Translational cancer research最新文献

Background: FOXF2, a member of the transcription factor FOX family proteins, plays a key role in tumorigenesis and tumor aggressiveness. However, the potential molecular mechanism of FOXF2 in esophageal squamous cell carcinoma (ESCC) remains largely unknown. Exploring its role and mechanism in ESCC progression may help identify new diagnostic markers and therapeutic targets. The aim of this study is to investigate the potential functions of the FOXF2 gene within the context of ESCC and to elucidate the underlying molecular pathways involved.

Methods: Using the GoMiner database, GeneCard database, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the COMPARTMENTS subcellular localization database, we identified the most likely downstream molecule of the FOXF2 gene, EZR; the subcellular locations of FOXF2 and EZR; the possible biological pathways [Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)]; and the protein interactions networks of the EZR gene enriched from the OMICS datasets via Metascape. We also used The Cancer Genome Atlas database to analyze the correlation between EZR and ERBB signaling pathway. In addition, we verified the RNA and protein expression of the target genes using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, we employed Western blot analysis and plasmid transfection and lentiviral infection techniques to gene edit FOXF2 and EZR in different EC cells to obtain stable overexpression or knockdown of the cell lines. This was followed by ex vivo and in vivo experiments including migration assay, cell scratch assay, clone formation assay, and a xenotransplantation mouse model to validate the functional phenotype of the gene-edited cells.

Results: We found that knockdown of FOXF2 expression significantly enhanced the growth, invasion, and metastasis of ESCC cells both in vitro and in vivo. Moreover, we demonstrated that FOXF2 was predominantly expressed in the nucleus and directly interacted with EZR, thereby inhibiting EZR transcriptional expression, resulting in suppressed ERBB2 signal function, ultimately halting ESCC growth and metastasis.

Conclusions: Taken together, these results reveal the tumor-suppressive functions of FOXF2 in inhibiting EZR-mediated ERBB2 activation, suggesting that FOXF2 could serve as a potential novel predicting prognostic biomarker for ESCC.

Background: In cuproptosis, excess copper ions induce cell death via fatty acylation in the tricarboxylic acid (TCA) cycle. However, the effects of cuproptosis-TCA-related long non-coding RNAs (lncRNAs) on the clinical prognosis of non-small cell lung cancer (NSCLC) and the associated tumor microenvironment remain unclear. The purpose of this study is to use cuproptosis-TCA related lncRNAs to predict the prognosis of NSCLC.

Methods: Molecular signature databases and cuproptosis-related publications were made use of identifying cuproptosis-TCA-related genes. They were identified based on Pearson correlation analysis. The prognostic features associated with these lncRNAs were evaluated using the absolute contraction and selection operator and a receiver operating characteristic curve analysis. Additionally, downstream functional enrichment and immunoinfiltration were analyzed to examine the immunotherapeutic responses of patients with NSCLC.

Results: Eleven cuproptosis-TCA-associated lncRNAs were identified. A high-risk group was compared with a low-risk group based on risk scores, and the high-risk group had a significantly lower overall survival (OS). We established a prognostic risk profile, and based on these characteristics and clinical staging, a nomogram was constructed. An analysis of functional enrichment revealed the involvement of pathways associated with cellular and humoral immunity and fatty acylation. Risk scores differed significantly based on immune cells and pathways (antigen-presenting cell co-stimulation). Moreover, TP53, TTN, and MUC16 mutation status were strongly associated with risk scores, with patients identified as having a higher risk of NSCLC being more responsive to immunotherapy.

Conclusions: Eleven cuproptosis-TCA-associated lncRNAs can be used to predict the prognosis of NSCLC patients, thereby providing a new theoretical basis for immunotherapy.

Background: Chromosomal instability (CIN) has been identified as a factor that increases the susceptibility of tumor cells to kinesin family member 18A (KIF18A) inhibitors. Limited research exists on genes that are associated with sensitization to KIF18A inhibitors (KIF18Ais). Our study aimed to identify a gene linked to heightened sensitivity to KIF18Ais in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and uterine corpus endometrial carcinoma (UCEC).

Methods: The Cancer Genome Atlas (TCGA) and X2K Appyter databases were used to analyze potential kinases associated with KIF18A-related genes in CESC and UCEC. In vitro assessments, such as Cell Counting Kit-8 (CCK-8), transwell, and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays, were performed to evaluate the combined effects of KIF18A and cyclin-dependent kinase 1 inhibitors (CDK1is) in CESC and UCEC cell lines.

Results: Our findings indicated that the combination of KIF18A with kinases may potentially augment the efficacy of KIF18Ais, given its close involvement in cell cycle and chromosome segregation. Through bioinformatics analysis, we observed a significant up-regulation of CDK1 expression in CESC and UCEC, which exhibited a strong correlation with KIF18A expression. Our hypothesis regarding the potential of CDK1 as a combination therapeutic target for KIF18A was supported by our cell experiments, which demonstrated that inhibition of CDK1 notably increased the sensitivity of CESC and UCEC cells to KIF18Ais. The combined use of CDK1is and KIF18Ais exhibited a synergistic effect in inhibiting cell migration and inducing apoptosis in CESC and UCEC cells.

Conclusions: This study provides evidence that targeting both KIF18A and CDK1 exerts synergistic anti-tumor effects in CESC and UCEC via inhibiting cell proliferation and migration and inducing apoptosis, suggesting a promising therapeutic strategy for these cancers.

Background: The rising incidence of parotid gland tumors, with a focus on pleomorphic adenomas (PMA) and Warthin tumors (WT), necessitates accurate preoperative distinction due to their treatment variability and PMA's malignant potential. Traditional imaging, while valuable, has limited accuracy. This study employs multi-slice computed tomography (MSCT) radiomics coupled with serum alpha-L-fucosidase (AFU) levels to develop a diagnostic model aimed at elevating clinical discernment and precision therapy delivery.

Methods: Ninety-one patients were randomly assigned to one of two cohorts: training or validation, at a ratio of 7:3 (64 vs. 27). The region of interest (ROI) on each tumor from the collected MSCT images was delineated to extract radiomics features. In the training cohort, the least absolute shrinkage and selection operator (LASSO) regression and 5-fold cross-validation were adopted to screen the extracted features and calculate Rad-score. Four diagnostic models were developed after univariate and multivariate logistic regression analysis of Rad-score and clinical factors. The performance of four models was then evaluated in the validation cohort by the comparison of receiver operating characteristic (ROC) curve and calibration curve to select the best one. Finally, the clinical application value of the best model was assessed via the nomogram and decision curve analysis (DCA) curve.

Results: Multivariate logistic regression analysis revealed serum AFU, Rad-score and gender as independent diagnostic factors for PMA and WT distinguishment. The nomogram combining the three factors had an area under the curve (AUC) of 0.934 [95% confidence interval (CI): 0.863-1.000] and 0.987 (95% CI: 0.956-1.000) in the training and validation cohorts, respectively, with great goodness-of-fit and clinical value.

Conclusions: The optimized nomogram combining MSCT radiomics and AFU improved the accuracy of distinguishing PMA from WT, suggesting its potential for developing new biomarkers.

Background: Wilms tumor is one of the most common pediatric kidney cancers with poor prognosis. This study aims to explore the predictive values of lymph nodes (LNs), positive lymph node density (LND) and log odds of positive lymph nodes (LODDS) for the 5-year mortality of children with Wilms tumor.

Methods: The cohort study collected the data of 874 participants with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database. The univariate COX proportional risk model was used to explore the possible covariates. The univariate and multivariable COX proportional risk model were employed for exploring the correlations of LNs, LND, and LODDS with the 5-year mortality of Wilms tumor patients. The predictive values of LNs, LND, and LODDS for the 5-year mortality of children with Wilms tumor were evaluated via concordance and 95% confidence interval (CI).

Results: The follow-up time was 5 years, and 804 participants survived in the end. The results delineated that LND >0 [hazard ratio (HR) =1.92, 95% CI: 1.01-3.67] as well as LND ≥0.93 (HR =4.87, 95% CI: 2.42-9.81) were correlated with increased risk of 5-year mortality while LODDS ≥-0.34 (HR =4.09, 95% CI: 2.18-7.65) was linked with elevated risk of 5-year mortality. The concordance of LNs for predicting the 5-year mortality of Wilms tumor patients was 0.623 (95% CI: 0.566-0.681). The concordances of LND, and LODDS for predicting the 5-year mortality of Wilms tumor patients were 0.623 (95% CI: 0.566-0.681) and 0.616 (95% CI: 0.562-0.669).

Conclusions: The predictive value of LODDS for the 5-year mortality of children with Wilms tumor was similar with LNs and LND. The findings might provide a new tool for helping the clinicians identify those with poor prognosis, and timely treatments should be offered to these patients.

Background and objective: Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible.

Methods: To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases.

Key content and findings: The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics.

Conclusions: Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.

Background: Medulloblastoma (MB) is a highly malignant childhood brain tumor. Previous research on the genetic underpinnings of MB subtypes has predominantly focused on European and American cohorts. Given the notable genetic differences between Asian and other populations, a subtype-specific study on an Asian cohort is essential to provide comprehensive insights into MB within this demographic. The aim of this study is to investigate the genomic landscape of MB subtypes in an Asian cohort to better understand the genetic variations and potential implications for clinical practice.

Methods: We conducted a study on an Asian cohort comprising 113 MB patients. Genomic sequencing was performed using MGISEQ-2000 platform. We analyzed the participants' characteristics and compared them with previous studies. All germline variants of the ten susceptibility genes of interest (APC, BRCA2, PTCH1, PTCH2, ELP1, SUFU, CTNNB1, SMARCA4, GPR161, and TP53) were annotated and validated.

Results: Our study identified 14 valid germline variants that met our criteria, with these variants being detected in the genes APC, BRCA2, PTCH1, PTCH2, ELP1, and SUFU. Of these, six variants were classified as pathogenic in ClinVar: two in PTCH2 (c.C1573T), one in ELP1 (c.C583T), and three in PTCH1 (c.G1370T, c.C2066T, c.C529T). The remaining eight variants were of uncertain significance, including those in SUFU (c.T833C), ELP1 (c.T2A), BRCA2 (c.G7488C), and APC (c.C3247A, c.A1G, c.A8042G, c.A3056G, c.G822C). Our findings highlight a subtype-based germline variant landscape specific to the Asian cohort and reinforce the connection between SUFU, PTCH1, and the SHH subtype of MB. Additionally, the identification of ELP1-related cases supports the newest findings in this area and provides typical copy number variation (CNV) results for future investigation.

Conclusions: This study provides valuable insights into the genetic landscape of MB in an Asian cohort, emphasizing the importance of population-specific research. The subtype-specific germline variant landscape identified in this study contributes to the understanding of MB and its genetic underpinnings in Asian populations, potentially guiding future research and therapeutic strategies.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide due to limited treatment options. The tumor microenvironment (TME), which is usually immunosuppressive in HCC, appears to be a decisive factor for response to immunotherapy and strategies aimed at inducing a more inflamed TME hold promise to overcome resistance to immunotherapy. Within the TME, the interplay of various cell types determines whether immunotherapy is successful. Liver macrophages, in particular tumor associated macrophages (TAMs), are known to play a crucial role in tumor progression and represent potential future therapeutic targets. The presence of C-C motif chemokine receptor 2 (CCR2) expressing macrophages is known to be associated with pathogenic angiogenesis and bad prognosis for HCC patients. A recent study published in Cancer Research describes how immunosuppressive macrophages in the TME can be repolarized through targeting Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7)-regulated CC-chemokine ligand 2 (CCL2) signaling, which sensitizes HCC tumors to immunotherapy in a mouse model. This mini-review gives a brief overview about the current knowledge on SLAMF7 in the context of anti-cancer immunity and how the recent findings could be integrated into new therapeutic strategies for HCC.

Background: The clinical significance of human epidermal growth factor receptor 2 (HER2) low and HER2(0) expression in hormone receptor-positive (HR+) breast cancer patients remains uncertain. This study aimed to explore the clinical and pathological characteristics, prognosis, and endocrine therapy (ET) sensitivity among HR+ breast cancer patients with HER2 low and HER2(0) expression.

Methods: We conducted a retrospective analysis of 390 HR+, HER2-negative breast cancer patients who underwent radical surgery at The First Affiliated Hospital of Bengbu Medical University between December 2014 and December 2017. HER2 status was classified per ASCO/CAP 2018 guidelines: tumors with an immunohistochemistry (IHC) score of 0 were defined as HER2(0), and those with a score of 1+ or 2+ with negative FISH for ERBB2 gene amplification were categorized as HER2 low. Clinical and pathological characteristics, ET sensitivity, and survival outcomes were analyzed. Primary endpoints included disease-free survival (DFS) and overall survival (OS), with ROC curve analysis employed to determine prognostic thresholds.

Results: Of the 390 HR+ breast cancer patients, 32.6% had HER2(0) expression [HER2(0) cohort] and 67.4% had HER2 low expression (HER2-low cohort). Most baseline characteristics were balanced between the two cohorts, and the HER2(0) cohort had significantly worse DFS and OS than the HER2-low cohort (both P<0.05). Within the same pN stage (pN0-2), patients with HER2 low expression had a better prognosis (all P<0.05). But at pN3, patients had worse survival outcomes (P=0.003). Patients with the IHC score >4 had significantly better OS (P<0.001) and DFS (P=0.003). No significant difference in OS and DFS was observed in the IHC score ≤4 group between cohorts (both P>0.05), whereas in the IHC score >4 group, the HER2-low cohort had better OS (P<0.001) and DFS (P=0.01).

Conclusions: Patients with HER2 low expression have distinct clinical characteristics and a better prognosis compared to those with HER2(0) expression. Our study provides further real-world evidence for personalized treatment of breast cancer patients.