Overall Survival Of Hepatocellular Carcinoma Patients Research Articles

Exploring the Molecular Mechanisms of Huaier on Modulating Metabolic Reprogramming of Hepatocellular Carcinoma: A Study based on Network Pharmacology, Molecular Docking and Bioinformatics.

Huaier (Trametes robiniophila Murr), a traditional Chinese medicine, is widely used in China as a complementary and alternative therapy to treat hepatocellular carcinoma (HCC). Past studies have shown that Huaier can arrest the cell cycle, promote apoptosis and inhibit the proliferation of cancer cells. However, how it regulates the metabolism of HCC is still unclear. This study explores the metabolic-related function of Huaier in treating HCC with an in-silico approach. A network pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of metabolic reprogramming in HCC with Huaier. The compounds of Huaier were obtained from public databases. Oral bioavailability and drug likeness were screened using the TCMSP platform. The differential gene expressions between HCC and non-tumor tissue were calculated and used to find the overlap from the targets of Huaier. The enrichment analysis of the overlapped targets by Metascape helped filter out the metabolism-related targets of Huaier in treating HCC. Protein-protein interaction (PPI) network construction and topological screening revealed the hub nodes. The prognosis and clinical correlation of these targets were validated from the cancer genome atlas (TCGA) database, and the interactions between the hub nodes and active ingredients were validated by molecular docking. The results showed that Peroxyergosterol, Daucosterol, and Kaempferol were the primary active compounds of Huaier involved in the metabolic reprogramming of HCC. The top 6 metabolic targets included AKR1C3, CYP1A1, CYP3A4, CYP1A2, CYP17A1, and HSD11B1. The decreased expression of CYP3A4 and increased expression of AKR1C3 were related to the poor overall survival of HCC patients. The molecular docking validated that Peroxyergosterol and Kaempferol exhibited the potential to modulate CYP3A4 and AKR1C3 from a computational perspective. This study provided a workflow for understanding the mechanism of Huaier in regulating the metabolic reprogramming of HCC.

Comprehensive analysis of INTS family related to expression, prognosis, diagnosis and immune features in hepatocellular carcinoma

PurposeThe integrator subunit (INTS) family, a group exclusive to metazoans, participates in various biologic processes. However, their roles in hepatocellular carcinoma (HCC) remain largely unexplored. MethodsPublic databases were utilized to investigate the transcriptional and protein expression, and clinical relevance of the INTS family in HCC. Meanwhile, the effects of INTS13 knockdown and overexpression on cell proliferation and apoptosis were studied using HCC cell lines. ResultsThe mRNA expression of most INTSs were higher in tumor than normal tissues. Higher expression of INTS1/2/3/4/7/8/9/11/12/13 were correlated with poorer overall survival (OS) in Kaplan-Meier Survival Analysis. Multivariate analysis revealed higher level of INTS13 was an independent prognostic factor for shorter OS. Furthermore, genetic alteration of INTS3/6/7/8/9/10 were found in HCC patients and was associated with shorter disease-free survival and progression-free survival. INTS1/2/3/5/7/11/13/14 were associated with activation of tumor-induced immune response and immune infiltration in HCC. Knockdown of INTS13 inhibited cell proliferation and induced apoptosis in HCC cell lines, while overexpression of INTS13 had the opposite effect. ConclusionOur results indicate that INTS13 is an independent prognostic biomarker in HCC. Furthermore, INTS13 enhances cell proliferation and decreases cell apoptosis in HCC cell lines leading to a poorer OS in HCC patients.

OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1

BackgroundDeubiquitinating enzymes (DUBs) cleave ubiquitin on substrate molecules to maintain protein stability. DUBs reportedly participate in the tumorigenesis and tumour progression of hepatocellular carcinoma (HCC). OTU deubiquitinase 5 (OTUD5), a DUB family member, has been recognized as a critical regulator in bladder cancer, breast cancer and HCC. However, the expression and biological function of OTUD5 in HCC are still controversial.ResultsWe determined that the expression of OTUD5 was significantly upregulated in HCC tissues. High levels of OTUD5 were also detected in most HCC cell lines. TCGA data analysis demonstrated that high OTUD5 expression indicated poorer overall survival in HCC patients. OTUD5 silencing prominently suppressed HCC cell proliferation, while its overexpression markedly enhanced the proliferation of HCC cells. Mass spectrometry analysis revealed solute carrier family 38 member 1 (SLC38A1) as a candidate downstream target protein of OTUD5. Coimmunoprecipitation analysis confirmed the interaction between OTUD5 and SLC38A1. OTUD5 knockdown reduced and OTUD5 overexpression increased SLC38A1 protein levels in HCC cells. However, OTUD5 alteration had no effect on SLC38A1 mRNA expression. OTUD5 maintained SLC38A1 stability by preventing its ubiquitin-mediated proteasomal degradation. SLC38A1 silencing prominently attenuated the OTUD5-induced increase in HCC cell proliferation. Finally, OTUD5 knockdown markedly suppressed the growth of HCC cells in vivo.ConclusionsOTUD5 is an oncogene in HCC. OTUD5 contributes to HCC cell proliferation by deubiquitinating and stabilizing SLC38A1. These results may provide a theoretical basis for the development of new anti-HCC drugs.

HHLA2 promotes hepatoma cell proliferation, migration, and invasion via SPP1/PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2,or B7-H5) in HCC remains unclear.Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels.HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OEenhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway.Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.

E2F-mediated POLA2 upregulation is correlated with macrophage infiltration and poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the major histological type of primary liver cancer with a relatively poor prognosis, because most HCC cases are usually diagnosed at an advanced stage. Thus, it is essential to explore novel candidate biomarkers for early diagnosis and prognosis predication of HCC. HCC transcription sequencing data were downloaded and analyzed. POLA2 expression pattern was characterized in tumor development process. POLA2 expression was evaluated by western blotting. Kaplan-Meier plot was utilized to evaluate POLA2's ability for prognosis predication. Correlation analysis and enrichment analysis were performed to explore the functional role of POLA2 in HCC development. Knockdown of E2F1 or E2F4 was used to evaluate their ability in regulating POLA2 expression. CYBERSORT (https://cibersortx.stanford.edu/) was used to estimate the infiltration levels of immune cells. POLA2 was overexpressed in HCC. Moreover, western blotting results showed that POLA2 was upregulated by transcription factors E2F1 rather than E2F4 in HCC. POLA2 facilitated cell cycle progression, DNA replication and DNA repair. High POLA2 expression was correlated with poor overall survival in HCC patients. POLA2 induced macrophage infiltration in the tumor microenvironment by upregulating the expression CSF1 and VEGFA expression. POLA2 is a novel diagnostic and prognostic biomarker of HCC with potential clinical value.

Predicting survival of patients with advanced hepatocellular carcinoma receiving combination targeted immunotherapy: an evaluation of volumetric imaging parameters.

To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.

E3 ubiquitin ligase CHIP interacts with transferrin receptor 1 for degradation and promotes cell proliferation through inhibiting ferroptosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the major form of liver malignancy with high incidence and mortality. Identifying novel biomarkers and understanding regulatory mechanisms underlying the development and progression of HCC are critical for improving diagnosis, treatment and patient outcomes. Carboxyl terminus of Hsc-70-interacting protein (CHIP) is a well-described U-box-type E3 ubiquitin ligase which promotes the ubiquitination and degradation of numerous tumor-associated proteins. Recent studies have shown that CHIP can play as a tumor-suppressor gene or an oncogene in different kinds of malignancies. To date, the function and mechanism of CHIP in hepatocellular carcinoma remains largely unknown. Based on TCGA data, we found that compared with high CHIP expression, the overall survival of HCC patients with low expression of CHIP was better. In addition, CHIP overexpression markedly enhanced HCC cell proliferation and colony formation. Conversely, knockdown of CHIP restrained the proliferation and colony formation of HCC cells. Meanwhile, knockdown of CHIP decreased mitochondrial cristae or ruptured outer mitochondrial membrane, promoted the accumulation of Fe2+ and ferroptosis of HCC cells. Further research for the first time confirmed that CHIP interacts and degrades transferrin receptor 1 (TfR1) by ubiquitin-proteasome pathway, which leads to the inhibition of ferroptosis and promotes the proliferation of HCC cells. The analysis of proteomics data from CPTAC revealed a negative correlation between CHIP and TfR1 protein expression levels in HCC. These findings indicate that CHIP acts as a negative modulator of ferroptosis and functions as an oncogene in HCC.

Hepatocellular Carcinoma with Inferior Vena Cava Thrombus in a Child

Hepatocellular carcinoma (HCC) in children is the second common malignant liver tumor after hepatoblastoma. Chronic hepatitis B virus (HBV) infection causes most hepatocellular cancer worldwide. Metastases to the inferior vena cava (IVC) and right atrium (RA) tumor thrombi are even less common. We reported a case of a 13-year-8-month-old girl with HCC and IVC involvement. Vascular invasion predicts poor overall survival in HCC patients. Patients with HCC involving the IVC had a higher risk of sudden mortality and a poor treatment outcome. It is difficult to treat, and no standard therapy has been established. This case report aimed to describe HCC with IVC involvement. This is a rare disease with a poor prognosis, therefore it is important to detect and manage early.

Clonorchis sinensis infection amplifies hepatocellular carcinoma stemness, predicting unfavorable prognosis.

Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and the underlying mechanism remains unclear. This study was designed to investigate the association between C. sinensis infection and HCC and reveal the relationship between C. sinensis infection and cancer stemness. A comprehensive analysis of 839 HCC patients categorized into C. sinensis (-) HCC and C. sinensis (+) HCC groups was conducted. Chi-square and Mann-Whitney U tests were used to assess the association between C. sinensis infection and clinical factors. Kaplan-Meier and Cox regression analyses were used to evaluate survival outcomes. Immunohistochemistry was used to determine CK19 and EpCAM expression in HCC specimens. Compared to C. sinensis (-) HCC patients, C. sinensis (+) HCC patients exhibited advanced Barcelona Clinic Liver Cancer (BCLC) stage, higher male prevalence and more liver cirrhosis as well as elevated alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), eosinophil, complement 3 (C3), and complement 4 (C4) values. C. sinensis infection correlated with shorter overall survival (OS) (p < 0.05) and recurrence-free survival (RFS) (p < 0.05). Furthermore, Cox multivariate analysis revealed that C. sinensis infection was an independent prognostic factor for OS in HCC patients. Importantly, C. sinensis infection upregulated the expression of HCC cancer stem cell markers CK19 and EpCAM. HCC patients with C. sinensis infection exhibit a poor prognosis following hepatectomy. Moreover, C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Clonorchis sinensis (C. sinensis) is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi. C. sinensis has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma and even hepatocellular carcinoma (HCC). A substantial body of evidence links C. sinensis to cholangiocarcinoma, However, the connection between C. sinensis and HCC and the intricate mechanisms underlying its contribution to HCC development remain incompletely elucidated. Our study demonstrates clear clinicopathological associations between C. sinensis and HCC, such as gender, BCLC stage, liver cirrhosis, MVI, AFP, CA19-9, circulating eosinophils and complements. Furthermore, we found that the co-occurrence of C. sinensis exhibited a significant association with shorter OS and RFS in patients diagnosed with HCC. A major finding was that C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Our results provide a more comprehensive comprehension of the interplay between C. sinensis and HCC, shedding fresh light on the carcinogenic potential of C. sinensis.

Improving the Conversion Success Rate of Hepatocellular Carcinoma: Focus on the Use of Combination Therapy with a High Objective Response Rate.

The high mortality rate in hepatocellular carcinoma (HCC) is partially due to the fact that a significant number of patients are diagnosed at an intermediate or advanced stage, with surgical treatment options unavailable. Conversion therapy, which involves both locoregional and systemic treatments, has the potential to downstage tumors in selected patients with initially unresectable HCC, thereby making surgical treatment a possibility and potentially increasing long-term survival. To optimize the conversion rate, it is necessary to maximize successful conversions and clearly define the target population for conversion treatment through a collaborative effort. In this review article, we summarize the clinical experience and evidence for conversion therapy in patients with 'potentially resectable' HCC from four perspectives: 1) defining the target population for conversion therapy, 2) selecting the appropriate conversion strategy, placing emphasis on the utilization of combination therapy that exhibits a significant objective response rate, 3) determining the timing and urgency of surgical resection, 4) promoting the adoption of a multidisciplinary team model. The authors are optimistic that with the continuous progress in treatment and a deeper understanding of HCC, the success rate of HCC conversion therapy will increase, and the overall survival of HCC patients will be prolonged.

Suppressing MTERF3 inhibits proliferation of human hepatocellular carcinoma via ROS-mediated p38 MAPK activation

Mitochondrial transcription termination factor 3 (MTERF3) negatively regulates mitochondrial DNA transcription. However, its role in hepatocellular carcinoma (HCC) progression remains elusive. Here, we investigate the expression and function of MTERF3 in HCC. MTERF3 is overexpressed in HCC tumor tissues and higher expression of MTERF3 positively correlates with poor overall survival of HCC patients. Knockdown of MTERF3 induces mitochondrial dysfunction, S-G2/M cell cycle arrest and apoptosis, resulting in cell proliferation inhibition. In contrast, overexpression of MTERF3 promotes cell cycle progression and cell proliferation. Mechanistically, mitochondrial dysfunction induced by MTERF3 knockdown promotes ROS accumulation, activating p38 MAPK signaling pathway to suppress HCC cell proliferation. In conclusion, ROS accumulation induced by MTERF3 knockdown inhibits HCC cell proliferation via p38 MAPK signaling pathway suggesting a promising target in HCC patients.

Regular Alpha-Fetoprotein Tests Boost Curative Treatment and Survival for Hepatocellular Carcinoma Patients in an Endemic Area.

Guidelines vary on alpha-fetoprotein (AFP) testing for hepatocellular carcinoma (HCC) screening. This study aims to reassess AFP's role in HCC surveillance, utilizing a comprehensive, recent, nationwide cohort. Utilizing the National Health Claims Database from the Korean National Health Insurance Service, this research included data from 185,316 HCC patients registered between 2008 and 2018. Specifically, 81,520 patients diagnosed with HCC from 2008 to 2014 were analyzed. The study focused primarily on mortality and, secondarily, on the status of curative treatments. Multivariate analysis revealed that frequent AFP testing significantly impacts overall survival in HCC patients. Specifically, each additional AFP test correlated with a 6% relative improvement in survival (hazard ratio = 0.94, 95% CI: 0.940-0.947, p < 0.001). Patients who underwent AFP testing three or more times within two years prior to HCC diagnosis showed improved survival rates, with 55.6% receiving liver transplantation or hepatectomy. This trend was particularly pronounced in hepatitis B patients undergoing antiviral treatment. The findings highlight the potential of regular AFP testing to enhance survival in HCC patients, especially those with hepatitis B. Integrating frequent AFP testing with ultrasonography could increase the likelihood of early detection and access to curative treatments.

Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma.

Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R2=0.729, R=0.854, p<0.001) whereas PFS showed a weak correlation (R2=0.218, R=0.467, p=0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R2=0.800, R=0.894, p=0.016) whereas PFS showed a negligible correlation (R2=0.020, R=0.140, p=0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R2=0.856, R=0.925, p=0.003) as did PFS (R2=0.946, R=0.973, p<0.001). PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.

Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours

Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p<0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p= 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.

AKR1B10 inhibits the proliferation and metastasis of hepatocellular carcinoma cells by regulating the PI3K/AKT pathway.

Hepatocellular carcinoma (HCC) is one of the most frequent and aggressive malignant neoplasms, and is associated with a poor prognosis. Therefore, there is a crucial need to develop novel cancer therapies and identify novel therapeutic targets. Aldo-keto reductase family 1 member B10 (AKR1B10) is expressed in various types of cancer. However, the role of AKR1B10 in the pathological process of HCC and its underlying molecular mechanism is poorly understood. AKR1B10 expression was evaluated pan-cancer and in HCC using the Genomic Data Commons-The Cancer Genome Atlas (GDC-TCGA) and International Cancer Genome Consortium (ICGC) databases. The relationship between elevated AKR1B10 expression and overall survival in HCC patients was analyzed using a Kaplan-Meier plot. The effects of AKR1B10 on the proliferation, migration, and invasion of HCC cells were evaluated. The proliferation of HCC was measured using CCK-8 and colony formation assays. Transwell and wound healing assays were used to assess the migration and invasion of HCC cells. Western blots were used to detect the expression of proliferative and epithelial-mesenchymal transition (EMT) related proteins in HCC cells, including CCND1, E-cadherin, N-cadherin, vimentin, Twist1, PI3K/p-PI3K, and AKT/p-AKT. AKR1B10 expression was significantly upregulated pan-cancer and in liver cancer. Upregulated AKR1B10 expression was associated with a worse overall survival. HCC cell proliferation, migration, and invasion were found to be influenced by AKR1B10 activity, as demonstrated using DepMap analysis. AKR1B10 knockdown in Huh7 cells reduced proliferation, migration, invasion, and EMT. Mechanistically, AKR1B10 increased the expression of proliferative and EMT-related proteins CCND1, E-cadherin, N-cadherin, vimentin, and Twist1. PI3K and AKT phosphorylation levels decreased following AKR1B10 knockdown. In conclusion, AKR1B10 promoted the proliferation, migration, and invasion of HCC cells via the PI3K/AKT signaling pathway, a potential prognostic indicator.

Novel predictive nomograms based on aspartate aminotransferase‑to‑platelet ratio index for hepatocellular carcinoma with post‑operative adjuvant transarterial chemoembolization.

The clinical significance of systemic inflammation assessed with laboratory analysis of blood samples has been validated in a variety of cancers. The present study was conducted to investigate prognostic significance of preoperative aspartate aminotransferase-to-platelet ratio index (APRI) for the outcome of hepatocellular carcinoma (HCC) patients receiving post-operative adjuvant transarterial chemoembolization (PATACE). A total of 201 patients who underwent PATACE were retrospectively analyzed. A nomogram for HCC was developed using predictors based on multivariate Cox models, and bootstrapping was performed for validation. According to the ROC curve, which was used to divide patients into two cohorts: High APRI group (APRI>1.02) and Low APRI group (APRI≤1.02). In subgroup survival analysis, patients with a relatively low APRI had significantly longer disease-free survival (DFS) and overall survival (OS) than patients with a relatively high APRI, regardless of Barcelona Clinic Liver Cancer (BCLC) stages (BCLC 0/A or BCLC B/C, both P<0.05); while in China liver cancer staging I/II and TNM I/II stage patients, relatively low APRI was associated with improved DFS and OS (both P<0.05). Multivariate Cox models demonstrated that APRI and BCLC stages were independent prognostic factors of DFS and OS (both P<0.05). Nomograms for DFS and OS were constructed, respectively. Calibration curve analysis showed that the standard curve fitted well with the predicted curve. Time-receiver operating characteristic curve analysis revealed that the nomogram had high efficiency. Decision curve analysis demonstrated the high clinical value of the nomogram. APRI is an independent prognostic factor of DFS and OS in HCC patients receiving PATACE, and the combination of APRI with the HCC staging system can refine risk stratification to provide a more accurate prognostic assessment for the outcome of patients receiving PATACE.

DTL is a Novel Downstream Gene of E2F1 that Promotes the Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), one of the world's most prevalent malignancies, accounts for 90% of primary liver cancer cases. Recent studies have shown an increased expression of denticles E3 ubiquitin protein ligase homolog (DTL) in several different tumor types, but its function and regulatory mechanisms remain unclear. This study aimed to investigate the expressions of the Cullin4 (CUL4) complex in HCC and elucidate the roles of DTL in HCC cells. The relative expression of the CUL4 complex and its clinical significance were analyzed with The Cancer Genome Atlas (TCGA) data, and the level of DTL was confirmed by immunohistochemistry. The functions of DTL1 and upstream E2F1 were evaluated by a Western blot, MTT, transwell, and xenograft in HCC cell lines. The elevated mRNA expression of the CUL4 complex, including CUL4B, DDB1 (Damage Specific DNA Binding Protein 1), and DTL, was associated with the overall survival of HCC patients. We also found that the DTL protein was elevated in HCC tissues, and patients with highly expressed DTL and nucleus-located DTL had a poorer survival time. DTL knockdown significantly inhibited cancer proliferation, migration, and invasion. Further experiments showed that E2F1 was an upstream regulatory molecule of DTL, which was bound to the promoter of DTL, promoting the expression of DTL. The study results demonstrate that E2F1-DTL signaling promotes the growth, migration, and invasion of HCC cells, which provides new insights and a potential biological target for future HCC therapies.

MEX3C as a potential target for hepatocellular carcinoma drug and immunity: combined therapy with Lenvatinib

BackgroundThe immune microenvironment within hepatocellular carcinoma (HCC) is remarkably intricate. Although the combination of an immune checkpoint inhibitor and Lenvatinib can extend the overall survival of HCC patients, the outcome remains suboptimal.MethodsWe assessed alterations in MEX3C expression during hepatocarcinogenesis by validating multiple databases and subsequently developed a predictive model. Subsequently, we enriched the associated genes of MEX3C to investigate its functional role. We examined the correlation between MEX3C expression levels and immune infiltrating cells. The effects of MEX3C knockdown and Lenvatinib on hepatoma cells were observed by cell function experiments.ResultsMEX3C expression is elevated in HCC compared to normal tissues, and its high expression correlates with poor prognosis. Immune checkpoint expression was elevated in the high MEX3C expression group, concomitant with heightened myeloid-derived suppressor cell (MDSC) expression. The combination of MEX3C knockdown and Lenvatinib demonstrated a stronger inhibitory effect on HCC cells compared to Lenvatinib alone.ConclusionMEX3C shows promise as a potential therapeutic target for treating HCC. Furthermore, the combination of MEX3C knockdown and Lenvatinib could offer a novel therapeutic avenue for HCC treatment.

LINC01980 induced by TGF-beta promotes hepatocellular carcinoma metastasis via miR-376b-5p/E2F5 axis

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies worldwide. However, the molecular mechanism of HCC metastasis is largely unknown. Long non-coding RNA (lncRNA) plays a key role in gene regulation, and dysregulation of lncRNA is critical to cancer metastasis. LINC01980 has been reported in ESCC recently, but the mechanism underlying its function in HCC is still unknown. In this study, we found that LINC01980 was upregulated and associated with notably poor overall survival in HCC patients. Functionally, LINC01980 played a carcinogenic role and promoted HCC metastasis. Mechanically, LINC01980 enhanced the E2F5 expression via competitively binding miR-376b-5p, thereby inducing epithelial-mesenchymal transition and promoting HCC cells migration and invasion. In addition, LINC01980-mediated HCC cells metastasis was dependent on E2F5. What's more, TGF-β activated LINC01980 transcription through the canonical TGF-β/SMAD signaling pathway in HCC. In conclusion, LINC01980, activated by the canonical TGF-β/SMAD pathway, promoted HCC metastasis via miR-376b-5p/E2F5 axis. Therefore, LINC01980 might be a potential prognostic biomarker and therapeutic target of HCC.

Artesunate Sensitizes human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy

ABSTRACT Sorafenib is the most widely used first-line drug for the treatment of the advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance often limits its therapeutic efficacy. To evaluate the efficacy of artesunate against sorafenib-resistant HCC and to investigate its underlying pharmacological mechanisms, a “sorafenib resistance related gene-ART candidate target” interaction network was constructed, and a signaling axis consisting with artesunate candidate target AFAP1L2 and sorafenib target SRC, and the downstream FUNDC1-dependent mitophagy was identified as a major contributor to the sorafenib resistance and a potential way of artesunate to mitigate resistance. Notably, our clinical data demonstrated that AFAP1L2 expression in HCC tissues was markedly higher than that in adjacent non-cancerous liver tissues (P < 0.05), and high AFAP1L2 expression was also significantly associated with an unfavorable overall survival of HCC patients (P < 0.05). Experimentally, AFAP1L2 was overexpressed in sorafenib resistant cells, leading to the activation of downstream SRC-FUNDC1 signaling axis, further blocking the FUNDC1 recruitment of LC3B to mitochondria and inhibiting the activation of mitophagy, based on both in vitro and in vivo systems. Moreover, artesunate significantly enhanced the inhibitory effects of sorafenib on resistant cells and tumors by inducing excessive mitophagy. Mechanically, artesunate reduced the expression of AFAP1L2 protein, suppressed the phosphorylation levels of SRC and FUNDC1 proteins, promoted the FUNDC1 recruitment of massive LC3B to mitochondria, and further overactivated the mitophagy and subsequent cell apoptosis of sorafenib resistant cells. In conclusion, artesunate may be a promising strategy to mitigate sorafenib resistance in HCC via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy. Abbreviations: AFAP1L2, actin filament associated protein 1 like 2; ANOVA, analysis of variance; ANXA5, annexin V; ART: artesunate; CETSA, cellular thermal shift assay; CI: combination index; CO-IP: co-immunoprecipitation; CQ: chloroquine; CT, computed tomography; [18F]-FDG, fluoro-2-D-deoxyglucose F18; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC, hepatocellular carcinoma; H&E Staining: hematoxylin – eosin staining; HepG2R, sorafenib resistant HepG2; IF, immunofluorescence; IHC, immunohistochemistry; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; miR, microRNA; mRNA: messenger RNA; OE, overexpression; OS, overall survival; PET, positron emission tomography; qRT-PCR: quantitative real-time PCR; sh, short hairpin; shNC: negative control shRNA; shAFAP1L2: short hairpin AFAP1L2; SORA, sorafenib; SPR, surface plasmon resonance; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; SUV, standardized uptake value; TEM, transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20.