Exosomal microRNAs in hepatocellular carcinoma, expanding research field

Abstract

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.

Key Words: Exosomes; MicroRNA; Hepatocellular carcinoma; Liver cancer; Tumor microenvironment

Core Tip: This study summarized the origin of exosomal microRNAs (miRNAs) in hepatocellular carcinoma (HCC), the function of exosomal miRNAs in HCC, and the potential clinical implication in HCC, providing a better understanding of exosomal miRNAs in the progression of HCC patients.

INTRODUCTION

Exosomes, another name for small extracellular vesicles, are a particular class of extracellular vesicles that come from multivesicular bodies (MVBs) and range in size from 40 to 160 nm. MVBs serve as biological information exchange carriers, helping to modify the cellular milieu[1-3]. Exosomes have been shown to carry a variety of payloads, including RNA, proteins, lipids, and DNA. These cargoes include messenger RNAs, long noncoding RNAs, microRNAs (miRNAs), and circular RNAs, all of which are involved in intercellular communication[3]. As medical testing techniques have advanced, an increasing number of compounds of various kinds carried by exosomes have been found. Besides, the curial role of exosomes in both physiological and pathological processes of hepatocellular carcinoma (HCC) has been extensively studied and validated[4].

MECHANISMS OF EXOSOMAL MIRNAS IN HCC

In this review, the mechanism of exosomal microRNAs in HCC was introduced from two sides: (1) The exosomal miRNAs and liver cancer; and (2) the exosomal miRNA-mediated connections between TME and tumor cells in HCC. In terms of the exosomal miRNAs and liver cancer, the authors summarized that: (1) Exosomes delivered by HCC cells could promote the malignant progression of HCC; (2) other than liver cancer cells, exosomal miRNAs released by tumor cells can also encourage the development of premetastatic niches in the liver; and (3) exosomal miRNAs may also be connected to several liver disease etiologies associated with HCC. In summary, exosomal miRNAs could influence the progression of liver cancer; the formation of metastasis site of liver, and the progression of liver disease related to HCC. All these reports indicate that exosomal miRNAs might play a crucial role in the whole life span of HCC. As for the interactions between TME and tumor cells, the authors discussed the various biological roles of exosomal miRNAs derived from the nonparenchymal cells (like hematopoietic stem cells, cancer-associated fibroblasts, immune cells, and tumor-associated macrophages), suggesting that cell-cell communication mediated by exosomal miRNAs could influence the formation, progression, and metastasis of HCC. Taken together, the scientific evidence collected in this review demonstrates the crucial role of exosomal miRNAs in the development of HCC. However, all these studies are mainly biological research, focusing on the biological role of exosomal miRNAs. More clinical studies should be carried out to explore the clinical significance of exosomal miRNAs in HCC.

CLINICAL IMPLICATIONS

For early-stage liver cancer, aggressive surgery and transaterial chemoembolization continue to be the most effective treatment modalities. However, chemotherapy, targeted therapy, and immunotherapy, however, are only partially able to extend the survival of patients with advanced liver cancer. Herein, to improve the treatment efficiency of HCC, we need to focus on two sides. On one hand, we need to find new biomarkers to improve the early detection rate of HCC. On the other hand, novel and alternative medicines must be discovered to enhance the prognosis of HCC patients. In this review, the authors claim that exosomal miRNA could promote the formation and metastasis of HCC, indicating the potential role of miRNA in serving as a biomarker of early diagnosis of HCC. This potential implication has been reported in various kinds of studies[5]. For instance, serum exosomal miR-638 has been reported as a prognostic marker of HCC[6]. In addition, exosomes could mediate cell-cell communication between tumor microenvironment and HCC cells, thus it can serve as effective vehicles for drug delivery. For instance, exosome-derived circCCAR1 has been shown to support anti-PD1 resistance and CD8⁺ T-cell dysfunction in HCC[7]. Moreover, various kinds of research suggested that exosomal miRNAs could enhance the chemosensitivity of tumor cells[8], indicating that exosomal miRNAs might be a potential target to improve the efficiency of chemotherapy in HCC patients. We need to conduct more research to verify these hypotheses.

CONCLUSION

Accumulating evidence indicates that exosomal miRNAs play a crucial in the initiation and progression of HCC. Besides, exosomal miRNAs mediate the communication between the HCC cells and TME. All these studies focus on the biological role of exosomal miRNAs in HCC, and more clinical research should be carried out to investigate the clinical implications of exosomal miRNAs in HCC.

ACKNOWLEDGEMENTS

The authors would like to express their gratitude to the anonymous reviewers whose comments helped to make this article much better.