Exosomal miR-21 regulates the TETs/PTENp1/PTEN pathway to promote hepatocellular carcinoma growth

Liang-Qi Cao,Xue-Wei Yang,Xiao-Feng Jiang,Yu-Bin Chen,Da-Wei Zhang,Ping Xue

doi:10.1186/s12943-019-1075-2

Liang-Qi Cao, Xue-Wei Yang + Show 4 more

Open Access

https://doi.org/10.1186/s12943-019-1075-2

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Abstract

BackgroundAs an important means of communication, exosomes play an important role in the development of hepatocellular carcinoma (HCC).MethodsBioinformatics analysis, dual-luciferase reporter assays, methylation-specific quantitative PCR, and ChIP-PCR analysis were used to gain insight into the underlying mechanism of miR-21 in HCC.ResultsThe detection of miRNAs in exosomes of HCC showed that miR-21 expression in exosomes was positively correlated with the expression level of miR-21 in cells and negatively correlated with the expression of its target genes PTEN, PTENp1 and TETs. HCC cell-derived exosomes could increase miR-21 and p-Akt expression in HCC cells and downregulate the expression of PTEN, PTENp1 and TETs. MiR-21 inhibitors or PTENp1 overexpression vectors could weaken the effect of the abovementioned exosomes and simultaneously weaken their role in promoting cell proliferation and migration and inhibiting apoptosis. Further studies showed that miR-21 not only directly regulated the expression of PTEN, PTENp1 and TETs but also increased the methylation level of the PTENp1 promoter by regulating the expression of TETs, thereby inhibiting the expression of PTENp1 and further downregulating the expression of PTEN.ConclusionsExosomal miR-21 can regulate the expression of the tumor suppressor genes PTEN and PTENp1 in various ways and affect the growth of HCC cells.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks fifth in incidence and third in mortality [1]
hepatocellular carcinoma (HCC) cells secrete exosomes with high levels of miR-21, and miR-21 has an inverse relationship with PTENp1 and Phosphatase and tensin homolog (PTEN) expression The secretion of exosomes in normal hepatocytes and HCC cells was detected, and the results showed that both types of cells could secrete exosomes that expressed exosome-specific markers (Fig. 1a, b), and their diameters were mainly between 70 and 120 nm (Fig. 1c)
The expression of miR-21 was generally upregulated in HCC cells, but its expression in HCC cells from different sources was significantly different, and miR-21 expression was significantly upregulated in exosomes derived from HCC cells with high expression of miR-21 (Fig. 1d)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks fifth in incidence and third in mortality [1]. It is necessary to study the molecular mechanism of the occurrence and development of HCC and the signaling pathways that regulate tumor invasion and metastasis. Phosphatase and tensin homolog (PTEN) is an important target gene of miR-21, which inhibits tumor cell apoptosis and increases tumor cell growth, metastasis and invasion by downregulating the expression of PTEN. PTEN is a tumor suppressor gene with bispecific phosphatase activity, and its expression is generally decreased in liver cancer and other tumors [11]. Yu et al [12] found that the expression of PTENp1 was generally low or undetectable in clinical samples of primary clear cell renal cell carcinoma due to methylation and was positively correlated with the expression of the tumor suppressor gene PTEN. As an important means of communication, exosomes play an important role in the development of hepatocellular carcinoma (HCC)

Methods

Results

Conclusion