Cancer Letters

Cancer Letters

Volume 475, 10 April 2020, Pages 119-128
Cancer Letters

Original Articles
Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression

https://doi.org/10.1016/j.canlet.2020.01.022Get rights and content

Highlights

  • Exosomal hsa_circ_0051443 was a novel biomarker for the diagnosis of HCC.

  • Exosomal hsa_circ_0051443 serves as a mediator in cell–cell communication in HCC.

  • Exosomal hsa_circ_0051443 acts as a ceRNA to suppress HCC progression.

Abstract

Extracellular communication in the tumor microenvironment is critical. Results of qRT-PCR show that circ-0051443 is significantly lower in the plasma exosomes and tissues from patients with hepatocellular carcinoma (HCC) than healthy controls. Compared with the producer cells, circ-0051443 is mainly packaged into exosomes. A receiver operating characteristic curve (ROC) shows that the patients with HCC can be distinguished from the controls by exosomal circ-0051443. The role of exosomal circ-0051443 in HCC was determined by animal and cell analyses. Circ-0051443 is transmitted from normal cells to HCC cells via exosomes and suppresses the malignant biological behaviors by promoting cell apoptosis and arresting the cell cycle. Exosomal circ-0051443 decreases the weight and volume of the xenograft tumors in nude mice via BAK1 upregulation in these tumors. BAK1 expression is mediated by exosomal circ-0051443 through competitive bound to miR-331-3p. Therefore, exosomal circ-0051443 can serve as a predictor and potential therapeutic target for HCC.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major cause of cancer-related deaths worldwide [1,2]. This malignancy is associated with chronic diseases and cirrhosis in >90% of the cases [3]. Despite the wide application of surveillance programs, > 70% of patients with HCC are diagnosed at the late stage [4,5]. Therefore, elucidation of the physiopathological mechanisms underlying the occurrence and development of HCC and identification of effective targets for diagnosis and treatment are urgently needed.

Circular RNAs (circRNAs), a type of noncoding RNAs (ncRNAs) in metazoans [6], have neither 5′–3′ polarity nor a poly A tail in the closed loop structure [7]. CircRNAs mediate gene expression at the transcriptional and post-transcriptional levels by binding to microRNAs and other molecules and then inhibiting their functions [8]. Many recent studies have suggested that circRNAs are closely related to tumors. Chen L et al. proposed that circRNAs have regulatory functions in oral cancer and are a potential target for oral cancer therapy [9]. Hsiao KY et al. demonstrated that circRNA CCDC66 promotes the growth and metastasis of colon cancer [10]. Many circRNAs, including circRNA_100269 in gastric cancer [11], hsa_circ_0001982 in breast cancer [12], and circSMARCA5 in prostate cancer [13], have been shown to be associated with tumors. However, studies on circ-0051443 are limited, and its relationship with HCC remains unclear.

Exosomes are small vesicles (diameter: 40–150 nm) released by cells via fusion of the plasma membrane with multivesicular bodies (MVBs) [14]. The biogenesis of exosomes is divided into three processes: (a) biogenesis of the MVBs, (b) transport of the MVBs to the plasma membrane, and (c) release of the intraluminal vesicles of the MVBs via fusion with plasma membranes. As one of the three major extracellular vesicles [[15], [16], [17]], exosomes contain complex components, including lipids, nucleic acids, proteins, and other metabolites [18,19]. Evidence from recent studies has indicated that exosomes are associated with the biological processes and pathogenesis of certain diseases, such as Alzheimer's disease [20], liver diseases [21], and cardiovascular disease [22].

In the present study, we detected exosomal circRNAs in plasma samples from three patients with HCC and three healthy controls via microarray sequencing. Analysis of the microarray results reveals that circ-0051443 is poorly expressed in the plasma exosomes from the patients with HCC. We then detected the expression of this circRNA in tissues and plasma exosomes. Our findings indicate a significant reduction of circ-0051443 in the HCC tissues and plasma exosomes of the patients with HCC. However, data on the biological effects of exosomal circ-0051443 in HCC are unavailable. The purpose of our study is to identify potential markers for the diagnosis of HCC and investigate whether intercellular communication is affected by exosomal circ-0051443, which is correlated with the progression of HCC.

Section snippets

Study subjects and design

All subjects signed the written informed consent form, and the study protocol was approved by the institutional review board of The First Affiliated Hospital of Sun Yat-sen University. This study analyzed plasma specimens from 60 patients with HCC and 60 healthy control subjects, together with 60 matched tumor and normal adjacent tissues from patients with HCC from The First Affiliated Hospital of Sun Yat-sen University.

Cell lines

One normal human liver cell line (HL-7702) and two hepatocellular cancer

Patient characteristics

Table 1 summarizes the characteristics of the patients with HCC and the healthy controls. The patients with HCC and the controls show no differences in gender, age, and drinking status (P > 0.05). Nevertheless, we found that HCC is strongly related to hepatocirrhosis.

Expression of plasma exosomal circ-0051443 in the patients with HCC

Exosomal RNAs were extracted from the plasma samples. The plasma-derived exosomes of the patients with HCC and controls were isolated and characterized. The size of the exosomes from the patients with HCC is consistent with that

Discussion

HCC is the third most common cause of cancer-related death after lung and stomach cancer and the fifth most common tumor in patients worldwide [25]. We find that circ-0051443 is downregulated in HCC tissues and plasma. In addition, normal cells package circ-0051443 into exosomes, secrete them into HCC cells, and then significantly suppress the malignant behavior of HCC cells by reducing the proliferation and migration of cancer cells. Moreover, exosomal circ-0051443 suppress tumor growth in vivo

Data availability statement

All data are available upon request.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Wei Chen: Supervision, Methodology, Writing - original draft. Yingyao Quan: Supervision, Methodology, Writing - original draft. Shaoyi Fan: Data curation, Software. Hua Wang: Formal analysis, Data curation. Jinyu Liang: Visualization, Resources. Li Huang: Validation. Liuhua Chen: Investigation. Qi Liu: Data curation, Formal analysis. Peiheng He: Conceptualization, Project administration, Writing - review & editing. Yibiao Ye: Conceptualization, Project administration, Writing - review & editing.

Declarations of competing interest

None.

Acknowledgments

None.

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    Wei Chen and Yingyao Quan Contributed equally to this work.

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