Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis

Abstract

Cirrhosis is frequently the final stage of disease preceding the development of hepatocellular carcinoma (HCC) and is one of the risk factors for HCC. Preventive surveillance for early HCC in patients with cirrhosis is advantageous for achieving early HCC prevention and diagnosis, thereby enhancing patient prognosis and reducing mortality. However, there is no highly sensitive diagnostic marker for the clinical surveillance of HCC in patients with cirrhosis, which significantly restricts its use in primary care for HCC. To increase the accuracy of illness diagnosis, the study of the effective and sensitive genetic biomarkers involved in HCC incidence is crucial. In this study, a set of 120 significantly differentially expressed genes (DEGs) was identified in the GSE121248 dataset. A protein–protein interaction (PPI) network was constructed among the DEGs, and Cytoscape was used to extract hub genes from the network. In TCGA database, the expression levels, correlation analysis, and predictive performance of hub genes were validated. In total, 15 hub genes showed increased expression, and their positive correlation ranged from 0.80 to 0.90, suggesting they may be involved in the same signaling pathway governing HBV-related HCC. The GSE10143, GSE25097, GSE54236, and GSE17548 datasets were used to investigate the expression pattern of these hub genes in the progression from cirrhosis to HCC. Using Cox regression analysis, a prediction model was then developed. The ROC curves, DCA, and calibration analysis demonstrated the superior disease prediction accuracy of this model. In addition, using proteomic analysis, we investigated whether these key hub genes interact with the HBV-encoded oncogene X protein (HBx), the oncogenic protein in HCC. We constructed stable HBx-expressing LO2-HBx and Huh-7-HBx cell lines. Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) results demonstrated that CDK1, RRM2, ANLN, and HMMR interacted specifically with HBx in both cell models. Importantly, we investigated 15 potential key genes (CCNB1, CDK1, BUB1B, ECT2, RACGAP1, ANLN, PBK, TOP2A, ASPM, RRM2, NEK2, PRC1, SPP1, HMMR, and DTL) participating in the transformation process of HBV infection to HCC, of which 4 hub genes (CDK1, RRM2, ANLN, and HMMR) probably serve as potential oncogenic HBx downstream target molecules. All these findings of our study provided valuable research direction for the diagnostic gene detection of HBV-related HCC in primary care surveillance for HCC in patients with cirrhosis.

Identification of hub genes and pathways in hepatitis B virus‐associated hepatocellular carcinoma: A comprehensive in silico study

“…However, the exact mechanism by which HBV affects CDK1 expression and leads to HCC progression is still not fully understood and requires further studies. Moreover, it has been suggested that CDK1 is a predictive biomarker in HBV‐related HCC, and its overexpression is associated with a negative prognosis and the advancement of tumors 31 . Increased levels of CDK1 expression are linked to more advanced tumor grades and stages, suggesting its role in promoting cancer aggressiveness.…”

Identification and verification of novel immune-related ferroptosis signature with excellent prognostic predictive and clinical guidance value in hepatocellular carcinoma

“…We obtained GSE36376 cohort (193 HCC and 240 adjacent normal tissues), GSE14520 cohort (247 HCC and 241 adjacent normal tissues), GSE25097 cohort (268 HCC and 243 adjacent normal tissues) and GSE10143 cohort (80 HCC tissues) from GEO. LIRI cohort (273 HCC and 203 adjacent normal tissues), the last external cohort, was obtained from the ICGC ( Liu et al, 2019 ; Yang et al, 2021b ; Jin et al, 2022 ; Li et al, 2022 ). ImmPort ( immport.org/home ) and InnateDB ( innatedb.ca/ ) databases provided 2,660 immune-related genes (IRGs), while FerrDb ( zhounan.org/ferrdb ) database shared 259 ferroptosis-related genes (FRGs) for us.…”

Histomolecular characterisation of hepatitis B virus induced liver cancer

“…Of these, CDKN3, which influences the cell cycle and is intimately connected to the occurrence and progression of HCC, was paramount hum gene in promoting HBV induced hepatic cancer. 24 SET and MYND domain containing 3 (SMYD3), zymogen granule protein 16 (ZG16), family with sequence similarity 110 member C (FAM110C), and cytochrome P450 family 26 subfamily a member 1 (CYP26A1) are distinct genes to distinguish HBV infection and HBVinduced HCC and are anticipated to be novel targets for the occurrence of HBV-associated HCC and prognostic evaluation. 25 2 of 9 -ADUGNA…”

“…In order for liver cirrhosis to progress into HCC, three critical genes such as cyclin‐dependent kinase inhibitor 3 (CDKN3), Cytochrome P450 family 2 subfamily C member 9 (CYP2C9), and Lecithin‐Cholesterol Acyltransferase were appear to be crucial. Of these, CDKN3, which influences the cell cycle and is intimately connected to the occurrence and progression of HCC, was paramount hum gene in promoting HBV induced hepatic cancer 24 . SET and MYND domain containing 3 (SMYD3), zymogen granule protein 16 (ZG16), family with sequence similarity 110 member C (FAM110C), and cytochrome P450 family 26 subfamily a member 1 (CYP26A1) are distinct genes to distinguish HBV infection and HBV‐induced HCC and are anticipated to be novel targets for the occurrence of HBV‐associated HCC and prognostic evaluation 25 …”