MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

Abstract

Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their ‘dual’ role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments.

MicroRNA-204-5p Inhibits Hepatocellular Carcinoma by Targeting the Regulator of G Protein Signaling 20

“…miRNAs have attracted increasing attention owing to their emerging roles in the cellular evolution and biological processes of HCC. That is, the expression levels of some miRNAs are upregulated in malignant tissues, playing roles similar to oncogenes . For example, miR-21 promoted the production and progression of HCC cells by initiating the Akt/ERK pathway and inducing epithelial–mesenchymal transition (EMT) .…”

“…That is, the expression levels of some miRNAs are upregulated in malignant tissues, playing roles similar to oncogenes. 16 For example, miR-21 promoted the production and progression of HCC cells by initiating the Akt/ ERK pathway and inducing epithelial−mesenchymal transition (EMT). 29 Additionally, miR-135b promotes HCC through the APC axis.…”

“…miRNAs can regulate gene expression post-transcriptionally, which influences the expression of both onco- and tumor-suppressor genes . Abnormal expression of miRNAs can lead to the differential expression of regulated target genes or an imbalance in signaling pathways, resulting in a variety of diseases . Research has revealed an incredible effect of miR-204-5p in various cancers, which constrains the multiplication of HCC cells by controlling the target genes of E2F1, SIX1, and SIRT1. − However, the regulatory relationship between miRNAs and RGS20 in HCC has not been reported. ,, Therefore, it is important to clarify whether miRNAs can directly affect the expression of RGS20 and how miRNAs and RGS20 are engaged in regulating the biological processes of HCC cells.…”

“…15 Abnormal expression of miRNAs can lead to the differential expression of regulated target genes or an imbalance in signaling pathways, resulting in a variety of diseases. 16 Research has revealed an incredible effect of miR-204-5p in various cancers, which constrains the multiplication of HCC cells by controlling the target genes of E2F1, SIX1, and SIRT1. 17−19 However, the regulatory relationship between miRNAs and RGS20 in HCC has not been reported.…”

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…Additionally, insights into immunomodulatory mechanisms can inform the exploration of novel therapeutic approaches that restore immune control over HBV, potentially leading to innovative immunotherapies[ 19 ]. Thus, comprehending the immunological intricacies of HBV reactivation not only enhances our understanding of disease progression but also empowers the medical community to devise more effective and targeted strategies for its management[ 20 , 21 ].…”