Translational cancer research最新文献

Background: Primary choriocarcinoma of the pulmonary artery is an exceedingly rare malignant neoplasm, which is often misdiagnosed due to its nonspecific clinical presentation. While this condition is characterized by the presence of trophoblastic cells, typically associated with gestational trophoblastic diseases, we encountered a case occurring in an extragenital location. The rarity of such tumors makes it challenging for clinicians to consider them in differential diagnosis, especially when the initial symptoms mimic more common conditions such as pulmonary thromboembolism (PTE).

Case description: We present a clinical case of a 32-year-old female with suspected PTE, attributed to severe cough, hemoptysis, chest pain, oral contraceptive use, and a pulmonary artery filling defect observed on computed tomography pulmonary angiography (CTPA). The patient was treated with standard anticoagulation therapy; however, there was no improvement in the clinical condition. A biopsy was subsequently performed, leading to the histopathologic diagnosis of primary pulmonary artery choriocarcinoma with the presence of malignant trophoblastic cells within the pulmonary artery. The patient underwent chemotherapy and achieved complete remission within a 1-year follow-up period, as confirmed by β-human chorionic gonadotropin (β-HCG) tests and imaging examinations showing marked improvement.

Conclusions: This case underscores the importance of early recognition and accurate diagnosis of primary pulmonary artery choriocarcinoma, a condition that can be easily overlooked due to its rarity and deceptive clinical presentation. Timely diagnosis is crucial for the initiation of appropriate treatment, such as chemotherapy, which in this instance, contributed to the patient's survival. This report highlights the need for heightened clinical suspicion and the use of invasive diagnostic procedures in cases where the clinical picture is atypical and does not respond to standard therapeutic interventions.

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: 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: 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: 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.

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.