Noncoding RNA-mediated macrophage and cancer cell crosstalk in hepatocellular carcinoma

Abstract

The tumor microenvironment (TME) is a well-recognized system that plays an essential role in tumor initiation, development, and progression. Intense intercellular communication between tumor cells and other cells (especially macrophages) occurs in the TME and is mediated by cell-to-cell contact and/or soluble messengers. Emerging evidence indicates that noncoding RNAs (ncRNAs) are critical regulators of the relationship between cells within the TME. In this review, we provide an update on the regulation of ncRNAs (primarily micro RNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) in the crosstalk between macrophages and tumor cells in hepatocellular carcinoma (HCC). These ncRNAs are derived from macrophages or tumor cells and act as oncogenes or tumor suppressors, contributing to tumor progression not only by regulating the physiological and pathological processes of tumor cells but also by controlling macrophage infiltration, activation, polarization, and function. Herein, we also explore the options available for clinical therapeutic strategies targeting crosstalk-related ncRNAs to treat HCC. A better understanding of the relationship between macrophages and tumor cells mediated by ncRNAs will uncover new diagnostic biomarkers and pharmacological targets in cancer.

Keywords: circular RNA (circRNA); hepatocellular carcinoma (HCC); long noncoding RNA (lncRNA); microRNA (miRNA); noncoding RNA (ncRNA); tumor microenvironment (TME); tumor-associated macrophage (TAM).

Graphical abstract

Figure 1

The polarization of macrophages and their characteristics In response to different inducers in cell microenvironment, macrophages polarize into two extreme phenotypes (M1 and M2) and display distinct functions. M2 macrophages can be divided into four advanced subtypes, M2a, M2b, M2c, and M2d, based on their different stimuli and roles.

Figure 2

TAM-involved tumor immune microenvironment Various tumor-infiltrating cells, mainly including TAMs (i.e. M0, M1- and M2-like type), NK cells, CD8⁺ cells, γδ T cells, and regulatory T (Treg) (CD4⁺ CD25⁺ Foxp3⁺ Treg) cells, form a niche in the tumor microenvironment. Within the niche, intense communication occurs between macrophages and other immune cells through cell-to-cell contact and/or soluble messengers, resulting in tumor suppression or progression.

Figure 3

ncRNA functions in tumor progression miRNAs regulate gene expression by inducing RNA cleavage or degradation or blocking RNA translation. lncRNAs function as molecular signals, decoys, guides, or scaffolds to mediate gene expression by interacting with DNAs, mRNAs, proteins, or other ncRNAs. circRNAs mediate gene expression by acting as miRNA sponges and protein scaffolds. Both of those ncRNAs play important roles in cancer progression, such as tumor transformation, growth, and angiogenesis.

Figure 4

Macrophage-derived ncRNA-mediated crosstalk between macrophages and HCC cells Macrophage-derived ncRNAs not only regulate the activation or polarization of macrophages but also are involved in cancer cell proliferation, migration, invasion, EMT progress, stem cell properties, aerobic glycolysis, chemoresistance, or the progression from NAFLD to HCC, by cell-to-cell contact, cytokines, exosomes, or microvesicles.

Figure 5

Tumor-derived ncRNA-mediated crosstalk between macrophages and HCC cells Tumor-cell-derived ncRNAs not only regulate cancer cell proliferation, cell cycle, migration, invasion, EMT progress, stem cell property, mitochondrial metabolism, glucose metabolism, apoptosis, autophagy, and radio- or drug resistance but also are involved in the polarization or reprogramming, immunosuppression, secretion of inflammatory mediators, recruitment, or infiltration of macrophages by exosomes, cytokines, soluble protein, or chemokines.

Figure 6

Promoting function of tumor-derived lncRNAs by mediating the crosstalk between macrophages and HCC cells On the one hand, tumor-derived lncRNA acts as an oncogene in the biological function of the cells from which it originated, and on the other hand, it induces the M2-like polarization of TAMs while inhibiting its M1-like polarization cells through cytokines, chemokines, exosomes, or soluble proteins, thereby prompting macrophages to secrete a large amount of anti-inflammatory cytokines, further enhancing tumor progression.