Diagnostic Marker For Hepatocellular Carcinoma Research Articles

Assessment of prognostic and diagnostic value of some biomarkers in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an increasing problem worldwide. Determining a prognosis is important for the management of HCC. We aimed to investigate the impact of interleukin (IL)-29, galectin-3, leptin, fibronectin and protease-activated receptor-1 on the prognosis and diagnosis of patients with HCC. 60HCC patients (75% male) and 20healthy volunteers (70% male) were enrolled in this prospective study. Serum samples were obtained during the first admission before any adjuvant or metastatic treatments were administered. Serum biomarkers were determined using ELISA kits. All patients had cirrhosis, and the Child- Pugh stages were as follows: 61.5% Child- Pugh A, 35.9% Child- Pugh B and 2.6% Child- Pugh C (61.7% hepatitis B virus, 11.7% hepatitis C virus, 6.7% hepatitis B virus+ hepatitis C virus, 11.7% alcoholic and 8.3% cryptogenic). Fifty-three percent of the HCC patients died within a median of 7.5months. The mean serum level of IL-29in patients with HCC was higher than that in the control group (32.55 pg/ml vs 11.46 pg/ml, p<0.015). Galectin-3levels were significantly higher in the HCC group (6.7 ng/ml vs 1.38 ng/ml, p< 0.001). Fibronectin levels were higher in the control group than in the HCC group (260 635 ng/mlvs 257 353ng/ml). However, the mean protease-activated receptor-1 and leptin levels were similar between the two groups (p> 0.05). The biomarkers were divided into two groups according to their median level. In the log rank analysis, biomarkers had no effect on survival (p> 0.05). IL-29and galectin-3levels were significantly higher in HCC patients. Although IL-29and galectin-3can be used as diagnostic markers for HCC, they had no prognostic value in HCC patients.

Evaluation of Homocystein and Micro RNA as Diagnostic Markers for Hepatocellular Carcinoma in Virus Hepatitis C Egyptian Patients

Evaluation of Homocystein and Micro RNA as Diagnostic Markers for Hepatocellular Carcinoma in Virus Hepatitis C Egyptian Patients

A comprehensive analysis of the MAGE family as prognostic and diagnostic markers for hepatocellular carcinoma

The Melanoma Antigen Gene (MAGE) family is a large, highly conserved group of proteins which was reported to participate in the progression of multiple cancers in humans. However, the function of distinct MAGE genes in hepatocellular carcinoma (HCC) is largely unclear. In this study, we comprehensively evaluated the expression, clinical significance, genetic alteration, interaction network and functional enrichment of MAGEs in HCC. Our research showed that many MAGE genes were dysregulated in HCC. Among them, MAGEA1, MAGEC2, MAGED1, MAGED2, MAGEF1 and MAGEL2 were significantly associated with clinical stage and differentiation of HCC. MAGED1, MAGED2, MAGEA6, MAGEA12, MAGEA10, MAGEB4, MAGEL2 and MAGEC3 significantly correlated with HCC prognosis. Further functional enrichment analysis suggested the dysregulated MAGEs may play important roles in signal transduction. These results indicate that multiple dysregulated MAGEs might play important roles in the development of HCC and can be exploited as useful biomarkers for diagnosis and treatment in HCC.

Lipocalin-2: A novel diagnostic marker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Viral hepatitis, alcoholism and non-alcoholic steatohepatitis are the most common risk factors. Despite the advances in HCC screening and treatment options, HCC still has a high mortality rate and a high rate of recurrence after treatment. Lipocalin-2 (LCN-2) is a glycoprotein transporter that is highly expressed in HCC tissues. To evaluate serum LCN-2 as a diagnostic marker for HCC. The study was carried out in Zagazig university hospitals. It included 210 HCC patients (subdivided in three subgroups), 72 liver cirrhosis patients without HCC and 18 normal control persons (the total is 300 subjects). All the study subjects were evaluated by history taking, physical examination, routine laboratory investigations, alpha-fetoprotein (AFP) and LCN-2 in addition radiology. In comparison between HCC and control, there was a statistically significant difference in hemoglobin percent (HB%), platelet count, serum ALT, AST, ALP, bilirubin, albumin and creatinine. In comparison to AFP, LCN-2 > 225 ng/ml had a higher diagnostic performance in HCC patients and was more accurate in differentiation between cirrhosis and HCC patients. LCN-2 is a good candidate for HCC diagnosis and screening.

MiRNA-141 and its target long non-coding RNA HOTAIR as diagnostic marker in hepatocellular carcinoma on top of hepatitis C virus

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the fifth most common cancer worldwide. miRNAs are a group of non-coding small RNAs that regulate the expression of other protein-coding RNAs. Long non-coding RNA (lncRNAs) are known as key regulators of gene expression. This work aimed to study the interaction between lncRNA HOTAIR and miRNA- 141 expression in HCC patients on top of hepatitis C virus and to investigate their expression in patients with HCV in comparison to healthy controls. This study was conducted on 145 subjects: 45 healthy subjects, 50 HCC patients on top of HCV & 50 HCV patients. All subjects were subjected to: measurement of miRNA-141& HOTAIR expression in serum by real time PCR. The expression of lncRNA HOTAIR was significantly higher in HCV and HCC groups compared to control group (p value <0.001). There was significant higher expression of lncRNA HOTAIR in HCC group compared to HCV group (p value <0.001). miRNA -141 expression in both HCV and HCC groups was significantly decreased compared to control group. The expression of miRNA -141 in HCC group was significantly decreased compared to HCV group. There was an inverse correlation between miRNA -141 and lncRNA HOTAIR expression, as well as between miRNA- 141 expression and size of focal lesions. There was a direct correlation between lncRNA HOTAIR and the size of focal lesions. In conclusion, up-regulated lncRNA HOTAIR expression and down-regulated miRNA- 141 expression, may act as promising predictors for HCC.

A Circulating Long Noncoding RNA Panel Serves as a Diagnostic Marker for Hepatocellular Carcinoma.

Background Circulating long noncoding RNAs (lncRNAs) have been demonstrated to serve as diagnostic biomarkers for various cancers. We aimed to elucidate the diagnostic efficacy of eight serum lncRNAs HULC, MALAT1, Linc00152, PTENP1, PTTG3P, SPRY4-IT1, UBE2CP3, and UCA1 and their combinations for the diagnosis of hepatocellular carcinoma (HCC). Methods A total of 129 patients with HCC, 49 patients with liver cirrhosis, 27 patients with chronic hepatitis B, and 93 healthy controls were enrolled in this study. The levels of serum lncRNAs were assessed by quantitative real-time polymerase chain reaction. The correlations between serum lncRNAs and clinicopathological characteristics were further analyzed. The receiver operating characteristic (ROC) curve and area under curve (AUC) were utilized to estimate the diagnostic capacity of serum lncRNAs and their combination with AFP for HCC. A logistic regression model was performed to establish a multiple-lncRNA panel. Results The levels of serum HULC, MALAT1, Linc00152, PTTG3P, SPRY4-IT1, UBE2CP3, and UCA1 were significantly higher in HCC patients than in patients with benign liver diseases and healthy controls, whereas serum PTENP1 was significantly decreased in HCC patients compared with healthy participants. Positive correlations between serum Linc00152 and GGT, serum PTTG3P and GGT, and serum SPRY4-IT1 and ALT were noted in HCC patients. ROC analysis revealed that all these lncRNAs had a significantly predictive value for HCC except for PTENP1. The best performance of single lncRNA was obtained by Linc00152 with an AUC of 0.877. When combined with AFP, the combination of Linc00152 and AFP gained the highest accuracy, yielding an AUC of 0.906. Through logistic regression analysis, the panel consisting of serum linc00152, UCA1, and AFP provided the greatest predictive ability, obtaining an AUC of 0.912 with 82.9% sensitivity and 88.2% specificity. Conclusion The panel of serum Linc00152, UCA1, and AFP demonstrates a novel and noninvasive biomarker with relatively high sensitivity and specificity for HCC diagnosis.

Evaluation of Serum Midkine as a Marker of Hepatocellular Carcinoma in Cirrhotic Patients

Background: Hepatocellular carcinoma (HCC) is the fifth most common malignancy. Midkine (MK) is a cytokine or a growth factor belongs to the carbohydrate-binding proteins. MK is over expressed in hepatocellular carcinoma. Furthermore, patients with high MK expression in the tumor frequently have a worse prognosis than those with low MK expression. Objectives: The aim of the work was to evaluate serum midkine as a marker for Hepatocellular carcinoma in cirrhotic patients. Patients and Methods: This study was conducted on 90 subjects who were divided into three groups: group I included 40 patients with liver cirrhosis and hepatocellular carcinoma, group II included 40 patients with HCV related liver cirrhosis without HCC and group III with 10 healthy subjects as controls. Plasma level of midkine was measured for all subjects. Results: Serum levels of midkine were highest in patients of group I with HCC compared to those with liver cirrhosis and the control groups (p value< 0.001). Also midkine values increased with tumor number and overall size. According to the ROC curve, the best cutoff value for midkine differentiating HCC from liver cirrhosis cases was 8500pg/mL, above which the sensitivity to discriminate HCC = 100% and below which the specificity to discriminate liver cirrhosis = 87.5% with 94.5% accuracy. Conclusion: Serum midkine level was significantly elevated in HCC patients, so it can be used as a diagnostic marker for HCC. Also, it was directly correlated to the tumor number and overall size so it has a good prognostic value.

Evaluation of Serum Midkine as a Marker of Hepatocellular Carcinoma in Cirrhotic Patients

Background: Hepatocellular carcinoma (HCC) is the fifth most common malignancy. Midkine (MK) is a cytokine or a growth factor belongs to the carbohydrate-binding proteins. MK is over expressed in hepatocellular carcinoma. Furthermore, patients with high MK expression in the tumor frequently have a worse prognosis than those with low MK expression. Objectives: The aim of the work was to evaluate serum midkine as a marker for Hepatocellular carcinoma in cirrhotic patients. Patients and Methods: This study was conducted on 90 subjects who were divided into three groups: group I included 40 patients with liver cirrhosis and hepatocellular carcinoma, group II included 40 patients with HCV related liver cirrhosis without HCC and group III with 10 healthy subjects as controls. Plasma level of midkine was measured for all subjects. Results: Serum levels of midkine were highest in patients of group I with HCC compared to those with liver cirrhosis and the control groups (p value< 0.001). Also midkine values increased with tumor number and overall size. According to the ROC curve, the best cutoff value for midkine differentiating HCC from liver cirrhosis cases was 8500pg/mL, above which the sensitivity to discriminate HCC = 100% and below which the specificity to discriminate liver cirrhosis = 87.5% with 94.5% accuracy. Conclusion: Serum midkine level was significantly elevated in HCC patients, so it can be used as a diagnostic marker for HCC. Also, it was directly correlated to the tumor number and overall size so it has a good prognostic value.

The exosome encapsulated microRNAs as circulating diagnostic marker for hepatocellular carcinoma with low alpha-fetoprotein.

Diagnosis of hepatocellular carcinoma (HCC) remains challenging to clinicians, particularly in a patient with low alpha-fetoprotein. Here, in silico, ex vivo and in vitro data were combined to identify liver-specific exosomal miRNAs as an early diagnostic marker for HCC. Transcriptome profiling for mRNA and small RNA in same HCV-HCC and normal liver tissues followed by cross-validation of 41 deregulated miRNAs (log2 FoldChange > 1.5, Padj < .1) with GEO/TCGA datasets of HCV/HBV related HCC vs normal/adjacent tissue revealed three miRNAs were commonly deregulated (miR-10b/miR-21/miR-182) among all HCC irrespective of viral etiology. Targets of top deregulated miRNAs were identified by TargetScan/miRwalk and validated in mRNA transcriptome data followed by Panther/Gene Ontology enrichment/Cytoscape analysis suggested that targets were mostly from carcinogenesis pathways. Hence, those miRNAs were validated in normal and HCV-HCC tissues by qRT-PCR and subsequently in plasma-derived-exosomes of both HBV/HCV infected non-HCC (chronic hepatitis [CH]/liver cirrhosis [LC]) and HCC samples, and in liver-specific Anti-Asgr2 immuno-enriched exosomes. Exosomes were verified using Nanosight/TEM/immune-blotting with anti-Alix/anti-GRP78/anti-Asgr2. Along with miR-21-5p, miR-10b-5p/miR-221-3p/miR-223-3p was found significantly upregulated in the exosome of HCC patients than CH/non-HCC. The comparable expression pattern was seen in anti-Asgr2 immuno-precipitated exosomes. Interestingly, the AFP level was found below 250 ng/mL in about 94% of HCV-HCC and 62% of HBV-HCC patients. ROC analysis showed that miR-10b-5p + miR-221-3p + miR-223-3p + miR-21-5p could differentiate CH/non-HCC(CH + LC) from HCC with AUROC: 0.86 (97.5% CI: 0.77-0.94)/0.80 (97.5% CI: 0.70-0.89), sensitivity: 74%/58% and specificity: 86%/95% while miR-10b-5p + miR-221-3p + miR-223-3p showed AUROC: 0.84 (97.5% CI: 0.74-0.94)/0.74 (97.5% CI: 0.63-0.84), sensitivity: 86%/86% and specificity:66%/53% for low AFP-HCC vs CH/non-HCC, respectively, having better sensitivity than the combination of four miRNAs. Multivariate analysis further revealed low Albumin and high miR-21-5p as probable independent risk factor for HCC.

Genomic characterization of HBV-infected hepatocellular carcinoma patients using circulating tumor DNA.

575 Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology. Surgery or ablation may be curative for early-stage HCC. Thus, effective detection strategies are needed. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as a potential diagnostic marker of HCC in HBV-infected patients. Methods: We identified early stage (BCLC 0-A) HCC cases (n = 21) and cancer-free controls (n = 15) from a cohort of Asian patients with HBV, undergoing surveillance at Thomas Jefferson University Hospital between 2013-2017. Blood samples were collected. Circulating cell-free DNA was isolated from plasma and assayed by capture-based next-generation sequencing of a targeted panel of 23 genes implicated in HCC pathogenesis. Sequencing data analysis and somatic mutation identification were conducted using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic analysis, we evaluated gene alterations and clinical factors (age, gender, cirrhosis) in an exploratory early detection HCC model. Results: Mutant ARID1A, ATM, CDKN2A, CTNNB1, ERBB2, TP53 genes were increased in HCC cases relative to non-cancer patients (85.7% vs 53.3%, P = 0.058; 42.9% vs 6.7%, P = 0.025; 38.1% vs 6.7%, P = 0.051; 42.9% vs 0%, P = 0.005; 52.4% vs 13.3%, P = 0.016; 100% vs 66.7%, P = 0.008, respectively). HCC patients had higher prevalence of cirrhosis than controls (90.5% vs. 60%, P = 0.046). Using the 6 mutant genes alone, the AUC for discriminating HCC from non-cancer patients was 0.827 (95% confidence interval [CI]: 0.701-0.953), which was greater than the AUC for discriminating cirrhosis from non-cirrhosis (0.531). When the 6 mutant genes were combined with clinical factors, the AUC of the exploratory HCC detection model increased to 0.914 ( P= 0.045). Conclusions: We identified 6 genomic aberrations in ctDNA that were more prevalent in HCC patients compared with non-cancer patients. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant further validation in future studies.

The expression level and diagnostic value of microRNA-22 in HCC patients

Background Involvements of microRNA-22 (miR-22) in cancer have attracted much attention, but its role in diagnosis of hepatocellular carcinoma (HCC) is still largely unknown. Therefore, the aim of this study was to investigate the expression level and the prognostic value of miR-22 in HCC patients. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate serum level of miR-22 in 108 HCC patients and 67 healthy controls. The relationship between miR-22 expression level and clinicopathologic characteristics was analysed via chi-square test. Receiver operating characteristic (ROC) curve was built to estimate the diagnostic value of serum miR-22 in HCC. Results miR-22 expression was significantly down-regulated in HCC compared to that in healthy controls (p < .05). And the low miR-22 expression was significantly associated with vein invasion (p = .002), TNM stage (p = .013) and high serum levels of AFP (α-fetoprotein), ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase. miR-22 had a high diagnostic value with area under the curve of 0.866 corresponding with a sensitivity of 89.3% and a specificity of 68.9%, respectively. Conclusion miR-22 expression was down-regulated in HCC patients. Serum miR-22 might be a novel diagnostic marker in HCC.

Circulating biomarkers for early detection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths worldwide. HCC patients face a dismal prognosis because symptoms usually appear in an advanced stage of disease. The detection of early stage HCC allows for curative surgical treatment and therefore saves lives. Specific non-invasive or diagnostic markers for HCC may represent a valuable tool for detecting these tumors at an early stage. The clinically most established serological biomarker alpha-fetoprotein shows only limited diagnostic performance, however novel candidate biomarkers and biomarker panels for detecting HCC at early stages of development are being studied. In this review we will discuss the findings of these studies.

Circulating microRNAs (miR-21, miR-223, miR-885-5p) along the clinical spectrum of HCV-related chronic liver disease in Egyptian patients

Background and study aimsMicroRNAs (miRNAs), small single stranded RNAs, function in the post-transcriptional regulation of gene expression and incorporated in pathogenesis of HCV related chronic liver disease. This study was designed to evaluate the significance of serum miR-21, miR-223, and miR-885-5p as biomarkers in various clinicopathological stages of HCV related chronic liver disease. Patients and methodsSerum miR-21, miR-223, and miR-885-5p were quantified by quantitative RT PCR in 60 patients with HCV-related liver disease (presumably genotype 4), in addition to 25 healthy controls. HCV patients were classified into: chronic non-cirrhotic HCV (n = 15), HCV related liver cirrhosis (n = 15), and hepatocellular carcinoma (HCC) (n = 30). Results: Serum levels of miR-885-5p in cirrhotic patients ± HCC (n = 45) were significantly higher than the non-cirrhotic patients (n = 15); p = 0.007 and healthy control; p = 0.001. However, no such significance was detected between HCC and non-HCC HCV patients; p = 0.12. Serum miRNA-885-5p was able to discriminate cirrhosis ± HCC from healthy controls using ROC analysis; AUC 0.85, 87% sensitivity and 80% specificity. On the other hand, HCC patients had significantly higher serum miR-2 1evels than non-HCC patients (non-cirrhotic and cirrhotic groups, n = 30); p = 0.048 and the control group; p = 0.002. ROC could differentiate HCC from control group; AUC 0.89, 80% sensitivity, 80% specificity. Both serum bilirubin and albumin showed significant weak correlation with miRNA-885-5p (r = 0.42, p = 0.001) and (r = −0.27, p = 0.04), respectively but no such correlation was observed with serum miRNA-21. In contrast, miRNA-223 showed no significant difference across the studied groups. ConclusionAlong the spectrum of HCV-related chronic liver disease, miR-885-5p could be a potential marker for advanced liver damage while miR-21 could be a helpful diagnostic marker for HCC.

Aberrant p16 methylation as an early diagnostic marker in blood of hepatocellular carcinoma patients

BackgroundAlpha-fetoprotein (AFP) is currently used for serologic screening in hepatocellular carcinoma (HCC) but with low sensitivity ranging 41–65% with a high rate of false-negative and false-positive results. For the hypermethylation of the p16 inhibitor of cyclin-dependent kinase 4 (p16INK4A), a tumor suppressor gene results in the uncontrolled division of cells. This suggests that the loss of p16INK4A function due to promoter methylation may be an early event in HCC pathogenesis so the study aimed to assess aberrant p16INK4A gene methylation as an early diagnostic marker in HCC patients.ResultsOur study revealed a highly significant increase of p16INK4A methylation in patients versus controls (Fisher, 36.11; p < 0.01). P16INK4A methylation was detected in 86.6% (26/30) and none of the controls were methylated (100% specificity) compared to the low sensitivity of AFP 65.38% at a cutoff value of 28 ng/mL. Data revealed non-significant difference of p16INK4A methylation status between different HCC Barcelona stages (Fisher, 0.055; p > 0.05). While, AFP levels were statistically significantly higher in stages B and C (median = 243,400 ng/mL, respectively, when compared to stage A (median = 10 ng/mL) (H:16.667, p < 0.01)).ConclusionEarly diagnosis of HCC can be achieved through the detection of p16INK4A gene methylation in chronic liver disease (CLD) patients with normal serum AFP especially in known cirrhotic patients that deteriorate clinically without apparent etiology.

S100A14 protein as diagnostic and prognostic marker in hepatocellular carcinoma

BackgroundProtein S100A14 has recently been implicated in the progress of several types of cancers. This study aimed to investigate the clinical significance of S100A14 in the diagnosis of hepatocellular carcinoma (HCC).ResultsS100A14 was significantly elevated in the HCC group. A cut-off value for serum S100A14 between the HCC group and cirrhosis group is > 0.47 with a sensitivity of 100% and specificity of 88.57%. S100A14 level was a significant diagnostic factor for HCC and a good reference for HCC progression.ConclusionThese results suggest that S100A14 is a good diagnostic marker for HCC.

Role of Tie2, CD14, Angiopoietin as Angiogenetic Markers in Hepatocellular Carcinoma Complicating Hepatitis C Virus Infection

Background Identifying biomarkers for early detection of hepatocellular carcinoma (HCC) remains quite challenging. In this study we aimed to estimate the number of TIE2-expressing monocytes (TEMs) cells, which display pro-tumoral activities and are defined as CD14+, TIE2+, and angiopoietin-2; and its potential use as a possible diagnostic marker in HCC patients complicating HCV induced cirrhosis. Methods Current study was conducted on 112 patients. They were divided into two groups: Group I (78 patients) with HCC complicating HCV induced cirrhosis; and group II chronic hepatitis C patients (34 patients). Both groups were compared to (age and sex-matched) healthy persons as group III (38 persons). Result The number of the circulating TEMs: CD14+ and TIE2+ monocytes were significantly higher in the peripheral blood of HCC patients than HCV LC patients and healthy controls, sensitivity and specificity for HCC diagnosis were respectively: CD14 (89.7%, 83.3%), TIE 2 (76.9%, 83.3%), and Ang-2 (76.9%, 66.7%). Moreover, analysis of the P-value and the odd’s ratio showed that CD14 has the highest predictive value for HCC. Conclusion Our results suggest that TEMs and Ang-2can be used as diagnostic markers for HCC, especially among the high-risk group of patients.

CDCA Levels Are Prognostic and Diagnostic Markers for Hepatocellular Carcinoma

Background: Little is known about the precise molecular mechanisms involved in the progression of hepatocellular carcinoma (HCC). Cell division cycle-associated (CDCA) genes, consisting of seven family members, are pivotal for cell mitosis and contribute to tumorigenesis in a variety of cancers. However, the relationship between CDCA genes and HCC have not been largely reported. Here, we aimed to assess the prognostic and diagnostic value of CDCA genes in HCC. Methods: Multiple public databases integrating genetic, mRNA and proteomic microarray data were used to validate the survival and diagnostic value of CDCA genes in HCC. Furthermore, a functional analysis was conducted to predict the potential mechanisms involved. Findings: We observed significantly increased mRNA and protein levels of CDCA in HCC tissues compared with normal tissues, and high CDCA mRNA expression indicated unfavorable overall survival (OS) and recurrence-free survival (RFS) of patients. Besides, Cox regression analysis showed that CDCA subunits acted as independent prognostic factors for patient OS. Receiver operating characteristic (ROC) curve analysis showed that CDCA levels were of great diagnostic value in HCC. Moreover, the functional analysis revealed that CDCA proteins may regulate the biological activity of hepatoma through the AMPK and p53 signaling pathways. Interpretation: CDCA levels are prognostic and diagnostic markers for HCC and deserve further study. Funding Statement: This work was supported by The Scientific Research Project of Medical Service of National Clinical Research Base of Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine (NO. JDZX2015173), The National Natural Science Foundation of China (NO. 81702375) and The Natural Science Foundation of Guangdong Province (NO. 2016A030313200). Declaration of Interests: All authors have declared that they have no conflicts of interest related to the contents of this article. Ethics Approval Statement: Not required.

KCNK levels are prognostic and diagnostic markers for hepatocellular carcinoma.

Two-pore-domain (KCNK, K2P) K+ channels are transmembrane protein complexes that control the flow of ions across biofilms, which underlie many essential cellular functions. Because KCNK family members are known to contribute to tumorigenesis in various types of cancer, we hypothesized that they might be differentially expressed in hepatocellular carcinoma (HCC) cells as compared to healthy tissue and serve as diagnostic or prognostic biomarkers. We tested this hypothesis through bioinformatic analyses of publicly available data for the expression of various KCNK subunits in HCC. We observed reduced expression of KCNK2, KCNK15, and KCNK17 in liver cancer, as well as overexpression of KCNK9, all of which correlated with a better prognosis for HCC patients per survival analyses. Moreover, ROC curves indicated that KCNK2, KCNK9, KCNK15, and KCNK17 levels could be used as a diagnostic biomarker for HCC. Finally, our western blot and qRT-PCR results were consistent with those obtained from bioinformatic analyses. Taken together, these results suggest that KCNK2, KCNK9, KCNK15, and KCNK17 could serve as potential diagnostic and prognostic biomarkers of HCC.

Molecular mechanisms of circular RNAs, transforming growth factor-β, and long noncoding RNAs in hepatocellular carcinoma.

At the heart of hepatocellular carcinoma (HCC) lies disruption of signaling pathways at the level of molecules, genes, and cells. Non‐coding RNAs (ncRNAs) have been implicated in the disease progression of HCC. For instance, dysregulated expression of circular RNAs (circRNAs) has been observed in patients with HCC. As such, these RNAs are potential therapeutic targets and diagnostic markers for HCC. Long non‐coding RNAs (lncRNAs), a type of ncRNA, have also been recognized to participate in the initiation and progression of HCC. Transforming growth factor‐beta (TGF‐β) is another element which is now recognized to play crucial roles in HCC. It has been implicated in many biological processes such as survival, immune surveillance, and cell proliferation. In HCC, TGF‐β promotes disease progression by two mechanisms: an intrinsic signaling pathway and the extrinsic pathway. Through these pathways, it modulates various microenvironment factors such as inflammatory mediators and fibroblasts. An interesting yet‐to‐be resolved concept is whether the HCC‐promoting role of TGF‐β pathways is limited to a subset of HCC patients or it is involved in the whole process of HCC development. This review summarizes recent advancements to highlight the roles of circRNAs, lncRNAs, and TGF‐β in HCC.

Serum Serotonin as a Potential Diagnostic Marker for Hepatocellular Carcinoma.

To assess the potential role of serum serotonin level in hepatocellular carcinoma (HCC) diagnosis. A case-control study that involved 100 Egyptian adults. Subjects were divided into 4 groups: Group I: 21 patients with late-stage HCC on top of liver cirrhosis, Group II: 28 patients with early-stage HCC on top of liver cirrhosis, Group III: 26 patients with cirrhosis with no evidence of HCC, and Group IV: 25 healthy age- and sex-matched subjects were as a control group. Serum serotonin level was determined in all recruited subjects using high-performance liquid chromatography-fluorescent detection method. Alpha-fetoprotein had a statistically significant elevation in group I with a median of 1300 ng/L (195-2544 ng/L) compared to groups II and III (P ≤ 0.01). Regarding serum serotonin level, it had a statistically significant elevation in group II with a median of 275 ng/μL (204.7-400 ng/μL) compared to groups I, III, and IV with median of 33 ng/μL (30-50 ng/μL), 50 ng/μL (30-60 ng/μL), and 102 (85-150 ng/μL), respectively (P = 0.001). Receiver operating characteristic curve showed that serum serotonin at cutoff value of 108 ng/μL had a sensitivity of 100% and specificity of 92.3% in discriminating early-stage HCC from cirrhosis. Serum serotonin level is a rapid, sensitive, noninvasive diagnostic biomarker for the detection of early-stage HCC.