miR-200c-3p, miR-222-5p, and miR-512-3p Constitute a Biomarker Signature of Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

Abstract

Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.

Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response

“…De la Cruz-Ojeda investigated the relationship between three sorafenib-deregulated miRNAs (miR-200c-3p, miR-222-5p, and miR-512-3p) and sorafenib response in advanced HCCs. Notably, a hazard ratio analysis showed an association between miR-200c-3p baseline levels and increased survival, while miR-222-5p and miR-512-3p levels, analyzed one month after sorafenib treatment, were associated with a poorer prognosis [120]. Since miR-221 and miR-222 belong to the same bicistronic cluster, findings between that study and ours seem discordant, pointing out that further efforts need to be put in place to obtain robust data that can be translated into laboratory tests, in terms of methodology and evaluation of different patient cohorts.…”

Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine

“…Exosomal miR-30d is highly expressed in the sorafenib effective patients and thereby maybe serve as a predictive biomarker for the efficacy of sorafenib in HCC ( Kohno et al, 2020 ) . MiR-200c-3p, miR-222-5p and miR-512-3p constitute a biomarker signature of sorafenib effectiveness in advanced HCC ( de la Cruz-Ojeda et al, 2022 ). The baseline miR-200c-3p level is correlated with increased survival, whereas increased miR-222-5p and miR-512-3p levels at 1 month after sorafenib treatment are related to poor prognosis.…”

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure 1A). 83−85 Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, 4−6 oxidative stress, 7 cell proliferation, 8,9 inflammation, 10,11 hematopoiesis, 4,12 and tumorigenesis. 13,14 Recent studies revealed that miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine.…”

“…These functional miRNAs form the RISC via binding to AGO. Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure A). − Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , …”

“…A particular miRNA can target various mRNAs to induce translational repression or RNA degradation, and one mRNA can be regulated by multiple different miRNAs . By modulating gene expression at the post-translational level, miRNAs play a critical role in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , Importantly, miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine. − Therefore, circulating miRNAs are considered biomarkers of disease and can regulate gene expression in distal cells or organs. ,, …”