Biomarker For Hepatocellular Carcinoma Research Articles

Deciphering the oncogenic potential of ADAM9 in hepatocellular carcinoma through bioinformatics and experimental approaches

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study investigates the role and mechanisms of ADAM9 as a biomarker and potential therapeutic target in HCC. Utilizing RNA-sequencing data and clinicopathological characteristics from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted survival and meta-analyses, functional enrichment, and immune infiltration studies. Additionally, we evaluated the effects of ADAM9 silencing on HCC cell proliferation, migration, and invasion through in vitro experiments. Our results demonstrate that high ADAM9 expression is associated with poor prognosis and increased immune infiltration in HCC patients. Furthermore, ADAM9 knockdown significantly inhibited tumor cell proliferation and migration. These findings indicate that ADAM9 is a promising prognostic biomarker and potential therapeutic target in HCC. In conclusion, ADAM9 could offer avenues for developing strategies to inhibit tumor progression and improve patient outcomes.

The Prognostic Significance of Plasma Beta2-Glycoprotein I Levels in Hepatocellular Carcinoma Patients.

Beta2-glycoprotein I (β2-GPI) is a plasma glycoprotein with multiple physiological functions, but its relationship with hepatocellular carcinoma (HCC) is still poorly understood. HCC is one of the most common forms of liver cancer and is a leading cause of cancer-related death worldwide. This study aimed to investigate the association between β2-GPI and liver cancer and further validate its potential as a biomarker for HCC. Thirty-six patients diagnosed with HCC at the Division of Gastroenterology and Hepatology, E-Da Hospital, Taiwan, were included in the study. The expression levels of β2-GPI in plasma specimens from patients with HCC were determined by enzyme immunoassay and analyzed in relation to clinicopathological variables using the Chi-square test or Fisher's exact test. The predictive significance of β2-GPI for both overall survival (OS) and disease-free survival (DFS) was assessed using Kaplan-Meier estimates, and the statistical significance of differences was evaluated through the log-rank test. Cox proportional hazards regression models were used to evaluate the association between OS/DFS time and clinicopathological characteristics. Results: Plasma β2-GPI levels were significantly lower in patients with HCC compared to non-cancer controls and significantly correlated with aspartate aminotransferase (AST) levels of HCC. High plasma β2-GPI levels were significantly associated with better OS and DFS in HCC patients. Furthermore, in multiple variates analyses, OS was found to be significantly better in HCC patients with higher plasma β2-GPI expression. Elevated levels of β2-GPI protein in the plasma of HCC patients were identified as an independent factor predictive of improved OS and DFS. Activating β2-GPI in individuals at high risk could serve as a promising way for mitigating the progression of HCC.

Screening of cancer-specific biomarkers for hepatitis B-related hepatocellular carcinoma based on a proteome microarray

Hepatocellular carcinoma (HCC) is associated with one of the highest mortality rates among cancers, rendering its early diagnosis clinically invaluable. Serum biomarkers, specifically alpha-fetoprotein (AFP), represent the most promising and widely used diagnostic biomarkers for HCC. However, its detection rate is low in the early stages of HCC progression, and distinguishing specific false positives for other liver-related diseases, such as cirrhosis and acute hepatitis, remains challenging. Therefore, this study was conducted to identify biomarkers for hepatitis B (HBV)-related liver diseases by screening differentially expressed autoantibodies against tumor-associated antigens (TAAbs). We designed a large-scale multistage investigation, encompassing initial screening, HCC-focused, and ELISA validation cohorts to identify potential TAAbs in HBV-related liver diseases, spanning from healthy control (HC) individuals to patients with chronic hepatitis B (CHB), hepatitis B-related cirrhosis (HBC), and HCC, using protein microarray technology. The differential biological characteristics of TAAbs were analyzed using bioinformatics analysis. Validation of tumor-specific biomarkers for HCC was performed using ELISA. In the screening cohort, 547 candidate TAAbs were identified in the HCC group compared to those in the HC group. In the HCC-focused cohort, 64, 61, and 65 candidate TAAbs were identified in the CHB, HBC, and HCC groups, respectively, compared to those in the HC group. Thirty-four proteins exhibited continuously elevated expression from HCs to patients with CHB, HBC, and HCC. Among these, nine were identified as cancer-specific proteins. In the validation cohort, UBE2Z, CNOT3, and EID3 were correlated with liver function indicators in patients with hepatitis B-related HCC. Overall, UBE2Z, CNOT3, and EID3 emerged as cancer-specific biomarkers for HBV-related liver disease, providing a scientific basis for clinical application.

High throughput sequencing reveals alterations in B cell receptor repertoires associated with the progression of hepatic cirrhosis to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is developed as a consequence of chronic liver cirrhosis, and both diseases are difficult to diagnose and differentiate. Accurate noninvasive biomarkers for HCC and liver cirrhosis are urgently needed. Here we used high-throughput sequencing to characterize the B cell receptor (BCR) repertoires from 36 HCC tumor samples and 10 liver cirrhosis (LC) tissue biopsies to understand the immune alterations during hepatic carcinogenesis. The principal components analysis (PCA) showed that the pattern of BCR in HCC was distinct from that in LC. As measured by Clonality and Shannon indexes, the diversity of BCR repertoire was significantly lower in HCC than in LC (P < 0.01). Our results corroborated that the BCR diversity and composition could be closely correlated with hepatic carcinogenesis. And BCR repertoire may be used to predict the progression of HCC and design targeting immunotherapy in the near future.

Unveiling miRNA–Gene Regulatory Axes as Promising Biomarkers for Liver Cirrhosis and Hepatocellular Carcinoma

Unveiling miRNA–Gene Regulatory Axes as Promising Biomarkers for Liver Cirrhosis and Hepatocellular Carcinoma

Serum laminin γ2 monomer as a predictive biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection: a retrospective cohort study

This retrospective study evaluated the use of laminin γ2 monomer (LG2m) as a predictive biomarker for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Serum LG2m levels were measured in two cohorts of patients: cohort 1 comprised 56 patients with chronic liver disease for assessing LG2m stability, whereas cohort 2 included 89 patients with chronic HBV infection who did not have HCC for evaluating the usefulness of LG2m measurement in HCC prediction. LG2m was highly stable in cryopreserved serum, and an increased LG2m level was significantly associated with a higher risk of HCC in chronically HBV-infected patients (P = 0.012). Multivariable Cox regression analysis revealed that high LG2m was an independent significant risk factor for HCC (hazard ratio, 7.16; 95% confidence interval, 1.31–39.2; P = 0.023). These findings suggest that LG2m may serve as a useful biomarker for the prediction of future HCC in patients with chronic HBV infection.

Glycomics as prognostic biomarkers of hepatocellular carcinoma: A systematic review

Glycomics as prognostic biomarkers of hepatocellular carcinoma: A systematic review

Detection and validity of long non-coding RNAs HOST2, HOTAIR, HOXA-AS2, and MALAT1 as biomarkers for hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers in the world. Long noncoding RNAs (lncRNAs) could contribute significantly to HCC development through diverse mechanisms, such as the recruitment of many regulatory protein complexes. This study aimed to evaluate the expression levels of the lncRNAs HOST2, HOTAIR, HOXA-AS2, and MALAT1 in liver cirrhosis and HCC and also assess their diagnostic performance as biomarkers for HCC. MethodsIn total, 180 participants were in this study, classified into three groups (60 participants in each): Group I (hepatocellular carcinoma patients), Group II (liver cirrhosis patients), and Group III (apparently healthy individuals). The expressions of the HOST2, HOTAIR, HOXA-AS2, and MALAT1 lncRNAs were detected using a reverse-transcriptase real-time polymerase chain reaction (qRT-PCR). ResultsThe expression levels of HOST2, HOTAIR, HOXA-AS2, and MALAT1 lncRNAs were markedly increased in the HCC patients compared with those in the cirrhotic patients and controls. They also exhibited greater sensitivity as diagnostic biomarkers than alpha-fetoprotein. ConclusionsThe HOTAIR, HOST2, HOXA-AS2, and MALAT1 lncRNAs exhibit promising potential as valuable diagnostic biomarkers of HCC and in differentiating HCC from liver cirrhosis. Furthermore, combining alpha-fetoprotein can yield higher accuracy.

Female and diabetes are risk factors for alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II negative in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common type of tumor with a high incidence. Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II or des-gamma-carboxy prothrombin) are proven effective biomarkers for HCC. Combining them can enhance detection rates. However, when both AFP and PIVKA-II are negative, clinical diagnosis may be missed. This study aims to explore the risk factors for AFP and PIVKA-II negativity in HCC, thereby reducing missed diagnoses. A retrospective study enrolled 609 HCC patients at Shandong Public Health Clinical Center Affiliated with Shandong University from January 2010 to March 2022. Patients with negative AFP and PIVKA-II were the observed group, and others with at least 1 positive were controls. Epidemiological, clinical, laboratory, and radiological data were collected and analyzed to identify the frequency and factors influencing AFP and PIVKA-II negativity. Receiver operating characteristic (ROC) curves were used to assess the prediction model's ability to detect negative AFP and PIVKA-II in HCC. Gender (P = .045, 95% confidence interval [95%CI] = 1.013-3.277), diabetes mellitus (P = .018, 95%CI = 1.151-4.422), tumor size (P = .000, 95%CI = 0.677-0.841), glutamate transpeptidase (P = .003, 95%CI = 0.239-0.737), total bilirubin (P = .001, 95%CI = 0.235-0.705), and hepatitis B virus-associated infections (P = .007, 95%CI = 0.077-0.661) were significantly associated with AFP and PIVKA-II negativity in HCC. The prediction model had an area under curve of 0.832 (P < .001, 95%CI = 0.786-0.877), with a sensitivity of 81.2% and specificity of 75.5% in all HCC patients. Female diabetic patients with levels closer to normal for glutamate transpeptidase and total bilirubin are more likely to develop AFP and PIVKA-II-negative HCC. Imaging is crucial for screening liver cancer in these patients.

TMEM209 promotes hepatocellular carcinoma progression by activating the Wnt/β-catenin signaling pathway through KPNB1 stabilization

Hepatocellular carcinoma (HCC) is the most common malignancy in the liver, with a poor prognosis. Transmembrane protein 209 (TMEM209) involves multiple biological processes, such as substance transportation and signal transduction, and is abundantly expressed in tumor tissues. However, the relationship between TMEM209 and HCC has not been comprehensively elucidated. In this study, we aimed to illustrate this issue by in vitro and in vivo experiments. Bioinformatic analysis and clinical sample validation revealed that TMEM209 was upregulated in HCC and correlated with reduced survival duration. Functionally, TMEM209 promoted the proliferation, migration, invasion, and EMT of HCC cells in vitro and facilitated tumor growth and metastasis in xenograft models. Mechanistically, TMEM209 promoted the proliferation and metastasis of HCC in a KPNB1-dependent manner. Specifically, TMEM209 could bind to KPNB1, thereby competitively blocking the interaction between KPNB1 and the E3 ubiquitin ligase RING finger and CHY zinc finger domain-containing protein 1 (RCHY1) and preventing K48-associated ubiquitination degradation of KPNB1. Ultimately, the Wnt/β-catenin signaling pathway was activated, contributing to the progression of the malignant phenotype of HCC. In conclusion, the molecular mechanism underlying the TMEM209/KPNB1/Wnt/β-catenin axis in HCC progression was elucidated. TMEM209 is a potential biomarker and therapeutic target for HCC.

The potential role of Circular RNA New biomarkers for the prognosis of hepatocellular carcinoma

Abstract Introduction/Objective Hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer with related deaths worldwide. The non-coding RNAs as the functions of circRNAs in tumor progression have attracted great attention to the clinicopathological characteristics of HCC. Methods/Case Report The present study was conducted to investigate and evaluate the expression level of hsa_circ_2124, and hsa_circ_4018 downstream target gene pathways related to clinico-pathological parameters of HCC. Cell proliferation was examined by West-1 assay and protein expression levels by using western blotting analysis. Results (if a Case Study enter NA) The hsa_circ_2124 expression level was up-regulated in HepG2 and Hep3B cells, respectively compared to normal liver cells. Furthermore, hsa_circ_4018 was down-regulated in two HCC cell lines compared to the normal cell line (LO2 cells), demonstrating the heterogeneity characteristics of the circRNA expressions in different HCC cell lines. Our data showed a significant inhibition of hsa_circ_4018 in HCC cell lines which in turn inhibited cell proliferation and migration. Besides, there is an inhibition in cell proliferation after hsa_circ_2124 knockdown in the tested cell lines. In addition, our data reported that the Knockdown of hsa_circ_2124 reduced the expression of ERK, c-Myc, and β-catenin expression in Hep-G2 cells. Furthermore, hsa_circ_4018 showed significant inhibition in β-catenin and c-Myc expression levels in Hep3B cells compared to the control. The knockdown of hsa_circ_2124 induced G1-phase arrest in HepG2 cells compared to control, suggesting the role of hsa_circ_2124 in the inhibition of HCC progression. Conclusion All in all, our data revealed that hsa_circ_2124 or hsa_circ_4018 plays a role in the regulation of MAPK and Wnt/β-catenin signaling pathways, which might be potential therapeutic biomarkers for HCC.

Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.

Role of Circulating microRNAs in Liver Disease and HCC: Focus on miR-122.

miR-122 is the most abundant microRNA (miRNA) in the liver; it regulates several genes mainly involved in cell metabolism and inflammation. Host factors, diet, metabolic disorders and viral infection promote the development of liver diseases, including hepatocellular carcinoma (HCC). The downregulation of miR-122 in tissue is a common feature of the progression of liver injury. In addition, the release of miR-122 in the bloodstream seems to be very promising for the early diagnosis of both viral and non-viral liver disease. Although controversial data are available on the role of circulating miR-122 as a single biomarker, high diagnostic accuracy has been observed using miR-122 in combination with other circulating miRNAs and/or proteins. This review is focused on comprehensively summarizing the most recent literature on the potential role of circulating miR-122, and related molecules, as biomarker(s) of metabolic liver diseases, hepatitis and HCC.

Hypoxia-induced DTL promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through ubiquitin-mediated degradation of SLTM and subsequent Notch pathway activation

Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort (n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.

Insights about exosomal circular RNAs as novel biomarkers and therapeutic targets for hepatocellular carcinoma.

One of the most prevalent pathological types of Primary Liver Cancer (PLC) is the Hepatocellular Carcinoma (HCC) poses a global health issue. The high recurrence and metastasis rate of HCC, coupled with a low 5-year survival rate, result in a bleak prognosis. Exosomes, small extracellular vesicles released by various cells, contain diverse non-coding RNA molecules, including circular RNAs (circRNAs), which play a significant role in intercellular communication and can impact HCC progression. Studies have revealed the potential clinical applications of exosomal circRNAs as biomarkers and therapeutic targets for HCC. These circRNAs can be transferred via exosomes to nearby non-cancerous cells, thereby regulating HCC progression and influencing malignant phenotypes, such as cell proliferation, invasion, metastasis, and drug resistance. This review provides a comprehensive overview of the identified exosomal circRNAs, highlighting their potential as non-invasive biomarkers for HCC, and suggesting new perspectives for HCC diagnosis and treatment. The circRNA from exosomal organelles promotes metastasis and immune scape because of their unique chirality which is different from the Biomolecular Homochirality.

Assessment of combined serum sST2 and AFP levels in the diagnosis of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality. Alpha-fetoprotein (AFP) is the most widely used diagnostic serum biomarker, but it still has limited accuracy in detecting HCC, suggesting the necessity of seeking more ideal biomarkers with high sensitivity and specificity. Soluble growth stimulation gene 2 (sST2) form of growth stimulating expression gene 2 (ST2), is expressed in various organs and can bind competitively to interleukin 33 (IL-33). Whether sST2 can serve as a serum biomarker for HCC is largely unknown. Objective To investigate the value of sST2 as a serum diagnostic marker for HCC. Methods This study included 93 newly diagnosed HCC patients (HCC group), 90 chronic hepatitis B patients (CHB group), and 90 healthy individuals (HCs group). Spearman correlation analysis was used to explore the relationships between sST2 and the experimental indicators in HCC group. The receiver operating characteristic (ROC) curve evaluated the efficacy of sST2 alone or in combination with AFP in the diagnosis of HCC. Result The median level of sST2 was significantly higher in HCC group (24.00 [15.20-49.90] ng/mL) compared to CHB group (19.55 [15.23-24.95] ng/mL) and HCs group (7.65 [5.20-10.53] ng/mL). No significant correlations were found between sST2 and other clinical indicators in HCC group. The Area Under Curve (AUC) of ROC curve to distinguish HCC patients from healthy controls and CHB group was 0.861 (sensitivity 82.80%, specificity 72.10%) and 0.709 (sensitivity 80.60%, specificity 52.50%), respectively. When combined with AFP, the AUC increased to 0.963 (sensitivity 82.90%, specificity 94.20%), and 0.895 (sensitivity 72.0%, specificity 100%), respectively. Conclusions The serum level of sST2 increased in HCC and its diagnostic performance is comparable to that of AFP, supporting its potential as a promising biomarker for detection of HCC. The combined use of sST2 and AFP enhances diagnostic efficacy for HCC.

PD-L1+ neutrophils induced NETs in malignant ascites is a potential biomarker in HCC

BackgroundSince differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.MethodsThirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.ResultsSignificantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.ConclusionsOur findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.

Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy.

To investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC. In this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient. A total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS. The enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.

Exploring SSR1 as a novel diagnostic and prognostic biomarker in hepatocellular carcinoma, and its relationship with immune infiltration

Exploring SSR1 as a novel diagnostic and prognostic biomarker in hepatocellular carcinoma, and its relationship with immune infiltration

Integrated ubiquitomics characterization of hepatocellular carcinomas.

Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic. The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 patients with HCC. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1, and LAMA4 were highly expressed in the disease free survival-poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed cross talk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to protein kinase B-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo. This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.