A cuproptosis-related gene expression signature predicting clinical prognosis and immune responses in intrahepatic cholangiocarcinoma detected by single-cell RNA sequence analysis

Cancer Cell International, Journal Year: 2024, Volume and Issue: 24(1)

Published: March 2, 2024

Abstract Background Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with subset of tumors developing inside liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered metabolism comparatively higher needs, cuproptosis may play role in development ICC. However, studies investigating this possibility are currently lacking. Methods Single-cell bulk RNA sequence data were analyzed, correlations established between expression cuproptosis-related molecules ICC patient survival. Genes predicting survival used to create CUPT score using Cox LASSO regression tumor mutation burden (TMB) analysis. The CIBERSORT software was employed characterize immune infiltration within tumors. Furthermore, prediction, biological function enrichment, drug sensitivity analyses conducted explore potential implications signature. effects silencing solute carrier family 39 member 4 gene (SLC39A4) siRNA investigated assays measuring proliferation, colony formation, migration. Key genes detected western blotting. Results developed divided patients into high low groups. Those had significantly better prognosis longer In contrast, scores associated worse clinical outcomes TMB. Comparisons two groups also indicated differences infiltrate present Finally, we able identify 95 drugs potentially affecting pathway. Some these might be effective vitro experiments revealed that suppressing SLC39A4 lines resulted reduced It led increase upregulation key cuproptosis, namely ferredoxin 1 (FDX1) dihydrolipoyl transacetylase (DLAT). These findings strongly suggest cuproptosis-associated molecule pivotal metastasis Conclusions Changes signature can predict considerable accuracy. This supports notion influences diversity complexity microenvironment, mutational landscape, behavior Understanding hold promise for innovative strategies management disease.

Language: Английский

---

Precision immunotherapy for cholangiocarcinoma: Pioneering the use of human-derived anti-cMET single chain variable fragment in anti-cMET chimeric antigen receptor (CAR) NK cells

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 136, P. 112273 - 112273

Published: May 28, 2024

Cholangiocarcinoma (CCA) presents a significant clinical challenge which is often identified in advanced stages, therby restricting the effectiveness of surgical interventions for most patients. The high incidence cancer recurrence and resistance to chemotherapy further contribute bleak prognosis low survival rates. To address this pressing need effective therapeutic strategies, our study focuses on development an innovative cellular immunotherapy, specifically utilizing chimeric antigen receptor (CAR)-engineered natural killer (NK) cells designed target cMET tyrosine kinase. In investigation, we initiated screening phage library displaying human single-chain variable fragment (ScFv) identify novel ScFv molecules with specificity cMET. Remarkably, ScFv11, ScFv72, ScFv114 demonstrated exceptional binding affinity, confirmed by molecular docking analysis. These selected ScFvs, addition well-established anti-cMET ScFvA, were integrated into CAR cassette harboring CD28 transmembrane region-41BB-CD3ζ domains. resulting constructs transduced NK-92 cells, generating potent CAR-NK-92 cells. assess efficacy these engineered employed KKU213A expression KKU055 levels. Notably, co-culture resulted significantly increased cell death, whereas no such effect was observed summary, as promising CCA. armed molecule, have shown strong ability kill specifically, indicating their potential treatment CCA future.

Language: Английский

---

Unveiling the prognostic role of blood inflammatory indexes in a retrospective cohort of patients undergoing liver resection for intrahepatic cholangiocarcinoma

International Journal of Surgery, Journal Year: 2024, Volume and Issue: 110(11), P. 7088 - 7096

Published: July 5, 2024

Systemic inflammation is relevant in intrahepatic cholangiocarcinoma (iCCA), but controversial results exist on the prognostic role of inflammatory indexes and their correlation with tumor microenvironment. The authors aimed to explore biological values these indexes. A retrospective cohort study involving iCCA patients who underwent hepatic resection between 2010 2021 was conducted. neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte (LMR), clinic-pathological factors were recorded. Immune-cell subpopulations, isolated from surgical specimens, analyzed by flow cytometry. NLR LMR cut-offs calculated X-Tile software. Linear regression, Kaplan-Meier, Cox regression analyses total 101 considered. ≥3.83 <2.28 correlated worse survival. Patients divided into groups: 67 (66.3%) low-risk 34 (33.7%) high-risk (having at least one ratio). 5-year overall survival 49.8 18.9% for low- groups, respectively ( P =0.003). An elevated CA19-9 group gives 2.148 HR (95% CI: 1.060-4.349) mortality 2.182 1.206-3.948) disease recurrence. Flow cytometry analysis 20 specimens highlighted that associated tumor-derived =0.026) tumor-infiltrating lymphocytes =0.002). In a subset five vs patients, T-cell evaluation showed higher prevalence CD4+ compared CD8+ cells (78.5 vs. 21.5%, <0.0001). Conversely, demonstrated noteworthy infiltration (21.5 48.7%, =0.037). combination blood determined two survival-risk profiles. scores microenvironment suggests link immune-cell risk group. These findings open possibility patient stratification chance identify subgroups suitable dedicated follow-up targeted immuno-chemotherapy protocols.

Language: Английский

---

m6A demethylase ALKBH5 maintains stemness of intrahepatic cholangiocarcinoma by sustaining BUB1B expression and cell proliferation

Translational Oncology, Journal Year: 2024, Volume and Issue: 41, P. 101858 - 101858

Published: Jan. 17, 2024

ALKBH5 plays critical roles in various cellular processes via post-transcriptional regulation of oncogenes or tumor suppressors an N6-methyladenosine (m6A)-dependent manner. However, its function intrahepatic cholangiocarcinoma (ICC) remains unclear. In the present study, bioinformatic analyses The Cancer Genome Atlas (TCGA) data were performed, and association predicting overall survival patients with ICC was investigated. Then, clinical from Affiliated Changzhou No. 2 People's Hospital Nanjing Medical University (Changzhou, China) used to reveal different expression levels by Kaplan-Meier analysis. Subsequently, vitro vivo studies conducted explore verify downstream genes regulated ALKBH5. results TCGA demonstrated that is elevated high exhibited poor compared low expression. addition, assays promoted cell viability maintained stemness cells, leading progression. study also BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) gene targeting BUB1B suppressed growth. experiments revealed might through maintain altering may suppress

Language: Английский

---

Lenvatinib combined with PD-1 inhibitor plus Gemox chemotherapy versus plus HAIC for advanced biliary tract cancer

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 129, P. 111642 - 111642

Published: Feb. 6, 2024

Language: Английский

---