Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma

Abstract

Exosomes, extracellular vesicles with a diameter of 40 to 160 nm, are among the smallest extracellular vesicles released by cells. They deliver different cargoes, including proteins, DNAs, and RNAs, and facilitate communication between cells to coordinate a variety of physiological and pathological functions. Hepatocellular carcinoma (HCC) is the sixth common malignant tumor and the fourth leading cause of cancer-related death worldwide. Its molecular mechanism remains largely unknown, and there is a lack of reliable and noninvasive biomarkers for early diagnosis and prognosis prediction. Mounting evidence has shown that exosomes carry a variety of ncRNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which play critical roles in the occurrence and progression of HCC. In this review, we summarize the recent findings of exosomal miRNAs, lncRNAs, and circRNAs in HCC from their impact on the development of HCC to their potential applications in the diagnosis and treatment of HCC.

Keywords: exosome; hepatocellular carcinoma; long non-coding RNA; microRNA; tumor microenvironment.

Figure 1

Biogenesis of exosomes. Extracellular components are internalized along with the plasma membrane to form early endosomes. Exosomal cargoes enter early endosomes to form multivesicular bodies (MVBs) through an ESCRT-dependent mechanism, which is shown in this figure. MVBs bind with lysosomes and release cargoes from vesicles into the cytoplasm, or under the actions of Rab GTPases, SNARE, and calcium (Ca²⁺), they fuse with the plasma membrane and release ILVs into the extracellular matrix. Exosomal surface proteins include Rab GTPases, tetraspanins, and MHC class I and II molecules.

Figure 2

Summary of non-coding RNAs affecting HCC development. Exosomal ncRNAs mediate crosstalk between tumor cells and cells in the TME, where different types of cells interact with cancer cells, including infiltrating immune cells, CAFs, normal hepatic stellate cells (HSCs), adipocytes, and thin blood vessels that make up tumors. The complex multidirectional communication between these cells and tumor cells through exosomal ncRNAs promotes tumor growth, invasion, metastasis, and angiogenesis. The blue arrows indicate that the exosomal ncRNAs are originated from immune cells or acting on immune cells. The red up arrows show the function of promoting the corresponding exosomal ncRNAs, and red down arrows represent the function of inhibiting the corresponding exosomal ncRNAs. For example, adipocyte-stemmed circ-DB can facilitate tumor growth.