miR‐214‐5p targets KLF5 and suppresses proliferation of human hepatocellular carcinoma cells

Abstract

MicroRNAs (miRNAs) are small endogenous conserved RNAs regulating genes expression through base pairing with the 3'-untranslated region (3'-UTR) of target messenger RNAs. MiR-214-5p is a newly identified miRNA with its biological role largely unknown. In this study, we explored miR-214-5p expression status in 78 paired tumor and nontumor tissues obtained from patients with hepatocellular carcinoma (HCC) by RT-qPCR. The effects of miR-214-5p expression on HCC cell proliferation, cell cycle progression, and cell migration were measured by CCK-8 assay, flow cytometry, and wound-healing assay. A dual-luciferase activity assay was performed to identify whether KLF5 was a target of miR-214-5p. Kaplan-Meier curve and log-rank test were used to investigate the effects of miR-214-5p and KLF5 on overall survival and disease-free survival of patients with HCC. We found miR-214-5p expression was sharply reduced in HCC tissues and cell lines compared with the normal tissues and cell lines. Functional assay revealed that miR-214-5p overexpression could downregulate cell proliferation, cell migration, and arrested cell cycle at G0/G1 phase. Further, we validated Krüppel-like factor 5 (KLF5) as a direct target of miR-214-5p, and was upregulated in HCC and inversely correlated with the expression of miR-214-5p. Moreover, we found the low expression of miR-214-5p and high expression of KLF5 were correlated with tumor size, tumor stage, and poorer 5-year overall survival and disease-free survival of patients with HCC. In conclusion, our results suggested miR-214-5p functions as a tumor suppressor through targeting KLF5 in HCC. Also, miR-214-5p and KLF5 were identified as potential prognostic markers and might be therapeutic targets in HCC.

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

“…We show that knocking down eEF2K reduces the protein levels of KLF5 and SP1 and hence leads to a reduction in the levels of bound KLF5/SP1 to the VEGF promoter, hence inhibiting the transcription of VEGF . KLF5 has been reported to aid the proliferation and migration of cancer stem cells in HCC . SP1 is involved in tumor growth and invasion of HCC .…”

“…KLF5 has been reported to aid the proliferation and migration of cancer stem cells in HCC. [36][37][38] SP1 is involved in tumor growth and invasion of HCC. 39,40 KLF5 and SP1 are also potential tumor prognosis markers in other types of cancers (i.e., breast cancers) where eEF2K is highly expressed, 35,41,42 hence the regulation of KLF5 and SP1 by eEF2K may not only be limited to HCC.…”

6mer Seed Toxicity in Viral microRNAs

“…Although there was no v-miRNA with the same 6mer seed as miR-34a-5p, we found a v-miRNA that shared the same 2-7 nucleotides present in the predominant 5p arm of the miR-15/16-5p miRNA family. kshv-miR-K12-6-5p (miR-K12-6-5p) contains a GC-rich trinucleotide repeat seed sequence that is found in three miRNA families with ample published evidence for having tumor suppressive activities: miR-15/16-5p (Bonci et al, 2008;Calin et al, 2002Calin et al, , 2008Han et al, 2017;Hu et al, 2018;Huang et al, 2015;Ke et al, 2013;Klein et al, 2010;Lovat et al, 2015Lovat et al, , 2018Maximov et al, 2019;Pekarsky and Croce, 2015;Rahman et al, 2014;Yang et al, 2014), miR-214-3p (Cagle et al, 2019;Fan et al, 2017;Huang et al, 2014;Liu et al, 2016;Long et al, 2015;Pang et al, 2018;Phatak et al, 2016;Wang et al, 2012;Yang et al, 2015Yang et al, , 2018bZhang et al, 2017), and miR-103/107-3p Feng et al, 2012;Fu et al, 2019;Gao et al, 2017;Piao et al, 2012;Sharma et al, 2017;Song et al, 2015;Yamakuchi et al, 2010;Yang et al, 2018a;Zhang et al, 2019) (Figure 2A). miR-K12-6-5p shares an 8mer seed sequence with miR-15a-5p, miR-15b-5p, and miR-16-5p and a 6-, 7-, or 8mer seed with other members of this family (Figure 2A).…”

Transcriptional and Epigenetic Regulation of Krüppel-Like Transcription Factors

“…In gastric cancer, miR-145-5p directly targets KLF5 and promotes the differentiation of gastric cancer via KLF5 downregulation [75]. Separately, in hepatocellular carcinoma miR-214-5p acted as a tumor suppressor that could directly target and promote the downregulation of KLF5 [76]. These data demonstrate complex regulatory pathways involved in KLF5 regulation in cancer progression.…”