to affect EMT as it regulates another EMT biomarker e-cadherin ( 21 ).…”

“…The top six lncRNAs have been proven to exhibit multiple effects against glioma cells. H19 lncRNA has been shown to promote the proliferation, migration and invasion of glioma cells ( 19 ) through targeting of miR-200a. LINC00152 is similarly expressed at higher levels in gliomas where it increases proliferation and invasion ( 20 ).…”

“…Interestingly, one of the other shown lncRNA, H19 also seems to affect EMT in glioma cells ( 19 ). The very indication that this H19 affects MET comes through the miRNA it targets as this miRNA is very well known to be involved in regulation of EMT ( 29 ), thus making this miRNA an attractive cancer biomarker ( 30 ).…”

Bioinformatic analysis and clinical diagnostic value of hsa_circ_0004099 in acute ischemic stroke

“…Kovaleva [41] also found a variant of the HIF-1A gene C1772T polymorphism, which could be used as a molecular genetic molecule for predicting the risk of IS. CDK6 can activate the transcription of downstream genes involved in cell cycle regulation [42]. Zhao et al [43] found that miR-424 inhibited the proliferation and activation of microglial cells by targeting cell cyclins, such as CDK6 and CDC25A, and exerted neuroprotective effects on the ischemic brain.…”

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

“…Lnc-ATB, a long non-coding RNA, decreased the expression of miR-200c to promote cholangiocarcinoma (CCA) growth [ 47 ]. Lnc RNA H19 targeted miR-200a and promoted the invasion and migration of glioma cells [ 48 ].…”