Detection of promoter methylation status of suppressor of cytokine signaling 3 (SOCS3) in tissue and plasma from Chinese patients with different hepatic diseases

SOCS3 as an important negative regulator of IL6/JAK/STAT3 signaling pathway may be early critical determinants of carcinogenesis. This study aimed to explore the aberrant promoter methylation of SOCS3 gene in circulating DNA as a noninvasive biomarker for screening hepatocellular carcinoma (HCC) high-risk individuals and for prognosis of HCC patients after partial hepatectomy. We detected its methylation status in 116 liver tissues and 326 plasma specimens of different hepatic diseases and healthy subjects, and its mRNA and protein expression in tissues. Higher methylation rate was remarkably detected in HCC (47.92%), compared with corresponding non-tumor (25.0%), liver cirrhosis (LC) (10.0%), benign liver diseases (0%) and normal liver tissues (0%) (all P < 0.05). SOCS3 mRNA level was significantly lower in methylated HCC tissues (P < 0.05). The expressions of SOCS3 and pSTAT3 were affected by methylation status. Correlation and consistency of SOCS3 methylation were found between cancer tissue and corresponding plasma (P < 0.001, κ = 0.747). The detection rate of plasma for HCC reached 73.91%, with no false positive error. SOCS3 methylation status both in tissue and plasma was significantly associated with AFP400, tumor size, tumor differentiation, LC, metastasis and recurrence (all P < 0.05). Patients with SOCS3 methylation were followed up a markedly poorer prognosis than those unmethylated for disease-free survival (P < 0.05). These data indicate that methylation status of SOCS3 in plasma cell-free DNA can correctly reflect that in tissue DNA and be used as a noninvasive potential biomarker for chronic liver disease monitoring, predicting the degree of malignancy and poor prognosis of HCC.     

Deregulation of miR‐92a expression is implicated in hepatocellular carcinoma development

MicroRNAs (miRNAs) belong to a class of the endogenously expressed non‐coding small RNAs which primarily function as gene regulators. Growing evidence suggests that miRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. The miR‐17‐92 cluster especially is markedly overexpressed in several cancers, and is associated with the cancer development and progression. In this study, we have demonstrated that miR‐92a is highly expressed in hepatocellular carcinoma (HCC). In addition, the proliferation of HCC‐derived cell lines was enhanced by miR‐92a and inhibited by the anti‐miR‐92a antagomir. On the other hand, we have found that the relative amount of miR‐92a in the plasmas from HCC patients is decreased compared with that from the healthy donors. Interestingly, the amount of miR‐92a was elevated after surgical treatment. Thus, although the physiological significance of the decrease of miR‐92a in plasma is still unknown, deregulation of miR‐92 expression in cells and plasma should be implicated in the development of HCC.     

A five‐miRNA expression signature predicts survival in hepatocellular carcinoma

The aim of this study was to identify a microRNA (miRNA) expression signature for predicting HCC (hepatocellular carcinoma) survival. A total of 322 HCC patients in The Cancer Genome Atlas (TCGA) database were randomly divided into training and testing set. miRNAs, associated with survival time in the training set, were identified by using univariate Cox regression analysis. The risk score was formulated based on the expression levels of these miRNAs. Then the miRNA signature was validated in testing set through Kaplan–Meier analysis and log‐rank test. hsa‐miR‐301a, hsa‐miR‐132, hsa‐miR‐212, hsa‐miR‐489, and hsa‐miR‐1468 were identified to formulate risk score in training set and used to calculate the risk score of each patients in testing set. About 161 patients in testing set were segregated into high‐ and low‐risk group according to the median risk score. The survival time of high‐risk group was significantly shorter (p = 0.0248) than low‐risk group in testing test. The target genes of five miRNAs were significantly enriched in valine, leucine, and isoleucine degradation pathway and PPAR signaling pathway. hsa‐miR‐1468 had an up‐regulated tendency in HCC tissues compared to adjacent tumor tissues. The expression of hsa‐miR‐301a, hsa‐miR‐132, hsa‐miR‐212, hsa‐miR‐489, and hsa‐miR‐1468, which might be potential biomarkers to evaluate HCC patients' prognosis.     

Methylation of serum insulin‐like growth factor‐binding protein 7 promoter in hepatitis B virus‐associated hepatocellular carcinoma

Methylation of gene promoter CpG islands is an important early event in hepatocellular carcinoma (HCC), and detection of cell‐free tumor‐specific DNA methylation is becoming a useful noninvasive method for HCC. This study was aimed at determining the diagnostic value of serum insulin‐like growth factor‐binding protein 7 (IGFBP7) promoter methylation in hepatitis B virus‐associated HCC. A total of 217 subjects, including 136 HCC patients, 46 patients with chronic hepatitis B (CHB), and 35 healthy controls (HCs), were included. The methylation status of the serum IGFBP7 gene promoter was determined using methylation‐specific PCR. The frequency of serum IGFBP7 promoter methylation in HCC patients (89/136, 65%) was significantly higher than that in CHB patients (8/46, 17%; X² = 31.883, P < 0.001) and HCs (5/35, 14%; X² = 29.429, P < 0.001). Moreover, elevated IGFBP7 methylation frequency was also observed in HCC patients with vascular invasion compared with those without vascular invasion (84 versus 60%, X² = 6.633, P = 0.010). The sensitivities of serum IGFBP7 methylation and alpha‐fetoprotein (AFP) in detecting HCC were 65 and 57%, respectively. Of note, the combination of IGFBP7 methylation and AFP showed 85% for sensitivity. These results suggest that methylation of the serum IGFBP7 gene promoter may serve as a useful noninvasive biomarker for HCC diagnosis. © 2013 Wiley Periodicals, Inc.     

Expression and Clinical Significance of Livin Protein in Hepatocellular Carcinoma

In this study, the two-step PV method of immunohistochemistry was used to determine livin protein expression in HCC tissues, pericarcinoma tissues, hepatitis/hepatic cirrhosis tissues, and normal hepatic tissues, and livin protein expression was detected in the blood plasma of patients with HCC before and after surgery, subjects with hepatic cirrhosis and hepatitis, and healthy blood donors using ELISA. Livin protein expression was significantly higher in HCC tissues than that in normal hepatic tissues and hepatitis/hepatic cirrhosis tissues, with no significant difference between HCC tissues and pericarcinoma tissues. The HCC patients with positive livin protein expression had a significantly higher survival rate than those with negative livin protein expression. Livin protein expression was significantly higher in the blood plasma of patients with HCC before and after surgery and in patients with hepatic cirrhosis and hepatitis than that in healthy blood donors, whereas livin protein expression in the blood plasma of patients with HCC was not significantly different from that of patients with hepatic cirrhosis and hepatitis. Livin protein expression in HCC tissues did not correlate with that in the blood plasma of the same HCC patients. Livin protein expression may be a potential, effective indicator for assessing prognosis in patients with HCC.     

Up‐regulation of miR‐455‐5p by the TGF‐β–SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B

MicroRNAs (miRNAs) are involved in the tumourigenesis of various cancers by regulating their downstream targets. To identify the changes of miRNAs in oral squamous cell carcinoma (OSCC), we investigated the expression profiles of miRNAs in 40 pairs of OSCC specimens and their matched non‐tumour epithelial tissues. Our data revealed higher miR‐455‐5p expression in the tumour tissues than in the normal tissues; the expression was also higher in oral cancer cell lines than in normal keratinocyte cell lines. MiR‐455‐5p knockdown reduced both the anchorage‐independent growth and the proliferative ability of oral cancer cells, and these factors increased in miR‐455‐5p‐overexpressing cells. Furthermore, by analysing the array data of patients with cancer and cell lines, we identified ubiquitin‐conjugating enzyme E2B (UBE2B) as a target of miR‐455‐5p, and further validated this using 3′‐untranslated region luciferase reporter assays and western blot analysis. We also demonstrated that UBE2B suppression rescued the impaired growth ability of miR‐455‐5p‐knockdown cells. Furthermore, we observed that miR‐455‐5p expression was regulated, at least in part, by the transforming growth factor‐β (TGF‐β) pathway through the binding of SMAD3 to specific promoter regions. Notably, miR‐455‐5p expression was associated with the nodal status, stage, and overall survival in our patients, suggesting that miR‐455‐5p is a potential marker for predicting the prognosis of patients with oral cancer. In conclusion, we reveal that miR‐455‐5p expression is regulated by the TGF‐β‐dependent pathway, which subsequently leads to UBE2B down‐regulation and contributes to oral cancer tumourigenesis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Expression of Beclin‐1, an autophagy‐related marker,in chronic hepatitis and hepatocellular carcinoma and its relation with apoptotic markers

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors in worldwide. Multiple precancerous factors, including infection with hepatitis C virus (HCV), have been studied extensively. Autophagy is a highly regulated process, involved in the turnover of damaged organelles. The relationship between apoptosis and autophagy is still a debated topic especially in HCC. This study aimed to investigate the expression of beclin‐1 in chronic hepatitis and HCC and its relation with apoptotic markers. The study included the following: 20 chronic HCV hepatitis cases (first group), 35 HCC cases (second group), and 10 normal tissues as control (third group). All were stained for anti‐beclin‐1, Bcl‐2, Bcl‐XL, and Bax antibodies. A significant positive correlation was found between beclin‐1 and Bcl‐2 among the first group. While a significant inverse correlation was found between them in the second group. A positive correlation was found between beclin‐1 and Bcl‐XL expression in the first and the second groups. Also positive significant correlations were identified between beclin‐1 and Bax in the first and the second groups. Autophagy and apoptosis in the liver are interrelated processes. The high levels of beclin‐1 observed in hepatitis may suggest a central role that may limit liver damage and interact with progression to cancer where beclin‐1 later on becomes suppressed in aggressive HCC cases. So defective autophagy synergized with defective apoptosis may facilitate tumor progression. Knowledge of the role of autophagic molecules together with apoptotic markers in HCC could lead to improved treatment efficacy and overall prognosis.     

MicroRNA‐137‐mediated Src oncogenic signaling promotes cancer progression

The tyrosine kinase c‐Src is frequently overexpressed and activated in a wide variety of human cancers. However, the molecular mechanisms responsible for the upregulation of c‐Src remain elusive. To examine whether microRNA‐mediated c‐Src upregulation promotes cancer progression, we screened miRNAs with complementarity to the 3′‐UTR of c‐Src mRNA. Among these miRNAs, down‐regulation of miR‐137 was tightly associated with c‐Src‐mediated tumor progression of human colon cancer cells/tissues. Re‐expression of miR‐137 in human colon cancer cells suppressed tumor growth and caused the disruption of focal contacts, suppression of cell adhesion, and invasion, although restoration of c‐Src in miR‐137‐treated cells could not fully rescue the tumor‐suppressive effect of miR‐137. We found that miR‐137 targets AKT2 and paxillin also and miR‐137‐mediated regulation of c‐Src /AKT2 is crucial for controlling tumor growth, whereas that of c‐Src/paxillin contributes to malignancy. miR‐137 suppressed Src‐related oncogenic signaling and changed the expression of miRNAs that are regulated by Src activation. miR‐137 controls the expression of c‐Src/AKT2/paxillin and synergistically suppresses Src oncogenic signaling evoked from focal adhesions. In various human cancers that harbor c‐Src upregulation, the dysfunction of this novel mechanism would serve as a critical trigger for tumor progression.     

MiR‐1253 exerts tumor‐suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7‐H3)

Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR‐1253, a brain‐enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR‐1253 confers novel tumor‐suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR‐1253. We then explored the anti‐tumorigenic properties of miR‐1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high‐throughput screening. Deregulation of miR‐1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de‐methylation of miR‐1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR‐1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR‐1253. These data reveal novel tumor‐suppressive properties for miR‐1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.     

The microRNA‐9/B‐lymphocyte‐induced maturation protein‐1/IL‐2 axis is differentially regulated in progressive HIV infection

The fine control of T‐cell differentiation and its impact on HIV disease states is poorly understood. In this study, we demonstrate that B‐lymphocyte‐induced maturation protein‐1 (Blimp‐1/Prdm1) is highly expressed in CD4⁺ T cells from chronically HIV‐infected (CHI) patients compared to cells from long‐term nonprogressors or healthy controls. Stimulation through the T‐cell receptor in the presence ofIL‐2 induces Blimp‐1 protein expression. We show here that Blimp‐1 levels are translationally regulated by microRNA‐9 (miR‐9). Overexpression of miR‐9 induces Blimp‐1 repression, restoring IL‐2 secretion in CD4⁺ T cells via reduction in the binding of Blimp‐1 to the il‐2 promoter. In CHI patients where IL‐2 expression is reduced and there is generalized T‐cell dysfunction, we show differential expression of both miR‐9 and Blimp‐1 in CD4⁺ cells compared with levels in long‐term nonprogressors. These data identify a novel miR‐9/Blimp‐1/IL‐2 axis that is dysregulated in progressive HIV infection.     

Methylation of tumor associated genes in tissue and plasma samples from liver disease patients

To investigate whether aberrant hypermethylation in plasma DNA could be used as diagnosis makers for hepatocellular carcinoma (HCC), we performed methylation-specific PCR (MSP) to check the methylation status of five tumor associated genes in 36 cases of tissue and 42 cases of plasma samples from HCC and liver cirrhosis patients, respectively. The hypermethylation frequency of GSTP1 and RASSF1A showed significant difference between HCCs and liver cirrhosis with or without HBV infection (P < 0.05), but differences of the hypermethylation status of APC, E-cadherin, and P16 were not statistically significant. There were no significant differences in the hypermethylation status of five genes between the groups of cirrhosis with and without HBV infection. The significant differences of E-cadherin, GSTP1, P16, and RASSF1A in methylation between HCCs and liver cirrhosis were not observed in the plasma samples. Furthermore, the inconsistent results of MSP and real-time quantitative PCR for the paired samples of tissue and plasma suggested that plasma DNA could not fully stand for tissue DNA. In conclusion, hypermethylation of some specific, but not all, tumor associated genes may be involved in hepatocarcinogenesis; examination of the methylation status of E-cadherin, GSTP1, P16, and RASSF1A in the plasma samples might have limited usage for HCC diagnosis.     

Down‐Regulation of miR‐19a as a Biomarker for Early Detection of Silicosis

The accumulated data indicate that there is significant genetic heterogeneity underlying the etiology of silicosis. Recent reports have revealed that microRNAs (miRNAs) play an important role in regulating pulmonary fibrosis. This study, therefore, aimed to identify some miRNAs as biomarkers for silicosis, and to explore the early diagnostic value of biomarkers for silicosis. Total RNAs were collected from the peripheral blood leukocytes of 23 silicosis patients and 23 healthy controls, the different miRNAs were screened using microarrays. The potential biomarker miRNAs were identified by quantitative real‐time polymerase chain reaction (qPCR) and receiver operating characteristic (ROC) curves. Eighteen differential miRNAs in leukocytes were up‐regulated and twenty differential miRNAs were down‐regulated in the silicosis group, compared with the control group. The expression levels of miR‐181a and miR‐19a were 0.8854 ± 0.1037 and 0.2929 ± 0.0342 by the relative quantitation method 2^?△△CT of qPCR, respectively. The sensitivity and specificity for miR‐181a at a cut‐off value of 1.8917 were 70% and 75%, respectively, whereas, those for miR‐19a at a cut‐off value of 3.6828 were 95% and 95%, respectively. Thus, miR‐19a in peripheral blood leukocyte could be used as an effective biomarker for silicosis. Anat Rec, 299:1300–1307, 2016. © 2016 Wiley Periodicals, Inc.     

Progression from cirrhosis to cancer is associated with early ubiquitin post‐translational modifications: identification of new biomarkers of cirrhosis at risk of malignancy

Cirrhosis is a lesion at risk of hepatocellular carcinoma (HCC). Identifying mechanisms associated with the transition from cirrhosis to HCC and characterizing biomarkers of cirrhosis at high risk of developing into cancer are crucial for improving early diagnosis and prognosis of HCC. We used MALDI imaging to compare mass spectra obtained from tissue sections of cirrhosis without HCC, cirrhosis with HCC, and HCC, and a top‐down proteomics approach to characterize differential biomarkers. We identified a truncated form of monomeric ubiquitin lacking the two C‐terminal glycine residues, Ubi(1‐74), the level of which increased progressively, from cirrhosis without HCC to cirrhosis with HCC to HCC. We showed that kallikrein‐related peptidase 6 (KLK6) catalysed the production of Ubi(1‐74) from monomeric ubiquitin. Furthermore, we demonstrated that KLK6 was induced de novo in cirrhosis and increased in HCC in parallel with accumulation of Ubi(1‐74). We investigated in vitro the possible consequences of Ubi(1‐74) accumulation and demonstrated that Ubi(1‐74) interferes with the normal ubiquitination machinery in what is likely to be a kinetic process. Our data suggest that de novo KLK6 expression during early liver carcinogenesis may induce production of Ubi(1‐74) by post‐translational modification of ubiquitin. Given the deleterious effect of Ubi(1‐74) on protein ubiquitination and the major role of ubiquitin machinery in maintenance of cell homeostasis, Ubi(1‐74) might severely impact a number of critical cellular functions during transition from cirrhosis to cancer. Ubi(1‐74) and KLK6 may serve as markers of cancer risk in patients with cirrhosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt

The distribution of hepatitis C virus (HCV) genotypes was evaluated in individuals with hepatocellular carcinoma (HCC) and cirrhosis in Egypt. A total of 206 patients sero‐positive for HCV‐RNA among 400 surveyed individuals (186 with HCC, 100 with cirrhosis, and 114 healthy volunteers) were analyzed for HCV genotype. Of 206 patients, 129 had HCC, 65 had cirrhosis without HCC, and 12 were healthy volunteers. Phylogenetic analysis of sequence showed that of 206 samples, 186 contained HCV genotype 4 (90.3%), while 20 had HCV genotype 1 (9.7%). Among subjects with genotype 4, subtype 4a was predominant (79%), other subtypes included 4d, 4m, 4n, and 4o. Among those with HCV genotype 1, 15 had subtype 1g and five subtype 1a. Although subtype 4a was noted slightly more frequently in HCC (76%) compared to cirrhosis (66%) and controls (50%), there was no statistically significant difference between these three groups (P = 0.08). In conclusion, HCV genotype 4 predominates in Egypt. There was no association between subtypes of genotype 4 and the development of HCC. J. Med. Virol. 81:844–847, 2009. © 2009 Wiley‐Liss, Inc.     

Usefulness of the Novel Oncofetal Antigen Glypican-3 for Diagnosis of Hepatocellular Carcinoma and Melanoma

Glypican-3 (GPC3) mRNA and protein are expressed in >80% of human hepatocellular carcinomas (HCC) but not in normal tissues except for placenta and fetal liver. The oncofetal antigen GPC3 is a glycosylphosphatidyl inositol-anchored membrane protein and may be secreted. It is a novel tumor marker for human HCC: GPC3 protein was present in sera from 40-50% of HCC patients, but was not detected in sera from patients with liver cirrhosis or chronic hepatitis, or in sera from healthy individuals. alpha-Fetoprotein (AFP) and PIVKA-II (protein induced by vitamin K absence or antagonist-II), are well known major tumor markers for HCC. Generally, AFP shows high positivity for HCC but also high false-positivity in detection assays. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) is a recently described marker of HCC. Detection of AFP-L3 shows a much higher specificity than AFP, but a lower sensitivity. On the other hand, detection of PIVKA-II shows a lower false-positivity, but is not always sensitive enough to detect low levels secreted by small HCCs. There was no correlation between the three tumor markers, AFP, PIVKA-II, and GPC3 in terms of their presence in HCC cells. All three tumor markers showed similar positivity in patients with HCC, detecting 80% of patients with the disease. GPC3 is also a novel tumor marker for the diagnosis of human melanoma, especially in the early stages of the disease. Expression of GPC3 mRNA and protein was evident in tumor cells from >80% of patients with melanoma and melanocytic nevus, which is a common benign lesion. GPC3 protein was detected in sera from 40% (36/91) of melanoma patients, but not in sera from those with large congenital melanocytic nevus, or from healthy donors. Surprisingly, we detected serum GPC3 even in patients with stage 0, in situ melanoma. The positive detection rate of serum GPC3 at stage 0, I, and II (44.4%, 40.0%, 47.6%, respectively) was significantly higher than that of 5-S-cysteinyldopa, a well known tumor marker for melanoma (0.0%, 8.0%, and 10.0%, respectively). Interestingly, GPC3 was highly immunogenic in mice and elicited effective anti-tumor immunity with no evidence of autoimmunity. Thus, GPC3 is useful for diagnosis of HCC and melanoma and may also have a role in immunotherapy or tumor prevention. However, studies in humans are warranted.     

Detection of aberrant p16INK4A methylation in sera of patients with liver cirrhosis and hepatocellular carcinoma

Hepatocellular carcinomas (HCCs) show genomic alterations, including DNA rearrangements associated with HBV DNA integration, loss of heterozygosity, and chromosomal amplification. The genes most frequently involved are those encoding tumor suppressors. The p16INK4A tumor suppressor gene frequently displays genetic alteration in HCC tissues. The present study was performed to examine the incidence of methylated p16INK4A in the sera of liver cirrhosis (LC) and HCC patients, and to evaluate its role as a tumor marker of HCC. The sera of 23 LC patients and 46 HCC patients were examined in this study. The methylation status of p16INK4A was evaluated by methylation-specific PCR of serum samples. Methylated p16INK4A was detected in 17.4% (4/23) of LC patients and in 47.8% (22/46) of HCC patients. No association was demonstrated between p16INK4A methylation and serum AFP level. As the status of p16INK4A methylation was not associated with serum AFP level, it may have a role as a tumor marker of HCC.     

Prognostic impact of 8‐hydroxy‐deoxyguanosine and its repair enzyme 8‐hydroxy‐deoxyguanosine DNA glycosylase in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8‐hydroxy‐deoxyguanosine (8‐OHdG) DNA glycosylase (OGG1) enhances the repair of 8‐OHdG, which is the primary oxidative stress‐induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress‐induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8‐OHdG expressions in 86 resected HCC specimens. High 8‐OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8‐OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8‐OHdG expression than in those with low 8‐OHdG expression. The 8‐OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8‐OHdG group and the other group. The patients with low OGG1/high 8‐OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8‐OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8‐OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.