This study evaluated differences in the clinical appearance of patients with hepatocellular carcinoma (HCC) based on plasma level and regulation of microRNAs (miRNA-29c, miRNA-21, and miRNA-155). The observational-analytical study with a cross-sectional design was conducted on 36 HCC patients and 36 healthy controls. The blood samples were collected from 2 Province Hospitals (Dr. Sardjito Hospital and Prof. Dr. Margono Soekarjo Hospital) for HCC and the Blood Bank Donor of the Indonesian Red Cross for 36 healthy controls. These blood samples were treated as follows: plasma isolation, RNA isolation, cDNA synthesis, quantification by qRT-PCR using a sequence-specific forward primer, and normalization of miRNA using housekeeping-stably miRNA-16. There were only 27 HCC patients with complete clinical variables (neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), platelet count, albumin, C-reactive protein (CRP), and cholinesterase (ChE)) that were able to analyses for regulation miRNAs based on its fold change expression miRNA target. All 27 HCC subjects were follow-up until 3-years of monitoring for their overall survival. The miRNA plasma expression was analyzed by Bio-Rad CFX 96 Manager software to determine the cycle of quantification, followed by the calculation of expression levels using Livak’s methods. Data were analyzed using STATA 11.0, with a significant value of p<0.05. The miRNAs expression of HCC subjects were lower than that healthy control subjects in miRNA-29c (down-regulation 1.83-fold), higher than that healthy control subjects in miRNA 21 and miRNA-155 (up-regulation, 1.74-fold; 1.55-fold) respectively. NLR, CRP, ChE, and platelet count showed a significant difference in miRNA-29c regulation, though neutrophil count showed a significant difference in miRNA-21 and miRNA-155 regulation (p<0.05). Conclusion: Plasma biomarkers: miRNA-21 and miRNA-155 might be potential biomarkers as onco-miR in HCC subjects, while miRNA-29c might act as a tumor suppressor. Significant evidence was identified with clinical progression based on the regulation of miRNAs, which was consistent with miRNA -29c.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and the third leading cause of cancer-related deaths worldwide. HCC carries poor prognosis, its incidence and mortality increase annually. The most common hypothesis explaining the problem is the cell's high tendency to metastasize and recur, even after surgical treatment. Therefore, it is important to find new serological biomarkers to detect HCC in early stages. Plasma microRNAs are being actively investigated as minimallyinvasive biomarkers in HCC as well as other human cancers. This study is aimed to investigate the level of expression of miR-21, miR-29c, and miR-155 as novel serological biomarkers for hepatocellular carcinoma. This study is preliminary quasi experimental study, and further sample collection is still underway. This study involved 8 HCC patients and 8 healthy controls. Blood sample of HCC patients were obtained from RSUP dr. Sardjito, Yogyakarta, and the patients were selected according to specific inclusion and exclusion criteria. The collected blood samples were treated as follows: plasma isolation, RNA total isolation, cDNA synthesis, quantification by qRT-PCR, data analysis with Biorad CFX ManagerTM Softwere to determine Cq, followed by the calculation of expression levels using Livax Methods. The result revealed that miR-21 and miR-155 were upregulated, 1.68 fold and 2.38 fold respectively, compared to healthy control. Secondly, miR-29c was downregulated (3,45 fold) compared to healthy control. Based on the result of preliminary study, we concluded that miR-21 acts as oncomiR, while miR-29c and miR-155 act as tumor supressor miR in HCC. The three microRNAs might be detected in HCC and might be used as minimally-invasive biomarkers in HCC detection.
Hepatocellular carcinoma (HCC) is a common liver disease that causes significant public health problems throughout the world, including in Indonesia. The HCC is the six most common cancers and second cancer-related deaths among men in the world. Recently it was reported that the microRNA is an important player in hepatocarcinogenesis. The expression of MiRNA-200c is often regulated in primary HCC and HCC cell lines. Vascular endothelial growth factor-A (VEGF-A) is a regulator of angiogenesis that has been reported as miR-200c target gene. This study was conducted to measure expression levels in miR-200c and mRNAVEGF-A and their potential role as biomarkers at HCC. A total of 36 HCC patients and 36 healthy subjects were included in this study. The relative expression of miRNA-200c and mRNA VEGF-A was quantified using reverse transcription real time quantitative PCR (qRT PCR). Relative expression was calculated using. Unpaired t-test was used to compare the expression levels of circulating miRNA-200c and mRNA VEGF-A in HCC patients and healthy subjects. Pearson test was used to determine correlation between circulating miR-200c expression and mRNA VEGF-A expression levels. The expression levels of circulating miR-200c in HCC patients were lower compared to healthy subjects although it was not significant (p = 0.258). Conversely, the expression levels of circulating mRNA VEGF-A in HCC patients were significantly higher compared to healthy subjects (p = 0.001). The relative expression levels of circulating miR-200c were negatively correlated with mRNA VEGF-A in HCC patients. In conclusion, the expression levels of mRNA VEGF-A in HCC patients are significantly deregulated in compared to that in healthy subjects. Negative correlation between circulating miRN-200c and mRNA VEGF-A expression levels are reported in HCC patients. ABSTRAK Hepatocellular carcinoma (HCC) adalah penyakit hati yang umum dan menyebabkan masalah kesehatan masyarakat yang signifikan di seluruh dunia, termasuk di Indonesia. Karsinoma hepatoseluler adalah penyebab kematian keenam akibat kanker umumnya dan kedua pada laki-laki di seluruh dunia. Saat ini microRNA dilaporkan berperan penting dalam hepatokarsinogenesis. Ekspresi MiRNA-200c mengalami deregulasi pada jaringan HCC primer dan sel HVCC. Vascular endothelial growth factor-A (VEGF-A) adalah regulator angiogenesis yang dilaporkan sebagai gen target miR-200c. Penelitian ini dilakukan untuk mengkaji ekspresi miR-200c dan mRNA VEGF-A serta peran
INTRODUCTION: Clinical biomarkers can predict disease progression and clinical outcomes due to inflammation process. Circulating miRs can predict disease progression, therapeutic response and patient survival. Aims of study: to evaluate 1 year survival rate based on regulation miRs (miR29c, miR21, and miR155) plasma and clinical biomarkers [neutrophil to lymphocyte ratio/NLR, platelet to lymphocyte ratio/PLR, α-fetoprotein/AFP] in Hepatocellular Carcinoma (HCC) patients. METHODS: The longitudinal cohort design was conducted in 29 HCC patients. Subjects were recruited from Dr.Sardjito General Hospital, Yogyakarta, Indonesia during the year of 2012 until 2018. Outcome of the study was survival rate after enrolled the study until 12 months observation. All subjects were enrolled using criteria: MSCT 4 phases and histology examination. Exclusion criteria: co-morbidity with other malignancy. Blood sample collection was treated as follows: (1)plasma isolation, RNA isolation, cDNA synthesis, and quantification by qRT-PCR; (2)blood examination to determine NLR, PLR, and AFP. The miR's plasma level was analyzed by BioradCFX Manager96 software to determine Cq, the calculation of expression levels using Livak's methods. Hazard Ratio and Kaplan Meyer curve were analyzed using STATA 11.0. RESULTS: Baseline data: median of age 53 year old (min29; max74), 62.07% male, etiology [58.62% HBV, 6.90% HCV] and BCLC criteria [31% B, 59% C, 10% D], and 48% treated by TACE/TAE respectively. miR29c might be act as tumor suppressor, and the opposite, miR21 and miR155 as oncogene. The HRs were calculated using cutoff for each variable (miR regulations, NLR ≥ 4, PLR ≥ 165.83, PLR-tertile ≥ 292.40, and AFP ≥ 200). Down-regulation miR29c was the most dominant predictor for survival rate (HR = 4.88), while up-regulation miR155 was the second predictor (HR = 1.31). Most of clinical biomarkers showed HR < 1. The Kaplan Meier curve can be seen at Figures 1 and 2 CONCLUSION: Plasma miR was detected easily and stable. miRs regulation were played a role in tumor tissues dysregulation, tumor suppressors, or oncogenes. Thus, miRs can be used as diagnostic, targeting therapy and prognostic markers in HCC patients. Down-regulation miR29c as a tumor suppressor and up-regulation miR155 as an oncogene might be potential variable predictor for survival rate in HCC patient compared with miR21 and clinical biomarkers.
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