Translational Oncology最新文献

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.

Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.

Results: In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, p-value=3.4 × 10^-4). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, p-value=5.1 × 10^-7). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.

Conclusions: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.

This retrospective cohort study using SEER data from 2000 to 2020 examines the impact of radiotherapy on the risk of Secondary Primary Lung Cancer (SPLC) in 224,396 elderly female breast cancer survivors. Patients treated with radiotherapy displayed a 31 % increased SPLC risk compared to those not treated. Utilizing Cox Proportional Hazards and Poisson regression models, the study assessed various factors including age, race, and tumor characteristics. Propensity Score Matching (PSM) was employed to balance cohorts for survival analysis, which revealed that radiotherapy did not negatively impact overall survival despite the increased risk of SPLC. A nomogram was developed to aid clinical decision-making by predicting survival outcomes. The findings advocate for personalized treatment strategies and continuous monitoring to manage potential long-term adverse effects effectively, highlighting the need for a balanced approach in the treatment of breast cancer survivors.

The occurrence and development of tumor is mediated by a wide range of complex mechanisms. Subsequent to nitric oxide and carbon monoxide, hydrogen sulfide (H₂S) holds the distinction of being the third identified gasotransmitter. Alternation of H₂S level has been widely demonstrated to induce an array of disturbances in important cancer cell signaling pathways. As a result, the effects of H₂S-catalyzing enzymes in cancers also attract widspread attention. 3-mercaptopyruvate sulfurtransferase (3-MST) is privileged to be one of them. In fact, 3-MST is overexpressed in many tumors including human colon cancer, lung adenocarcinoma, and bladder urothelial carcinoma. But it is also lowly expressed in hepatocellular carcinoma. In this review, we focus on the generation of endogenous H₂S and polysulfides, facilitated by 3-MST. Additionally, we delve deeply into the potential role of 3-MST in tumorigenesis and development. The impact of 3-MST inhibition on the development of tumors and its potential for tumor therapy are also highlighted.

Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Studies have shown that CRC patients with KRAS mutations, especially KRAS^G12D, have an increased risk of metastasis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are crucial in the carcinogenesis and progression of various cancers, regulating multiple biological processes but the link between KRAS^G12D mutations and lncRNAs in CRC remains unclear. Therefore, this study was designed to identify a novel lncRNA involved in KRAS^G12D-mutated CRC and to elucidate its molecular mechanisms. The analysis of differentially expressed lncRNAs in the GSE201412 dataset revealed that LINC02159 was significantly upregulated following treatment with the KRAS^G12D inhibitor MTRX1133 Data from the GTEx database indicated that LINC02159 is highly expressed in CRC tumour tissues and is associated with better patient outcomes. In vitro and in vivo experiments suggest that LINC02159 acts as a tumour suppressor in CRC progression. Specifically, LINC02159 knockdown negated the inhibitory effects of MRTX1133 on tumourigenesis and its promotive effect on ferroptosis in KRAS^G12D-mutated CRC cells. LINC02159 expression is regulated by METTL14, with METTL14 knockdown decreasing m6A methylation of LINC02159, leading to its increased expression in CRC cells. Additionally, LINC02159 stabilised FOXC2 expression through de-ubiquitination. Rescue experiments further clarified that the METTL14/LINC02159/FOXC2 signalling axis is crucial for the inhibitory effects of MRTX1133 in KRAS^G12D-mutated CRC. Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRAS^G12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

Acute Myeloid Leukemia (AML) is a complex hematological malignancy distinguished by its heterogeneity in genetic aberrations, cellular composition, and clinical outcomes. This diversity complicates the development of effective, universally applicable therapeutic strategies and highlights the necessity for personalized approaches to treatment. In our study, we utilized high-resolution single-cell RNA sequencing from publicly available datasets to dissect the complex cellular landscape of AML. This approach uncovered a diverse array of cellular subpopulations within the bone marrow samples of AML patients. Through meticulous analysis, we identified 156 differentially expressed cytokine-related genes that underscore the nuanced interplay between AML cells and their microenvironment. Leveraging this comprehensive dataset, we constructed a prognostic risk score model based on seven pivotal cytokine-related genes: CCL23, IL2RA, IL3RA, IL6R, INHBA, TNFSF15, and TNFSF18. The mRNA levels of 7 genes in the risk score model have significant different. This model was rigorously validated across several independent AML patient cohorts, showcasing its robust prognostic capability to stratify patients into distinct risk categories. Patients classified under the high-risk category exhibited significantly poorer survival outcomes compared to their low-risk counterparts, underscoring the model's clinical relevance. Additionally, our in-depth investigation into the immune landscape revealed marked differences in immune cell infiltration and cytokine signaling between the identified risk groups, shedding light on potential immune-mediated mechanisms driving disease progression and treatment resistance. This comprehensive analysis not only advances our understanding of the cellular and molecular underpinnings of AML but also introduces a novel, clinically applicable risk score model. This tool holds significant promise for enhancing the precision of prognostic assessments in AML, thereby paving the way for more tailored and effective therapeutic interventions. Our findings represent a pivotal step toward the realization of personalized medicine in the management of AML, offering new avenues for research and treatment optimization in this challenging disease landscape.

Background: Hepatocellular carcinoma (HCC) represents a major malignancy globally, characterized by high malignancy and intricate molecular mechanisms. This study aims to explore the role of the long non-coding RNA (lncRNA) lnc-EST885 in HCC development.

Methods: Cell experiments including FISH, western blot, flow cytometry and functional analysis were used to elucidate the effects of lnc-EST885 on cell proliferation, apoptosis, migration and EMT processes. RNA pull-down and ESI-FT-ICR-MS were used to identify proteins that interact with lnc-EST885 and were verified by RIP-qPCR. Furthermore, the association of lnc-EST885 and TRAF4 with HCC prognosis and metastasis was evaluated through bioinformatics analysis and animal models.

Results: lnc-EST885 is one of the lncRNAs with the highest expression levels in M2-type macrophages. The expression of lnc-EST885 in HCC tissues is significantly higher than in normal tissues, and high expression is associated with poor prognosis. Functional experiments have shown that lnc-EST885 significantly promotes the proliferation and migration of liver cancer cells, inhibits apoptosis, and induces EMT. Studies in a mouse lung metastasis model have also confirmed that lnc-EST885 promotes the pulmonary metastasis of HCC cells in vivo. Mechanistic studies have revealed that lnc-EST885 can bind to the TRAF4 protein, activating the PI3K/AKT signaling pathway, thereby promoting the proliferation, migration, and EMT capability of liver cancer cells, contributing to the malignant phenotype of HCC.

Conclusion: lnc-EST885 plays a crucial role in the development of liver cancer, serving as a potential biomarker for predicting HCC prognosis and providing a new target for HCC treatment.

Objectives: The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism.

Materials and methods: The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay.

Results: 3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both in vitro and in vivo. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells in vivo and in vitro.

Discussion: 3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.

Gilteritinib treats acute myeloid leukemia (AML) with the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Dysregulation of histone modification affects the genesis and progression of AML. Strategies targeting key histone regulators have not been applied to the treatment of AML. Lysine demethylase 6B (KDM6B) is dysregulated in a variety of cancers and regulates the expression of oncogenes, which has potential in anticancer therapy. We explored whether GSK-J4 (an inhibitor of the demethylase KDM6B) has an anti-leukemic effect in the gilteritinib treatment of FLT3-ITD⁺ AML and the effect of gilteritinib combined with GSK-J4 in leukemia. In our study, we evaluated the anti-leukemic effect of GSK-J4 in gilteritinib therapy through in vitro and in vivo experiments. The results revealed that the combined treatment of gilteritinib and GSK-J4 has greater anti-proliferation and pro-apoptosis effects than gilteritinib alone. Gilteritinib and GSK-J4 performed synergistically to arrest the cell cycle. Gilteritinib mainly induces cell cycle phase arrest at the S or G0/G1, and GSK-J4 inhibits the cell cycle progression in the S phase and reduces cell viability by reducing the expression of key regulatory factors from the G1 phase to the S phase. At the same time, GSK-J4 enhances the expression of apoptosis-related proteins (Bax and cleavage caspase-9). In addition, gilteritinib or GSK-J4 monotherapy increases reactive oxygen species (ROS) production, and the combination has a synergistic effect, accelerating leukemic cell death. Our study provides proof that the combined therapy of gilteritinib and GSK-J4 has a synergistic antileukemic effect on FLT3-ITD⁺ AML.

Background: Gastric cancer (GC) poses a major global health challenge because of its unfavorable prognosis. Elevated telomerase activity has been linked to the rapid growth and invasiveness of GC tumors. Investigating the expression profiles of telomerase could improve our understanding of the mechanisms underlying telomere-related GC advancement and its applicability as potential targets for diverse therapeutic strategies for GC.

Methods: The TCGA and GEO databases were utilized to access transcriptome and clinical data related to GC. After assessing differentially expressed genes (DEGs), a prognostic risk model was developed through Cox univariate regression, LASSO-Cox regression. The prognostic risk model was validated using data from the GSE62254 cohort. The significant influence of the risk model on the tumor immune microenvironment (TIME) and its sensitivity to various drugs was assessed.

Results: Differential expression analysis identified 328 significantly telomere-related DEGs in GC, with 35 of them showing a significant association with GC prognosis. A predictive risk model composed of four telomere-related genes (TRGs) was established, enabling the accurate stratification of GC patients into two distinct prognostic groups. The LASSO risk model demonstrated notable variations in immune-cell infiltration and drug sensitivity patterns between high- and low-risk groups.

Conclusions: The study establishes suggestive relationships between four TRGs (LRRN1, SNCG, GAMT, and PDE1B) and the prognosis of GC. The comprehensive characterization of the TRG model reveals their possible roles in the prognosis, TIME, and drug sensitivity in GC.

Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs. SIGNIFICANCE: These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.