Overexpression of miR-4669 Enhances Tumor Aggressiveness and Generates an Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma: Its Clinical Value as a Predictive Biomarker

Abstract

Accumulating evidence suggests the involvement of tumor-derived exosomes in the development and recurrence of hepatocellular carcinoma (HCC). We previously identified miR-4669 as a highly expressed microRNA in circulating exosomes obtained from patients with post-transplant HCC recurrence. This study aimed to explore how overexpression of miR-4669 affects HCC development and recurrence. The impact of miR-4669 overexpression in Hep3B cells on tumor cell behavior and the tumor microenvironment was evaluated in vitro. In addition, the clinical value of exosomal miR-4669 for the prediction of treatment response to HCC downstaging therapies and following post-transplant HCC recurrence was explored. Overexpression of miR-4669 enhanced migration ability and led to acquired sorafenib resistance with an elevation of sirtuin 1 and long noncoding RNA associated with microvascular invasion. Active release of tumor-derived exosomes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) contributed to generating an immunosuppressive tumor microenvironment through the induction of M2 macrophage polarization. The retrospective analysis demonstrated the clinical value of exosomal miR-4669 for predicting treatment response to HCC downstaging therapies and for risk assessment of post-transplant HCC recurrence. In summary, the present data demonstrate the impact of exosomal miR-4669 on HCC recurrence through the enhancement of tumor aggressiveness and generation of an immunosuppressive tumor microenvironment.

Exosome Cargos as Biomarkers for Diagnosis and Prognosis of Hepatocellular Carcinoma

“…This interaction has been found to cause the spread of HCC and is associated with a worse overall survival rate in HCC patients [ 40 ]. The upregulation of miR-4669 resulted in the increased migratory capacity of HCC cells and conferred resistance to sorafenib treatment, accompanied by an upregulation of sirtuin 1 [ 41 ]. Zhang et al [ 42 ] observed that exosomal circ_0046600 could facilitate the advancement of HCC by sequestering miR-1258 and subsequently upregulating SERBP1.…”

Extracellular vesicles and cancer stemness in hepatocellular carcinoma – is there a link?

“…Another study showed that higher levels of miR-320d in serum EVs were linked to better recovery in HCC patients after surgery ( 92 ). Moreover, the expression of plasma exosomal miR-4669 could predict HCC recurrence after liver transplantation with specificity and sensitivity at around 75% ( 93 ). The expression of exosomal miR-122 was found to be significantly reduced post transarterial chemoembolization (TACE), and the ratio of serum exosomal miR-122 post TACE as compared to pre-TACE was positively correlated with prolonged disease-specific survival, indicating its potential clinical utility ( 94 ).…”

The role of exosomes in therapeutic resistance of hepatocellular carcinoma

“…Therefore, exosomal circRNA-SORE plays a crucial role in the maintenance and transmission of sorafenib resistance in HCC [15] . In addition, exosomal miR-494-3p, upregulated by the oncoprotein Golgi phosphoprotein 3 (GOLPH3), has been found to be transferred to recipient human umbilical vein endothelial cells (HUVECs) and HCC cells, suppressing PTEN protein expression by directly targeting the 3' UTR of PTEN mRNA, and subsequently promoting angiogenesis and enhancing sorafenib resistance [25] .…”