RESUMO
The TRIM family is associated with the membrane, and its involvement in the progression, growth, and development of various cancer types has been researched extensively. However, the role played by the TRIM5 gene within this family has yet to be explored to a great extent in terms of hepatocellular carcinoma (HCC). The data of patients relating to mRNA expression and the survival rate of individuals diagnosed with HCC were extracted from The Cancer Genome Atlas (TCGA) database. UALCAN was employed to examine the potential link between TRIM5 expression and clinicopathological characteristics. In addition, enrichment analysis of differentially expressed genes (DEGs) was conducted as a means of deciphering the function and mechanism of TRIM5 in HCC. The data in the TCGA and TIMER2.0 databases was utilized to explore the correlation between TRIM5 and immune infiltration in HCC. WGCNA was performed as a means of assessing TRIM5-related co-expressed genes. The "OncoPredict" R package was also used for investigating the association between TRIM5 and drug sensitivity. Finally, qRT-PCR, Western blotting (WB) and immunohistochemistry (IHC) were employed for exploring the differential expression of TRIM5 and its clinical relevance in HCC. According to the results that were obtained from the vitro experiments, mRNA and protein levels of TRIM5 demonstrated a significant upregulation in HCC tissues. It is notable that TRIM5 expression levels were found to have a strong association with the infiltration of diverse immune cells and displayed a positive correlation with several immune checkpoint inhibitors. The TRIM5 expression also displayed promising clinical prognostic value for HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Expressão Gênica , RNA Mensageiro , Biomarcadores , Proteínas com Motivo Tripartido/genética , Fatores de Restrição Antivirais , Ubiquitina-Proteína LigasesRESUMO
We report a case of Intrahepatic sarcomatoid cholangiocarcinoma(ISCC) , which is a rare subtype of cholangiocarcinoma. Primary sarcomatoid hepatocellular carcinoma degeneration is common after anticancer chemotherapy or hepatic artery embolization.however, intrahepatic sarcomatoid cholangiocarcinoma degeneration is relatively rare.Patients typically present with abdominal pain and weight loss. ISCC is highly invasive, prone to recurrence, and has a poor prognosis . Although, patient survival can be improved with radical surgical resection.be improved with radical surgical resection.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Sarcoma , Humanos , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/terapia , Dor Abdominal , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/diagnóstico por imagemRESUMO
The membrane-associated RING-CH (MARCH) family, a member of the E3 ubiquitin ligases, has been confirmed by a growing number of studies to be associated with immune function and has been highlighted as a potential immunotherapy target. In our research, hepatocellular carcinoma (HCC) patients were divided into C1 and C2 MARCH ligase-related patterns by the non-negative matrix factorization (NMF) algorithm. Multiple analyses revealed that the MARCH ligase-related cluster was related to prognosis, clinicopathological characteristics, and the tumor immune microenvironment (TIME). Next, the signature (risk score) of the MARCH prognosis was constructed, including eight genes associated with the MARCH ligase (CYP2C9, G6PD, SLC1A5, SPP1, ANXA10, CDC20, PON1, and FTCD). The risk score showed accuracy and stability. We found that the correlations between risk score and TIME, tumor mutation burden (TMB), prognosis, and clinicopathological characteristics were significant. Additionally, the risk score also had important guiding significance for HCC treatment, including chemotherapy, immunotherapy, and transarterial chemoembolization (TACE).
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/genética , Citocromo P-450 CYP2C9 , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas , Microambiente Tumoral , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de Aminoácidos , ArildialquilfosfataseRESUMO
Background: The tripartite motif (TRIM) family are important members of the Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). Previous studies have largely focused on gene expression and molecular pathways, while the underlying role of the TRIM family in the tumor immune microenvironment (TIME) remains poorly understood. Methods: We systematically explored the correlations of prominent TRIM genes with immune checkpoints and immune infiltrates in 231 HCC samples [International Cancer Genome Consortium (ICGC) cohort (n=231); The Cancer Genome Atlas (TCGA) cohort (n=370)]. A prognostic risk model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis in the ICGC cohort. Kaplan-Meier curves based on the overall survival (OS) were used to assess differences in survival between clusters. We utilized gene set variation analysis (GSVA) to characterize the differences in biological functions. Based on univariate and multivariate Cox progression analysis, we developed a risk score signature and verified its reliability and validity. The Tumor Immune Single-cell Hub (TISCH) single-cell database was employed to evaluate the correlation of TRIM genes with the tumor microenvironment. Results: Cluster 1 was preferentially associated with a favorable prognosis (P<0.001). The amino acid, fatty acid, and drug metabolism pathways were significantly enriched in cluster 2. A prognosis risk score project was established and evaluated based on the 9 independent prognostic genes (all P<0.05). The immune score and stromal scores of patients with low-risk scores were greater than those of patients with high-risk scores (all P<0.001). However, patients with a high-risk score exhibited lower responses to immune check-point inhibitors (ICIs), sorafenib, and transarterial chemoembolization (TACE) treatment (all P<0.05). Consistently, TRIM genes showed the same influence in the external TCGA cohort. TRIM gene-based signatures were implicated in TIME and their copy-number alterations dynamically impacted the abundance of tumor-infiltrating immune cells. Conclusions: Our findings revealed that MID1, TRIM5, TRIM22, TRIM28, TRIM 31, TRIM37, TRIM38, TRIM47, and TRIM74 could serve as efficient prognostic biomarkers and therapeutic targets in HCC. The identified TRIM gene-based signatures could serve as important TIME mediators in HCC, potentially increasing immune treatment efficacy.
RESUMO
Circular RNAs are known to regulate the biological processes of hepatocellular carcinoma (HCC), and humans with Down syndrome are at low risk of developing solid tumors due to the amplification of several tumor suppressor genes on human chromosome 21 (HSA21). Here, we aimed to investigate the potential role of circRNAs originating from HSA21 in the progression of HCC. CircRNA-sequencing was performed to analyze differentially expressed circRNAs in 4 HCC and peritumor tissues, and circRNAs originating from HSA21 were further analyzed. Circ_0061984 (circPTTG1IP) was chosen for further study because it showed the lowest expression in HCC tissues, and qRT-PCR was used to confirm the expression of circPTTG1IP in HCC patient tissues. The biological function of circPTTG1IP was detected in HCC cells both in vivo and in vitro. Moreover, luciferase reporter assays, circRNA immunoprecipitation, and fluorescence in situ hybridization (FISH) were used to investigate the potential mechanism of circPTTG1IP. Finally, the possible mechanisms of filgotinib in circPTTG1IP-driven HCC were assessed. CircPTTG1IP expression was decreased in HCC compared to peritumoral tissues. Moreover, low circPTTG1IP expression was revealed to be associated with a poor prognosis of HCC patients. Elevation of circPTTG1IP was revealed to inhibit HCC development both in vitro and in vivo. Mechanistically, circPTTG1IP was shown to function as a competing endogenous RNA (ceRNA) of RNF125 by binding miR-16-5p to increase the level of the E3 ubiquitin ligase RNF125, which further ubiquitinated and degraded JAK1 protein. Finally, we demonstrated that administration of filgotinib, a JAK1 inhibitor, restricted HCC progression induced by low circPTTG1IP expression. Thus, we revealed that circPTTG1IP is a novel tumor suppresser circRNA in HCC and that a low circPTTG1IP level promotes HCC development via the miR-16-5p/RNF125/JAK1 axis. Patients with low circPTTG1IP may benefit from filgotinib treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Janus Quinase 1/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , RNA Circular/genéticaRESUMO
Globally, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-associated mortalities. It has a high rate of metastasis and recurrence, which predict a poor prognosis. G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multifunctional scaffold protein that mediates the progression of various tumors. Studies have correlated GIT1 with HCC, however, these correlations have not been fully elucidated. Therefore, we aimed at evaluating the expression of GIT1 in HCC tissues and cells, and to investigate its role and potential mechanisms in HCC progression. The expression levels of GIT1 in HCC tissues and other cancers was determined by using the Oncomine and TCGA databases. Functional analysis of GIT1 in HCC was evaluated through in vitro and in vivo experiments, whereby, HCC cells were transfected with synthetically overexpressed and short hairpin RNA (shRNA) lentivirus-mediated plasmids. Kaplan-Meier and Cox regression methods were used to establish the associations between GIT1 and clinical outcomes of 158 HCC patients. GIT1 was found to be elevated in HCC tissues where it promoted the invasion, migration, and proliferation of HCC cells. Moreover, the overexpression of GIT1 prompted epithelial-mesenchymal transition (EMT) by activating extracellular regulated kinase 1/2 (ERK1/2) pathway, which was shown to be reversed by SCH772984, a specific ERK1/2 inhibitor. GIT1 was also found to be associated with malignant features of HCC, leading to a poorer prognosis. In conclusion, GIT1 promotes HCC progression by inducing EMT and may reflect the course of HCC patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Proteínas de Ciclo Celular , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Nus , PrognósticoRESUMO
Macrophage differentiation is associated with tumorigenesis, including the tumorigenesis of hepatocellular carcinoma (HCC). Herein, we explored the value of macrophage differentiation-associated genes (MDGs) in the prognosis of HCC using data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. We performed multivariate Cox regression analyses to identify the hub genes affecting HCC patient prognoses. The correlations between hub genes and macrophage differentiation and immune checkpoint inhibitors (PD-1, PD-L1, and CTLA4) were investigated. Finally, the potential mechanism was examined with gene set enrichment analysis (GSEA). In total, seventeen differentially expressed MDGs were obtained after intersecting data from the two databases. Multivariate analysis indicated that CDC42 expression was an independent prognostic indicator in both databases. Furthermore, CDC42 showed a strong correlation with the tumor infiltration levels of immune cells in HCC tissue. Correlation analysis revealed that CDC42 expression was positively associated with M2 macrophage markers and immune checkpoint inhibitors, which indicated that CDC42 expression might be related to M2 macrophage differentiation and HCC cell immune tolerance. Finally, GSEA showed that CDC42 expression was most significantly related to the Wnt signaling pathway. In conclusion, this study showed that CDC42 expression might be an important MDG in HCC and may prove to be a new gene for studying macrophage differentiation in HCC. Abbreviations: HCC: hepatocellular carcinoma; TCGA: The Cancer Genome Atlas; ICGC: International Cancer Genome Consortium; GSEA: gene set enrichment analysis; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; ROC: receiver operating characteristic; K-M: Kaplan-Meier; AUC: the area under the ROC curve; TNM: Tumor size/lymph nodes/distance metastasis.
Assuntos
Carcinoma Hepatocelular/genética , Diferenciação Celular/genética , Neoplasias Hepáticas/genética , Macrófagos , Carcinoma Hepatocelular/imunologia , Diferenciação Celular/imunologia , Biologia Computacional , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
Cancer cells can escape antitumor immune responses by exploiting inhibitory immune checkpoints. Immune checkpoint therapy, mainly including antiCTLA4 therapy and antiPD1/PDL1 therapy, can enhance antitumor immune responses by blocking the inhibitory signals of the immune system. This therapy has produced clinical advances in a fraction of patients. Deeper insight into the tumor microenvironment and immune checkpoint inhibitors will improve this therapy. Here, we review immune checkpoint inhibitors that prevent tumor immune escape and recent clinical studies of immune checkpoint therapy. We also compare the efficacy of different combination immunotherapies, describe how the relationship between the gut microbiome and immune system can determine the therapeutic outcomes for immune checkpoint inhibitors and introduce several novel immune checkpoints that are potential targets for antitumor immunotherapy in the future.
Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias/tratamento farmacológico , Evasão Tumoral/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Kidneytype glutaminase (GLS1) plays a significant role in tumor metabolism. Our recent studies demonstrated that GLS1 was aberrantly expressed in hepatocellular carcinoma (HCC) and facilitated tumor progression. However, the roles of GLS1 in intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Thus, the aim of this study was to evaluate the expression and clinical significance of GLS1 in ICC. For this purpose, combined data from the Oncomine database with those of immunohistochemistry were used to determine the expression levels of GLS1 in cancerous and noncancerous tissues. Second, a woundhealing assay and Transwell assay were used to observe the effects of the knockdown and overexpression of GLS1 on the invasion and migration of ICC cells. We examined the associations between the expression of GLS1 and epithelialmesenchymal transition (EMT)related markers by western blot analysis. Finally, we examined the associations between GLS1 levels and clinicopathological factors or patient prognosis. The results revealed that GLS1 was overexpressed in different digestive system tumors, including ICC, and that GLS1 expression in ICC tissue was higher than that in peritumoral tissue. The overexpression of GLS1 in RBE cells induced metastasis and invasion. Moreover, the EMTrelated markers, Ecadherin and Vimentin, were regulated by GLS1 in ICC cells. By contrast, the knockdown of GLS1 expression in QBC939 cells yielded opposite results. Clinically, a high expression of GLS1 in ICC samples negatively correlated with Ecadherin expression and positively correlated with Vimentin expression. GLS1 protein expression was associated with tumor differentiation (P=0.001) and lymphatic metastasis (P=0.029). Importantly, patients with a high GLS1 expression had a poorer overall survival (OS) and a shorter time to recurrence than patients with a low GLS1 expression. Multivariate analysis indicated that GLS1 expression was an independent prognostic indicator. On the whole, the findings of this study demonstrated that GLS1 is an independent prognostic biomarker of ICC. GLS1 facilitates ICC progression and may thus prove to be a therapeutic target in ICC.