MiR-199a Inhibits Tumor Growth and Attenuates Chemoresistance by Targeting K-RAS via AKT and ERK Signalings.

Wei Li,Xin Ge,Wei-Tao Liu,Zhong Zheng,Li-Hong Wang,Bing-Hua Jiang,Ling Chen,Ling-Zhi Liu,Xiang-Bo Ji,Jie-Yu Chen,Marie C Lin,Lin Wang,Zhu-Mei Shi

doi:10.3389/fonc.2019.01071

Abstract

Glioma is the most malignant brain tumors in the world, the function and molecular mechanism of microRNA-199a (miR-199a) in glioma is not fully understood. Our research aims to investigate miR-199a/K-RAS axis in regulation of glioma tumor growth and chemoresistance. The function of miR-199a in glioma was investigated through in vitro and in vivo assays. We found that miR-199a in tumor tissues of glioma patients was significantly downregulated in this study. Kinase suppressor of ras 1 (K-RAS), was indicated as a direct target of miR-199a, as well as expression levels of K-RAS were inversely correlated with expression levels of miR-199a in human glioma specimens. Forced expression of miR-199a suppressed AKT and ERK activation, decreased HIF-1α and VEGF expression, inhibited cell proliferation and cell migration, forced expression of K-RAS restored the inhibitory effect of miR-199a on cell proliferation and cell migration. Moreover, miR-199a renders tumor cells more sensitive to temozolomide (TMZ) via targeting K-RAS. In vivo experiment validated that miR-199a functioned as a tumor suppressor, inhibited tumor growth by targeting K-RAS and suppressed activation of AKT, ERK and HIF-1α expression. Taken together, these findings indicated that miR-199a inhibits tumor growth and chemoresistance by regulating K-RAS, and the miR-199a/K-RAS axis is a potential therapeutic target for clinical intervention in glioma.

Highlights

Malignant gliomas, as most common brain tumors around the world [1, 2], are classified according to their degree of malignancy as Grades I to IV [3, 4]
In tumor tissues of glioma patients, we showed that miR-199a expression were correlated with the clinical stages, which indicated that miR-199a in high grade tumors (n = 8, WHO Grades III-IV) were significantly lower when compared to those in low grade tumors (n = 8, WHO Grade I and n = 8, WHO Grade II) (Figure 1B)
To overexpress miR-199a, human glioma cells U87 and U251 were infected with lentivirus expressing miR-199a, and lentivirus expressing miR-NC was used as control

Summary

Introduction

As most common brain tumors around the world [1, 2], are classified according to their degree of malignancy as Grades I to IV [3, 4]. Glioma clinical treatment includes surgery, chemotherapy and radiotherapy [5, 6]. MicroRNAs (miRNAs) are a class of endogenous 18–22 nucleotides RNA molecules [8, 9], which always bind to the 3′-untranslated region (UTR) of specific target mRNAs, and regulate miR-199a Targets K-RAS in Glioma expression of several genes at the post-transcriptional level [10,11,12,13,14]. Accumulated evidence has clearly demonstrated that aberrant miRNA expression profiles [15] and dysregulations of specific miRNAs and their target genes, are closely associated with tumor initiation and promotion in glioma [16, 17]. The reported miR-199a downstream target genes include oncogenes PHLPP1, E2F3, FZD6/7, HK2, and MAP3K11 [18,19,20,21,22,23], which are functioned in pathogenesis of various cancers

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Results

Conclusion