Alternative Splicing-Based Differences Between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Genes, Immune Microenvironment, and Survival Prognosis
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ABSTRACT:
SUBMITTER: Luo D
PROVIDER: S-EPMC8574058 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND The potential roles of alternative splicing (AS) in HCC remain unknown. This study aimed to identify AS signatures associated with the prognosis that influence the immune microenvironment of HCC. MATERIAL AND METHODS The SpliceSeq tool was employed for genome-wide profiling of 7 AS events in 361 HCC patients from The Cancer Genome Atlas (TCGA). A prognostic signature was built by integrating Cox regression and the least absolute shrinkage and selection operator (LASSO). The support vector machine (SVM) and receiver operating characteristic curve (ROC) were employed to analyze the AS events in the signatures to discriminate the immune microenvironment. RESULTS There were 3546 AS events highly linked to the survival of patients with HCC. The AS signature could effectively stratify HCC patients. Clustering analysis revealed 3 different immune clusters characterized with significantly different prognoses and were significantly correlated with AS signatures. The AS events in the final prognostic signature classified the immune cluster with an average AUC of the ROC (0.88). Moreover, a potential regulatory network of splicing events in HCC is presented. CONCLUSIONS We established the prognostic signature based on AS, which can effectively stratify HCC patients and predict the immune subtypes. Moreover, novel RNA splicing patterns and splicing-regulatory networks involved in HCC were discovered.
| S-EPMC8381756 | biostudies-literature
Project description:Combined hepatocellular-cholangiocarcinoma (cHCC-CC) and intrahepatic cholangiocarcinoma (ICC) are classified into one category, but comparison of prognosis of the two carcinomas remains controversial. The aim of the current study was to investigate surgical outcomes for patients with ICC or cHCC-CC who underwent resection in order to elucidate whether the classification of ICC and cHCC-CC is justified. Subjects were 61 patients with ICC and 29 patients with cHCC-CC who underwent liver resection from 2001 to 2017. Clinic-pathological data from the two groups were compared. Tumor number and vascular invasion were independent risk factors for recurrence-free survival (RFS) in both groups (P < .001 for both). Of note, for patients with ICC, tumor cut-off size of 5 cm showed statistical significance in median RFS (>5 cm vs ≤5 cm, 0.5 years vs 4.0 years, P = .003). For patients with cHCC-CC, tumor cut-off size of 2 cm showed statistical significance in median RFS (>2 cm vs ≤2 cm, 0.6 years vs 2.6 years, P = .038). The median RFS of patients with cHCC-CC was 0.9 years (95% confidence interval: 0.3-1.6), which was poorer than that of patients with ICC (1.3 years, 0.5-2.1) (P = .028); the rate of RFS at 5 years was 0% and 37.7% respectively. Our study supports the concept of classifying ICC and cHCC-CC into different categories because of a significant difference in RFS between the two.
| S-EPMC6792494 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its 5-year survival rate is less than 20%, despite various treatments being available. Increasing evidence indicates that alternative splicing (AS) plays a nonnegligible role in the formation and development of the tumor microenvironment (TME). However, the comprehensive analysis of the impact on prognostic AS events on immune-related perspectives in HCC is lacking but urgently needed.MethodsThe transcriptional data and clinical information of HCC patients were downloaded from TCGA (The Cancer Genome Atlas) database for calculating immune and stromal scores by ESTIMATE algorithm. We then divided patients into high/low score groups and explored their prognostic significance using Kaplan-Meier curves. Based on stromal and immune scores, differentially expressed AS events (DEASs) were screened and evaluated with functional enrichment analysis. Additionally, a risk score model was established by applying univariate and multivariate Cox regression analyses. Finally, gene set variation analysis (GSVA) was adopted to explore differences in biological behaviors between the high- and low-risk subgroups.ResultsA total of 370 HCC patients with complete and qualified corresponding data were included in the subsequent analysis. According to the results of ESTIMATE analysis, we observed that the high immune/stromal score group had a longer survival probability, which was significantly correlated with prognosis in HCC patients. In addition, 467 stromal/immune score-related DEASs were identified, and enrichment analysis revealed that DEASs were significantly enriched in pathways related to HCC tumorigenesis and the immune microenvironment. More importantly, the final prognostic signature containing 16 DEASs showed powerful predictive ability. Finally, GSVA demonstrated that activation of carcinogenic pathways and immune-related pathways in the high-risk group may lead to poor prognosis.ConclusionsCollectively, these outcomes revealed prognostic AS events related to carcinogenesis and the immune microenvironment, which may yield new directions for HCC immunotherapy.
| S-EPMC8034091 | biostudies-literature
Project description:BackgroundThe impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features.MethodsWe retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform.ResultsThe analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group.ConclusionsThe activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.
| S-EPMC10786594 | biostudies-literature
Project description:ObjectiveAlternative splicing (AS) is the mechanism by which a few genes encode numerous proteins, and it redefines the concept of gene expression regulation. Recent studies showed that dysregulation of AS was an important cause of tumorigenesis and microenvironment formation. Therefore, we performed a systematic analysis to examine the role of AS in breast cancer (Breast Cancer, BrCa) progression.MethodsThe present study included 993 BrCa patients from The Cancer Genome Atlas (TCGA) database in the genome-wide analysis of AS events. We used differential and prognostic analyses and found differentially expressed alternative splicing (DEAS) events and independent prognostic factors related to patients' overall survival (OS) and disease-free survival (DFS). We divided the patients into two groups based on these AS events and analyzed their clinical features, molecular subtyping and immune characteristics. We also constructed a splicing factor (SF) regulation network for key AS events and verified the existence of AS events in tissue samples using real-time quantitative PCR.ResultsA total of 678 AS events were identified as differentially expressed, of which 13 and 10 AS events were independent prognostic factors of patients' OS and DFS, respectively. Unsupervised clustering analysis based on these prognostic factors indicated that the Cluster 1 group had a better prognosis and more immune cell infiltration. SFs were significantly related to the expression of AS events, and AA-RPS21 was significantly upregulated in tumors.ConclusionAlternative splicing expands the mechanism of breast cancer progression from a new perspective. Notably, alternative splicing may affect the patient's prognosis by affecting the infiltration of immune cells. Our research provides important guidance for subsequent studies of AS in breast cancer.
| S-EPMC8236959 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.
| S-EPMC9032805 | biostudies-literature
Project description:BackgroundIntrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer, and its long-term survival rate remains poor. RNA-binding proteins (RBPs) play an important role in critical cellular processes, failure of any one or more processes can lead to the development of multiple cancers. This study aimed to explore pivotal biomarkers and corresponding mechanisms to predict the prognosis of patients with ICC.MethodsThe transcriptomic and clinical information of patients were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Bioinformatic methods were used to identify survival-related and differentially-expressed biomarkers. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry were used to detect the expression levels of key biomarkers in independent real-world cohorts. Subsequently, a prognostic signature was constructed that effectively distinguished patients in the high- and low-risk groups. Independent prognosis analysis was used to verify the signature's independent predictive capabilities, and two nomograms were developed to predict survival.ResultsPIWIL4 and SUPT5H were identified and considered as pivotal biomarkers, and the same expression trends of upregulation in ICC were also validated via qRT-PCR and immunohistochemistry in the separate real-world sample cohorts. The prognostic signature showed good predictive capabilities according to the area under the curve. The correlation of the biomarkers with the tumour microenvironment suggested that the high riskScore was positively related to the enrichment of resting natural killer cells and activated memory CD4 + T cells.ConclusionIn the present study, we demonstrated that PIWIL4 and SUPT5H could be used as novel prognostic biomarkers to develop a prognostic signature. This study provides potential biomarkers of prognostic value for patients with intrahepatic cholangiocarcinoma.
| S-EPMC8649993 | biostudies-literature
Project description:BackgroundDue to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown.MethodsThis is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated.ResultsWe gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p = 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p = 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p = 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p < 0.001). These benefits were confirmed after correcting for the lead-time bias.ConclusionsCirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.
| S-EPMC7768136 | biostudies-literature
Project description:FoxM1 is an oncoprotein that is significantly overexpressed in many malignancies including hepatocellular carcinoma, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. This study explores the expression of FoxM1 in human ICC, its relationships with clinical outcomes, and its role in the proliferation, migration, and invasion of ICC in vitro and in vivo. The results show that FoxM1 was markedly elevated in tumor tissues versus the paired peritumoral tissues. Overexpression of FoxM1 was correlated with multiple tumor nodules, tumor size > 5 cm, positive lymph node metastasis and advanced TNM stage. Cox analysis revealed that overexpression of FoxM1 is an independent prognostic indicator for both the overall survival and disease-free survival of ICC patients after hepatectomy. Furthermore, up/downregulation of FoxM1 markedly promoted/inhibited ICC cell proliferation, migration, and invasion in vitro and in vivo. Bioinformatic analysis indicated that overexpression of FoxM1 resulted in the dysregulation of multiple signaling pathways in ICC, and selected components of some key signaling pathways such as c-Myc signaling were confirmed in vitro. In addition, overexpression of FoxM1 enhanced MMP-9 and MMP-2 protein expression in ICC cells. In conclusion, FoxM1 promotes ICC progression and is a reliable predictor of poor prognosis in ICC.
| S-EPMC6326658 | biostudies-literature
Project description:Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results: ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface (p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface (p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 (p = 0.048) and CD4_ICOS_TIGIT (p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy.
| S-EPMC10047585 | biostudies-literature