Circulating exosomal miR-92b: Its role for cancer immunoediting and clinical value for prediction of posttransplant hepatocellular carcinoma recurrence

Abstract

A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence. K E Y W O R D Sbasic (laboratory) research/science, biomarker, cancer/malignancy/neoplasia: risk factors, cellular biology, immunobiology, liver transplantation/hepatology, microarray/gene array, molecular biology: micro RNA, natural killer (NK) cells/NK receptors, translational research/ science 1 | INTRODUC TI ON Hepatocellular carcinoma (HCC) is the second leading cause of death from cancer in the world. 1 In general, malignant tumor regions are treated by radiofrequency ablation (RFA) or transarterial embolization (TAE) and/or removed by surgical resection.Our group compared the disease-free survival of HCC patients between surgical resection and RFA in the Barcelona Clinic Liver

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

“…These findings explain the usually inversely related expression of miR-21 and PTEN in tumor specimens, in which miR-21 is up-regulated whereas PTEN is downregulated, as well as the higher miR-21 expression in serum of HCC patients [60,61]. [72] In the cell-to-cell communication network, the role of other miRNA targeting PTEN is evidenced by the transfer of Hep-3B-derived exosomes, enriched in miR-155, to HepG2 cells. The downregulation of PTEN resulted in a Phosphatidylinositol 3 Kinase (PI3K)-AKT pathway activation, determining cell proliferation [62].…”

“…In HCC, NK cells are diminished in tumors compared to non-tumor regions; in addition, they possess a defective IFN-γ and TNF-α secretion caused by the defective recognition of tumor cells, or by inhibitory effects from other immune or cancer cells [19,97]. In particular, cancer cells, such as Hep-3B, can release miR-92b-rich exosomes that exert a suppressive action on NK by deregulating CD69 [72], which is a cell surface costimulatory molecule determining cell proliferation, cytokine secretion, and cytotoxicity (Table 1) [98]. miR-92b is classified as an oncomir in HCC [99], showing high levels both in tissues and in serum samples.…”

“…The recent discovery of the modulatory effect on NK cells attributes a dual role on this miRNA, fostering HCC progression. On one side it promotes proliferation by targeting SMAD7 in HCC cells [99], and on the other side, the released form ensures a favorable background for tumoral growth by inhibiting the tumor immune surveillance [72]. Cell-to-cell communication that involves immune cells assumes particular relevance in consideration of the new immunomodulatory therapies available for HCC.…”

EVs as Potential New Therapeutic Tool/Target in Gastrointestinal Cancer and HCC

“…Of note, a large body of evidence suggests that increased levels of several exosomal miRNAs were associated with a high probability of HCC recurrence [ 89 , 90 , 91 ]. Unquestionably, patients with HCC would benefit most from a simple blood-based method for the detection of cancer recurrence.…”

Diagnostic performance of blood-based liquid biopsies in hepatocellular carcinoma

“…In recent years, the diagnostic performance of blood-based liquid biopsies in HCC diagnosis has been widely studied. [ 8 – 10 ] However, these studies evaluated the sensitivities and specificities of a single liquid biopsy method. Besides, there were considerable discrepancies from inconsistent subjects, diverse detection techniques, and inconsistent results.…”