Adjacent Liver Research Articles

Radical surgery for stage IV gallbladder cancers: Treatment strategies in patients with limited metastatic burden.

The present study looked at the role of radical surgery in gallbladder cancers (GBC) with limited metastatic disease. The retrospective observational study was conducted to screen the database from 1st January 2010 to 31st December 2019. Patients of GBC found to have low-volume metastatic disease upon surgical exploration were included. Of the 1,040 patients operated for GBC, 234 patients had low-volume metastatic disease (microscopic disease in station 16b1 node or N2 disease isolated port-site metastases, or low burden peritoneal disease with deposits less than 1 cm, in adjacent omentum or adjacent diaphragm or Morrison's pouch or a solitary discontinuous liver metastasis in adjacent liver parenchyma) detected intraoperative. Of these, 62 patients underwent radical surgery for R-0 metastatic disease followed by systemic therapy, while the remaining 172 patients did not undergo radical surgery and were given palliative systemic chemotherapy. Patients who underwent radical surgery had significantly superior overall survival (19 months versus 12 months, p < 0.01) and superior progression-free survival (10 months versus 5 months, p < 0.01) when compared to the rest. This difference in survival was more significant amongst patients when operated on after neoadjuvant chemotherapy. Regression analysis showed that a sub-group of patients with incidental GBC with limited metastases showed more favorable outcomes with radical surgery. Authors suggest a possible role for radical treatment of advanced GBC with a limited metastatic burden. Neoadjuvant chemotherapy can be used for preferentially selecting patients of favorable disease biology for curative treatment.

Real-time administration of indocyanine green in combination with computer vision and artificial intelligence for the identification and delineation of colorectal liver metastases

IntroductionFluorescence guided surgery for the identification of colorectal liver metastases (CRLM) can be better with low specificity and antecedent dosing impracticalities limiting indocyanine green (ICG) usefulness currently. We investigated the application of artificial intelligence methods (AIM) to demonstrate and characterise CLRMs based on dynamic signalling immediately following intraoperative ICG administration. MethodsTwenty-five patients with liver surface lesions (24 CRLM and 1 benign cyst) undergoing open/laparoscopic/robotic procedures were studied. ICG (0.05 mg/kg) was administered with near-infrared recording of fluorescence perfusion. User-selected region-of-interest (ROI) perfusion profiles were generated, milestones relating to ICG inflow/outflow extracted and used to train a machine learning (ML) classifier. 2D heatmaps were constructed in a subset using AIM to depict whole screen imaging based on dynamic tissue-ICG interaction. Fluorescence appearances were also assessed microscopically (using H&E and fresh-frozen preparations) to provide tissue-level explainability of such methods. ResultsThe ML algorithm correctly classified 97.2 % of CRLM ROIs (n = 132) and all benign lesion ROIs (n = 6) within 90-s of ICG administration following initial mathematical curve analysis identifying ICG inflow/outflow differentials between healthy liver and CRLMs. Time-fluorescence plots extracted for each pixel in 10 lesions enabled creation of 2D characterising heatmaps using flow parameters and through unsupervised ML. Microscopy confirmed statistically less CLRM fluorescence vs adjacent liver (mean ± std deviation signal/area 2.46 ± 9.56 vs 507.43 ± 160.82 respectively p < 0.001) with H&E diminishing ICG signal (n = 4). ConclusionML accurately identifies CRLMs from surrounding liver tissue enabling representative 2D mapping of such lesions from their fluorescence perfusion patterns using AIM. This may assist in reducing positive margin rates at metastatectomy and in identifying unexpected/occult malignancies.

GNB1 promotes hepatocellular carcinoma progression by targeting BAG2 to activate P38/MAPK signaling.

G-proteins are intracellular partners of G-protein-coupled receptors. As a member of the G-protein family, GNB1 has been shown to play a pro-cancer role in lung cancer and breast cancer. However, the biological function and detailed mechanisms of GNB1 in hepatocellular carcinoma progression are unclear. In this study, we investigated the effects of GNB1 and its possible mechanism of action in hepatocellular carcinoma (HCC). The clinical significance of GNB1 was evaluated in a large cohort of HCC patients, showing that GNB1 was overexpressed in HCC compared to adjacent normal liver tissues, and increased GNB1 expression was associated with poor prognosis. We also demonstrated that GNB1 enhances cell proliferation, colony formation, and cell migration and invasion in vitro and promotes the epithelial-to-mesenchymal transition process in HCC cells. Tumor xenograft model assay confirmed the oncogenic role of GNB1 in tumorigenicity in nude mice. Activation of P38 signaling was found in the GNB1 overexpressed HCC cells. Further intervention of P38 confirmed it as an important signaling pathway for the oncogenic role of GNB1 in HCC. Moreover, co-immunoprecipitation followed by liquid chromatograph-mass spectrometry identified that GNB1 exerted oncogenic functions via the interaction of BAG2 and activated P38 signaling pathway. Together, our results reveal that GNB1 plays a pivotal oncogenic role in HCC by promoting the P38 pathway via cooperating with BAG2. GNB1 may serve as a prognostic biomarker for patients with HCC.

The Value of Deep Learning in Gallbladder Lesion Characterization

The similarity of gallbladder cancer and benign gallbladder lesions brings challenges to diagnosing gallbladder cancer (GBC). This study investigated whether a convolutional neural network (CNN) could adequately differentiate GBC from benign gallbladder diseases, and whether information from adjacent liver parenchyma could improve its performance. Consecutive patients referred to our hospital with suspicious gallbladder lesions with histopathological diagnosis confirmation and available contrast-enhanced portal venous phase CT scans were retrospectively selected. A CT-based CNN was trained once on gallbladder only and once on gallbladder including a 2 cm adjacent liver parenchyma. The best-performing classifier was combined with the diagnostic results based on radiological visual analysis. A total of 127 patients were included in the study: 83 patients with benign gallbladder lesions and 44 with gallbladder cancer. The CNN trained on the gallbladder including adjacent liver parenchyma achieved the best performance with an AUC of 0.81 (95% CI 0.71-0.92), being >10% better than the CNN trained on only the gallbladder (p = 0.09). Combining the CNN with radiological visual interpretation did not improve the differentiation between GBC and benign gallbladder diseases. The CT-based CNN shows promising ability to differentiate gallbladder cancer from benign gallbladder lesions. In addition, the liver parenchyma adjacent to the gallbladder seems to provide additional information, thereby improving the CNN's performance for gallbladder lesion characterization. However, these findings should be confirmed in larger multicenter studies.

NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it mostly arises as a consequence of persistent chronic inflammation. Recently, NLRP3 inflammasome has caught the attention of many research groups due to its involvement in different types of cancer. However, its direct role in HCC remains elusive. Our study aimed to evaluate the role of NLRP3 inflammasome and pyroptosis in HCC and to clarify the potential mechanism by which 17β-estradiol (E2) can be used as a protective factor against HCC. NLRP3, caspase-1 (CASP1) as well as gasdermin-D (GSDMD) mRNA expression levels were assessed in human HCC tissues and adjacent non-cancerous liver tissues. Also, HepG2 HCC cells were cultured and treated with E2, followed by detection of the mRNA levels of these three genes. Our results revealed that NLRP3, CASP1, and GSDMD mRNA expressions were significantly lower in HCC tissues than in controls, and this under-expression was closely correlated with advanced HCC stages and grades. In contrast, HepG2 HCC cells displayed significantly higher expression levels of NLRP3 inflammasome components and GSDMD in the two E2-treated groups compared to the untreated group. Also, NLRP3, CASP1, and GSDMD mRNA expression levels were positively correlated with each other. This study confirmed that lack of NLRP3 inflammasome is involved in HCC progression and 17β-estradiol-induced activation of NLRP3 inflammasome may be effective in HCC treatment as it inhibited tumor cell growth and proliferation by triggering CASP1-dependent pyroptosis in HCC cells.

Effect of hepatic fat fraction on major hepatocellular carcinoma features at magnetic resonance imaging

BackgroundHepatocellular carcinoma (HCC) is the fifth most frequent cancer on the world. Fat accumulation within hepatocytes is known as hepatic steatosis. In recent years, research has found that people with non-alcoholic fatty liver disease have a higher chance of developing HCC. The LI-RADS® (Liver Imaging Reporting and Data System) was created to facilitate consistent reporting of imaging findings in patients at risk of HCC. The aim of this study was to see how hepatic fat fraction affects the LI-RADS major HCC features on magnetic resonance imaging (MRI).ResultsAll HCCs (92/92; 100%) showed arterial phase hyperenhancement (APHE); however, a significant association between hepatic steatosis and late APHE was found. Encapsulation was observed in 51 HCC (55.4%); in hepatic steatosis patients 17 HCC (37.8%) displayed enhancing capsule in delayed phase of the study, compared to 34 HCC (72.3%) in non-steatotic patients. The HCC size ranged from 11 to 200 mm (Mean 42.2 ± 51.8 mm) in the hepatic steatosis group; however, in patients with negative hepatic steatosis the size ranged from 13 to 205 (Mean 62.9 ± 54.5 mm).ConclusionsHepatic steatosis had a significant association with absent enhancing capsule, late arterial enhancement, as well as a lesion size less than 50 mm. “Fat sparing in solid mass” and "non-enhancing capsule" ancillary features had a significant association with hepatic steatosis, while “mild–moderate T2 hyperintensity” and “fat in mass, more than adjacent liver” ancillary features had a significant association with absent hepatic steatosis.

Loss of 5-hydroxymethylcytosine induces chemotherapy resistance in hepatocellular carcinoma via the 5-hmC/PCAF/AKT axis

Multidrug resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC). Although recent studies have reported that the multidrug resistance phenotype is associated with abnormal DNA methylation in cancer cells, the epigenetic mechanism underlying multidrug resistance remains unknown. Here, we reported that the level of 5-hydroxymethylcytosine (5-hmC) in human HCC tissues was significantly lower than that in adjacent liver tissues, and reduced 5-hmC significantly correlated with malignant phenotypes, including poor differentiation and microvascular invasion; additionally, loss of 5-hmC was related to chemotherapy resistance in post-transplantation HCC patients. Further, the 5-hmC level was regulated by ten-eleven translocation 2 (TET2), and the reduction of TET2 in HCC contributes to chemotherapy resistance through histone acetyltransferase P300/CBP-associated factor (PCAF) inhibition and AKT signaling hyperactivation. In conclusion, loss of 5-hmC induces chemotherapy resistance through PCAF/AKT axis and is a promising chemosensitivity prediction biomarker and therapeutic target for HCC patients.

FOXP3 and SQSTM1/P62 correlate with prognosis and immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common highly malignant tumours worldwide. FOXP3 and SQSTM1/P62 have been shown to be abnormally expressed in tumour cells, but their function in different tumours remains controversial. The present study was designed to evaluate the expression of FOXP3 and P62 in HCC and their prognostic value as well as their relationship with immune infiltration in HCC patients. The Gene Expression Omnibus (GEO) database and TNMplot.com platform were used to analyse the expression of FOXP3 and P62. The Cancer Genome Atlas (TCGA) database and Kaplan-Meier plotter were used to assess the impacts of FOXP3 and P62 on clinical prognosis. In addition, TCGA database was also used to examine the correlation between the expression of FOXP3 and P62 and tumour immune infiltration using the CIBERSORT algorithm. Finally, immunohistochemistry (IHC) was used to determine expression levels of FOXP3 and P62 in 89 HCC and adjacent normal liver tissues, and their effects on clinicopathological features and prognosis were verified. FOXP3 expression was downregulated in HCC tissues, while P62 expression was upregulated. FOXP3 underexpression and P62 overexpression were closely related to decreased overall survival (OS) in HCC patients. Additionally, the abnormal expression of FOXP3 and P62 was closely related to the infiltration levels of 12 types of immune cells, including regulatory T cells (Tregs), M2 macrophages, M0 macrophages, and CD8 T cells. Notably, in the validation model, abnormal FOXP3 and P62 expression was significantly associated with adverse clinicopathological factors in HCC patients, including elevated α-fetoprotein (AFP) levels, poor tumour differentiation, and increased Ki67 levels. Furthermore, low FOXP3 and high P62 expression were independent risk factors for predicting OS prognosis in HCC patients. FOXP3 and P62 have been shown to be important prognostic factors in HCC patients and are associated with immune cell infiltration in HCC. These findings suggest that FOXP3 and P62 may be valuable prognostic biomarkers and potential therapeutic targets for HCC treatment.

Tumor decellularization reveals proteomic and mechanical characteristics of the extracellular matrix of primary liver cancer

Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including cell proliferation, migration, and invasion. Also in primary liver cancer, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, the exact changes occurring in liver cancer ECM remain uncharacterized and underlying tumor-promoting mechanisms remain largely unknown. Herein, an integrative molecular and mechanical approach is used to extensively characterize the ECM of HCC and CCA tumors by utilizing an optimized decellularization technique. We identified a myriad of proteins in both tumor and adjacent liver tissue, uncovering distinct malignancy-related ECM signatures. The resolution of this approach unveiled additional ECM-related proteins compared to large liver cancer transcriptomic datasets. The differences in ECM protein composition resulted in divergent mechanical properties on a macro- and micro-scale that are tumor-type specific. Furthermore, the decellularized tumor ECM was employed to create a tumor-specific hydrogel that supports patient-derived tumor organoids, which provides a new avenue for personalized medicine applications. Taken together, this study contributes to a better understanding of alterations to composition, stiffness, and collagen alignment of the tumor ECM that occur during liver cancer development.

Clinical Significance of Combined Epithelial-Mesenchymal Transition Markers Expression and Role of Rac1 in Hepatocellular Carcinoma.

Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression, invasion, and metastasis. We aimed to evaluate the correlations between clinicopathological characteristics and EMT markers in patients with hepatocellular carcinoma (HCC) who underwent surgical resection and to identify the key regulator in EMT process. Fresh-frozen HCC tissues and adjacent nontumor liver tissues from 30 patients who underwent surgical resection were provided by the Gachon University Gil Medical Center Bio Bank. Human HCC cell lines, Hep3B, SNU449, and Huh7 cells were transfected with Rac1 siRNA and exposed to hypoxic conditions. The combined EMT markers expression (down-expression of E-cadherin and overexpression of p21-activated kinases 1 (PAK1)/Snail) by Western blot in HCC tissues when compared to adjacent nontumor liver tissues was significantly associated with macrovascular invasion (p = 0.021), microvascular invasion (p = 0.001), large tumor size (p = 0.021), and advanced tumor stage (p = 0.015). Patients with combined EMT markers expression showed early recurrence and poor overall survival. In vitro studies showed that Rac1 knockdown decreased the expression of EMT markers including PAK1 and Snail in hypoxia-induced Hep3B cells and suppressed the migration and invasion of hypoxia-induced HCC cells. Rac1 may be a potential therapeutic target for inhibition of EMT process through the inhibition of PAK1 and Snail in HCC.

Potentially Functional Genetic Variants in the NRF2 Signaling Pathway Genes are Associated With HBV-related Hepatocellular Carcinoma Survival.

The nuclear factor E2-related factor 2 (NRF2) signaling pathway is one of the most important cell defense pathways. However, it is unclear whether genetic variants in NRF2 signaling pathway genes are associated with the survival of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). In the present study, we utilized a new hypothesis-driven approach based on biological pathways to investigate the associations between 17919 single nucleotide polymorphisms (SNPs) in 137 NRF2 signaling pathway genes and the overall survival (OS) of 866 patients with HBV-related HCC. As a result, two independent SNPs with potential biological function were identified to be significantly associated with HBV-related HCC OS: [SLC2A9 rs28643326 T>C: hazard ratio (HR) = 0.74, 95% confidence interval (95% CI) = 0.62-0.89, P < 0.001 and SLC5A10 rs2472711 G>T: HR = 0.81, 95% CI = 0.71-0.93, P = 0.003, respectively]. The expression quantitative trait loci (eQTL) analysis further revealed that the rs28643326 C allele was significantly associated with increased levels of SLC2A9 mRNA expression (P < 0.001), and higher mRNA expression levels of SLC2A9 in adjacent normal liver tissues were associated with better survival. Although the association between the rs2472711 T allele and the mRNA expression of SLC5A10 was not statistically significant (P = 0.200), the fact that rs2472711 is located at the DNase I hypersensitivity site and is a marker for promoter and enhancer histones also suggests that it may have the function of regulating its corresponding gene expression. In conclusion, genetic variants of NRF2 signaling pathway genes may serve as potential prognostic biomarkers for HBV-related HCC and also provide a solid basis for further mechanistic exploration.

Clinical and prognostic significance of CCPG1 in hepatocellular carcinoma.

This study aimed to examine the clinical and prognostic significance of cell-cycle progression gene 1 (CCPG1) in hepatocellular carcinoma (HCC). We firstly analyzed CCPG1 expression in various cancers using The Cancer Genome Atlas and the Genotype-Tissue Expression project databases. The relative expression levels of CCPG1 were determined in 164 paired HCC and adjacent tissues using immunohistochemistry. The correlation between CCPG1 and clinicopathological characteristics of HCC was analyzed. Cox proportional models were used to identify the prognostic factors for overall survival (OS) and disease-free survival (DFS). The expression of CCPG1 was lower in HCC tissues than in adjacent non-tumor liver tissues. The expression of CCPG1 was significantly correlated with tumor number (p = 0.02) and tumor differentiation (p = 0.04) in HCC. Lower expression of CCPG1 in HCC patients was associated with poor OS and DFS (p < 0.01). Relative low expression of CCPG1 in HCC is significantly correlated with the poor prognosis of HCC patients after surgical resection, suggesting its possible role as a potential prognostic marker for HCC.

Coiled-Coil Domain-Containing Protein 45 Is a Potential Prognostic Biomarker and Is Associated with Immune Cell Enrichment of Hepatocellular Carcinoma.

The role of coiled-coil domain-containing protein 45 (CCDC45) in the development of hepatocellular carcinoma (HCC) has not been reported. The present study is aimed at investigating the expression and prognosis of CCDC45 in HCC and its relevance to immune infiltration. We conducted CCDC45 expression analysis using The Cancer Genome Atlas (TCGA) tumor database, the Human Protein Atlas (HPA) database, and the Tumor Immunological Evaluation Resource (TIMER). We used the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) database to show the correlation of CCDC45 with clinical features. We examined the prognostic impact of CCDC45 expression levels on HCC patients with the Kaplan-Meier mapper database. Genes coexpressed with CCDC45 and its regulators were also identified using LinkedOmics. The enriched Gene Ontology (GO) categories and associated signaling pathways were estimated using GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Assay (GSEA) pathway data. Correlations between CCDC45 and cancer immune infiltration was analyzed through the TIMER and an integrated repository portal for Tumor-Immune System Interactions (TISIDB) databases. The expression of CCDC45 was elevated in HCC tissues compared to adjacent liver tissues, and overexpression of CCDC45 was significantly correlated with tumor stage. Furthermore, HCC patients with CCDC45 overexpression had a shorter overall survival (OS). Functional network analysis indicated that CCDC45 was involved in homologous recombination, spliceosome, and DNA replication. Interestingly, CCDC45 expression was positively correlated with the level of immune cell infiltration. CCDC45 is associated with prognosis and immune infiltration of HCC and may be a potential therapeutic target for HCC.

Evaluation of the Metabolic Activity of the Infiltration and Proliferation Areas of Hepatic Alveolar Echinococcosis in Rats Using Contrast-Enhanced Ultrasound.

This study evaluated the value of contrast-enhanced ultrasound (CEUS) in assessing the metabolic activity of infiltration and proliferation areas of hepatic alveolar echinococcosis (HAE) in rats. CEUS was performed on Wistar rats with HAE. The average grayscale value of the HAE lesion in peripheral infiltration and proliferation areas (PIPAs) and the adjacent normal liver tissue was analyzed quantitatively. Contrast imaging was classified as highly increased enhancement, moderately increased enhancement, and equal or decreased enhancement. Microvessel density (MVD) in the PIPAs was classified as strongly positive, moderately positive, and weakly positive. The metabolic activity of HAE in the PIPAs was classified as high activity, moderate activity, and low activity according to the MVD classification results. The kappa test was combined with the metabolic activity level of the PIPAs to analyze the consistency of CEUS intensity and MVD. CEUS can score the metabolic activity of the infiltration and proliferation areas around HAE lesions, and provides a basis for clinical treatment and follow-up visits. CEUS could be used as a more economical and effective imaging option for evaluating the metabolic activity of HAE lesions.

Immunosuppressive role of SPP1-CD44 in the tumor microenvironment of intrahepatic cholangiocarcinoma assessed by single-cell RNA sequencing.

To demonstrate the biological function of Secreted Phosphoprotein 1(SPP1) and its immune suppressive role in the progression intrahepatic cholangiocarcinoma (ICC). We collected 62,770 cells' published transcriptome data of nine patients whose paired adjacent liver and tumor tissues were both available. We applied differential gene expression analysis to screen potential ICC marker genes, survival analysis to verify the prognostic value of SPP1, and correlation analysis to decipher factors that are related to SPP1 expression. The CellChat was used to distinguish interactions between cancer and T cells. CytoSig was applied to query cytokines that modulate CD44. Further, we established a proliferation score and correlated the score with inhibitory signals to determine the proliferation-suppressive function of SPP1-CD44. SPP1 expression is significantly upregulated in tumoral epitheliums, and patients with higher SPP1 expression have worse survival (P < 0.05). Tumor cells communicate with T cells via SPP1-CD44 interactions. The average expression of SPP1 in malignant cells (SPP1m) and CD44 in T cells (CD44t) is moderately negatively correlated with T cell proliferation score. Immunosuppressive cytokine TGFβ-3 identified as an inducer of CD44 and was significantly negatively correlated with proliferation score (R = -0.88, P < 0.01), and the negative correlation was aggravated in samples with high CD44 expression. SPP1 is a prognostic marker of ICC and is associated with the genome heterogeneity. SPP1-CD44 hinders sustained proliferation of T cells, but immunosuppressive T cells in the tumor microenvironment may evade this inhibition by reducing CD44 expression.

MRI features of lymphoepithelioma-like intrahepatic cholangiocarcinoma

Objective: To investigate the MRI manifestations of lymphoepithelioma-like intrahep cholangiocarcinoma (LEL-ICC). Methods: MR images of 26 cases with LEL-ICC confirmed pathologically at Zhongshan Hospital Affiliated with Fudan University between March 2011 and March 2021 were retrospectively analyzed. The number, location, size, morphology, edges of lesions, non-scan signal intensity, cystic necrosis, enhancement mode, peak, and capsule, vascular invasion, lymph node metastasis, and other MR images were included for analysis. The apparent diffusion coefficient (ADC) value of the lesion and the surrounding normal liver parenchyma were measured. A paired-sample t-test was used to statistically analyze the measurement data. Results: All 26 cases of LEL-ICC had solitary lesions. Mass-type LEL-ICC was the most common [n=23, lesion size (4.02±2.32) cm] with distribution along the bile duct [n=3, lesion size (7.23±1.40 cm)]. Among the 23 lesions of mass type LEL-ICC, most of the lesions were close to the liver capsule (n=20), round (n=22), clearly bordered (n=13), and cystic necrosis (n=22). In the three lesions of LEL-ICC distributed along the bile duct, most of them were close to the liver capsule (n=2), irregular (n=3), blurred edges (n=3), and cystic necrosis (n=3). All 26 lesions showed a low/slightly low signal on T1WI, a high/slightly high signal on T2WI, and a slightly high or high signal on DWI. Three lesions showed fast-in and fast-out enhancement modes, and 23 lesions showed continuous enhancement. Twenty-five lesions showed peak enhancement in the arterial phase, and one lesion appeared in the delayed phase. The ADC value of 26 lesions and adjacent normal liver parenchyma was (1.112±0.274)×10-3 mm2/s and (1.482±0.346)×10-3 mm2/s, respectively, and the both had a statistically significant difference (P<0.05). Conclusion: Certain manifestations of LEL-ICC in magnetic resonance imaging are advantageous for diagnosis and differential diagnosis.

Impact of WTAP in small HCC and paired adjacent non-neoplastic liver tissue on recurrence: A cohort study with external extension analysis.

Background: To evaluate prognostic value of WTAP levels in tumor and paired adjacent non-neoplastic liver tissues (PANLT) for cases of hepatitis B virus (HBV)-positive Asian small hepatocellular carcinoma (sHCC) patients who received curative partial hepatectomy. Method: The investigation with two external cohorts were included. Associations between hazard risk of recurrence and continuous WTAP levels were investigated with restricted cubic spline models. Cox and inverse probability weighting models were established for survival analysis. Based on interaction effects, further stratification analysis was performed. Landmark analysis was employed to analyze cases of late recurrence. Finally, sensitivity analysis was performed to assess unmeasured confounders. Findings: In an investigation cohort of 307 patients, restricted cubic spline models indicated that hazard risk of recurrence increases with elevated WTAP levels for sHCC and PANLT. However, using Cox and inverse probability weighting models, no significant differences were observed in recurrence-free survival (RFS) between groups with different WTAP levels in sHCC. Multivariate analysis showed that patients with high PANLT WTAP levels had significantly worse RFS (HR 1.567, 95% CI 1.065-2.307; p = 0.023). Based on the significant interaction effect between WTAP levels in sHCC and PANLT, stratification analysis revealed that recurrence risk is more pronounced in patients with high WTAP levels in both PANLT and sHCC. Landmark analysis showed that late recurrence was more likely to occur in patients with high PANLT WTAP levels (HR 2.058, 95% CI 1.113-3.805; p = 0.021). Moreover, the detrimental effects of elevated PANLT WTAP levels on RFS were validated with two external cohorts. Sensitivity analysis confirmed the robustness of results. Conclusion: Increased PANLT WTAP expression levels independently predict high recurrence risk in HBV-positive Asian sHCC patients. Both tumor tissues and PANLT need to be considered together in future clinical practice to obtain a more comprehensive and accurate evaluation for recurrence risk.

Multiomics analyses and machine learning of nuclear receptor coactivator 6 reveal its essential role in hepatocellular carcinoma.

Nuclear receptor coactivator 6 (NCOA6), a coactivator of numerous nuclear receptors and transcription factors, regulates multiple critical cellular functions. Nuclear receptor coactivator 6 is dysregulated in various cancers, including hepatocellular carcinoma (HCC); however, its role remains largely unknown. Here we reported that NCOA6 was highly expressed in HCC compared to the adjacent liver tissue, and NCOA6 overexpression was significantly correlated with poor HCC prognosis. Experiments revealed that the knockdown of NCOA6 damaged the proliferation, migration, and invasion of HCC cells. Multiomics and immune infiltration analyses showed a close relationship between NCOA6 expression, multiple cancer-related malignant pathways, and the immunosuppressive microenvironment. Finally, we established an effective NCOA6-related microRNA (miRNA) signature to distinguish HCC from hepatitis\liver cirrhosis patients. To the best of our knowledge, this study is the first to provide a comprehensive analysis of NCOA6 expression in HCC. We found that NCOA6 plays an important role in HCC development and has a potential mechanism of action. Establishing an NCOA6-related miRNA signature will help develop novel diagnostic strategies for HCC patients.

Effect of miRNA-200b on the proliferation of liver cancer cells via targeting SMYD2/p53 signaling pathway.

Our previous study has verified that high level of SET and MYND domain-containing protein 2 (SMYD2) plays an important role in acquiring aggressive ability for liver cancer cells in hepatocellular carcinoma. MiR-200b as a tumor suppressor gene involves in a variety of cancers. This study aims to investigate the correlation between miR-200b and SMYD2 in hepatocellular carcinoma and the underlying mechanism. Firstly, the levels of SMYD2 and miR-200b in hepatocellular carcinoma tissues and matched adjacent non-tumor liver tissues were tested with real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Secondly, we evaluated the interaction between miR-200b and SMYD2 using dual-luciferase reporter assay. Thirdly, we elucidated the effect of miR-200b on SMYD2 and its downstream targets p53/CyclinE1. Finally, we silenced SMYD2 in hepatocellular carcinoma cell lines to investigate its effect on tumor proliferation and cell cycle progression, and further confirmed the correlation among SMYD2 and p53/CyclinE1. Compared with the matched adjacent non-tumor liver tissues, miR-200b was obviously decreased, and SMYD2 was significantly increased in hepatocellular carcinoma (both P<0.05). Spearman's rank correlation revealed that miR-200b expression was negatively correlated with SMYD2 (P<0.01). Computer algorithm and dual-luciferase reporter assay revealed that miR-200b directly targeted and suppressed SMYD2 in HEK 293T cells. The down-regulated miR-200b expression promoted hepatoma cell proliferation (P<0.05) and increased SMYD2 expression(P<0.01), while the up-regulated expression of miR-200b had an opposite effect. The knockdown of SMYD2 suppressed the proliferation of MHCC-97L cells (P<0.01), down-regulated CyclinE1, and up-regulated p53 expression (both P<0.05). MiR-200b is involved in hepatocellular carcinoma progression via targeting SMYD2 and regulating SMYD2/p53/CyclinE1 signaling pathway and may be used as a potential target for hepatocellular carcinoma treatment.

Identification of biomarkers for hepatocellular carcinoma based on single cell sequencing and machine learning algorithms.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers around the world. Precision oncology will be crucial for further improving the prognosis of HCC patients. Compared with traditional bulk RNA-seq, single-cell RNA sequencing (scRNA-seq) enables the transcriptomes of a great deal of individual cells assayed in an unbiased manner, showing the potential to deeply reveal tumor heterogeneity. In this study, based on the scRNA-seq results of primary neoplastic cells and paired normal liver cells from eight HCC patients, a new strategy of machine learning algorithms was applied to screen core biomarkers that distinguished HCC tumor tissues from the adjacent normal liver. Expression profiles of HCC cells and normal liver cells were first analyzed by maximum relevance minimum redundancy (mRMR) to get a top 50 signature gene feature. For further analysis, the incremental feature selection (IFS) method and leave-one-out cross validation (LOOCV) were conducted to build an optimal classification model and to extract 21 potentially essential biomarkers for HCC cells. Our results provided new insights into HCC pathogenesis that might be valuable for HCC diagnosis and therapy.