Translational cancer research最新文献

Background: It has been discovered that the prognosis of patients with differentiated thyroid cancer (DTC) correlates with age at initial diagnosis. However, there are disagreements over the optimal cutoff age among the numerous staging and risk stratification criteria, which make it inconsistent to predict the clinical prognosis of specific DTC patients. This study aimed to determine the optimum cutoff age for diagnosis in relation to the clinical outcomes of DTC using data from the Surveillance, Epidemiology and End Results (SEER) database.

Methods: The best age cutoff value was determined by the X-tile software. The link between clinical characteristics and cancer-specific survival (CSS) was examined using univariate and multivariate Cox regression models. An additional application of the independent prognostic criteria, such as age stratifications, was applied to construct a nomogram model for predicting the chances of patient survival.

Results: The most accurate diagnosis cutoff age for DTC patients was suggested to be 67 years old. The multivariate analysis, using factors determined by univariate analysis, showed that age [>67 years, hazard rate (HR) =5.049, 95% confidence interval (CI): 4.509-5.653, P<0.001], sex (female, HR =0.651, 95% CI: 0.584-0.727, P<0.001), tumor size (>20 and ≤40 mm, HR =2.296, 95% CI: 1.983-2.658, P<0.001; >40 mm, HR =4.976, 95% CI: 4.304-5.752, P<0.001), lymphadenectomy (HR =1.337, 95% CI: 1.186-1.506, P<0.001), distant metastasis (HR =12.166, 95% CI: 10.749-13.769, P<0.001) and surgical treatment (HR =0.173, 95% CI: 0.144-0.210, P<0.001) were independent factors for CSS. Patients in the high-risk group had worse survival rates, and the C-index for the CSS prediction model with age (cutoff of 67) and other independent clinicopathological variables was 0.906.

Conclusions: Accordingly, the optimal cutoff age for predicting death from DTC specifically is 67 years old at the time of the initial diagnosis. It might be a more suitable factor when used in risk stratification for patients with DTC.

[This corrects the article DOI: 10.21037/tcr-23-674.].

Background: Retinoic acid receptors (RARs) family are known to play a significant role in the occurrence and development of tumors. However, the relationship between RARs and stomach adenocarcinoma (STAD) has not yet been clearly identified. The aim of this study is to evaluate the expression profile and clinical value of the RARs family in STAD.

Methods: The expression level, clinical characteristics, prognostic value, immunity-related evaluations, genetic alteration and methylation site of RARs in STAD were explored using a series of online databases including gene expression profiling interactive analysis (GEPIA), tumor immune estimation resource (TIMER), University of Alabama at Birmingham cancer data (UALCAN), Human Protein Atlas (HPA), Kaplan-Meier plotter, gene set cancer analysis (GSCA), cBioPortal, MethSurv, GeneMANIA, LinkedOmics, Metascape, Search tool for the retrieval of interacting genes (STRING), tumor immune single-cell hub (TISCH) and cancer cell line encyclopedia (CCLE).

Results: We discovered dramatically increased expression of RARA and decreased expression of RARB in STAD tissues, and many clinical variables were closely related to RARs. Notably, higher expressions of RARA and RARB as well as lower expression of RARG correlated with worse overall survival (OS) for STAD patients. The clinical value of prognostic model indicated that RARs were identified to be potential prognostic biomarkers for STAD patients. Moreover, RARB was closely related to immune cell infiltration, which had effect on the role of RARB in STAD prognosis. And the genetic alteration of RARB was significantly associated with the longer disease-free survival (DFS) of STAD patients. Additionally, some CpG sites of the RARs family were related with the prognosis of STAD patients. Functional enrichment analyses indicated that several pathways in STAD might be pivotal pathways regulated by RARs. At the single-cell level, there was some extent of infiltration of tumor microenvironment-related cells in the RARs expression in STAD.

Conclusions: Our results evaluated the expression profile and clinical values of RARs in patients with STAD, which provided a basis for future in-depth exploration of the specific mechanisms of each member of RARs in STAD.

Background: CDC6 is critical in DNA replication initiation, but its expression patterns and clinical implications in cancer are underexplored. This study uses multi-omics data from The Cancer Genome Atlas (TCGA) to comprehensively analyze CDC6 across various cancers, aiming to evaluate its potential as a prognostic biomarker and explore its role in immunotherapy.

Methods: By leveraging multi-omics data from TCGA, we conducted a comprehensive analysis of CDC6 expression across a variety of cancer types. Least absolute shrinkage and selection operator (LASSO) regression was employed to assess the association of CDC6 with key molecules implicated in pancreatic cancer.

Results: CDC6 expression was found to be significantly upregulated across a broad spectrum of cancers. High levels of CDC6 expression were associated with poor prognosis in several cancer types. Notable associations were observed between CDC6 expression and tumor mutational burden (TMB), microsatellite instability (MSI), as well as immune cell infiltration. Co-expression analysis revealed significant associations between CDC6 and prevalent immune checkpoint genes. A risk model incorporating CDC6-related genes, including CCNA1, CCNA2, CCND1, CCND2, CDC25B, CDC6, and CDK2, was developed for pancreatic cancer.

Conclusions: CDC6 emerges as a promising prognostic biomarker and a potential target for immunotherapy across various cancers, including pancreatic cancer. It appears to modulate immune responses across cancer types, highlighting its regulatory role. Further exploration into the biological functions and clinical implications of CDC6 is warranted.

Background: Nasopharyngeal carcinoma (NPC) is particularly prevalent in East and Southeast Asia. Competing endogenous RNA (ceRNA) networks are known to play an essential role in the emergence of various diseases, including cancer. Building a network of protein-protein interactions (PPIs) and ceRNAs can facilitate the detection of potential connections between messenger RNAs (mRNAs) and various non-coding RNAs. However, the precise role of ceRNA networks in NPC has not been examined in detail. Therefore, the primary aim of the present study was to characterize a ceRNA network for NPC.

Methods: Datasets of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA microarrays were downloaded from the Gene Expression Omnibus (GEO) database. Data were standardized and differentially expressed genes (DEGs) were screened using the limma package. The ClusterProfiler software suite was used to perform enrichment analysis of differentially expressed mRNAs using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) techniques.

Results: A total of 160 lncRNAs, 8 miRNAs, and 147 mRNAs were differentially expressed in NPC samples. A ceRNA network was constructed using four lncRNAs, five miRNAs, and one mRNA that were dysregulated in NPC. Cellular functions of the abnormally expressed mRNAs were mainly associated with tumor cell movement, cell growth and proliferation, cell cycle, invasion, and metastasis.

Conclusions: The ceRNA network constructed herein clarified the regulatory mechanisms through which lncRNAs act as ceRNAs and participate in NPC development. Notably, lncRNAs, miRNAs, and mRNAs identified in this ceRNA network can serve as therapeutic targets and prognostic biomarkers for NPC.

Background: Apatinib is a tyrosine kinase inhibitor that has shown potential in combination with immune checkpoint inhibitors (ICIs) in gastric cancer (GC); however, its role in GC is unclear. This research aims to investigate the effect of low-dose apatinib in GC, and analyze the mechanisms of its underlying action.

Methods: A mouse model of GC was established, and the experimental mice were divided into different groups for different treatment: group NS (normal saline), group A (low-dose apatinib 50 mg/kg), group B (high-dose apatinib 200 mg/kg), group C [programmed cell death protein 1 (PD-1) inhibitor monotherapy], and group D (PD-1 inhibitor combined with low-dose apatinib). After 14 days of treatment, the tumor and blood samples were collected from all mice for histological and cytokine detection.

Results: Compared with the control group, mice in the low-dose apatinib group showed smaller tumor volumes and slower growth. CD31/α-smooth muscle actin (α-SMA) double staining revealed significantly higher coverage of perivascular cells in the low-dose apatinib group by contrast to the control and high-dose apatinib groups, suggesting that low-dose apatinib may alleviate hypoxia. Compared to the high-dose apatinib group, the expression of hypoxia inducible factor 1 alpha (HIF1α) significantly decreased in the low-dose apatinib group. Hematoxylin and eosin (HE) staining results showed a higher proportion of necrotic tumor tissues in the group of mice treated with low-dose apatinib combined with PD-1 inhibitor than in other groups. In addition, this combined treatment significantly reduced the expression of NG2 and HIF1α in mouse tumor tissues, indicating a more normalized vascular density, and also increased the proportion of CD8⁺ T cells.

Conclusions: Low-dose apatinib enhances the antitumor effect of PD-1 inhibitor by normalizing tumor-related blood vessels, alleviating intratumor hypoxia and altering immunosuppressive microenvironment (IM).

Background: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions. Patients with OSCC exhibit a poor response to conventional chemoradiotherapies, which are associated with severe side effects. Therefore, it is essential to identify an effective therapeutic method to treat patients with OSCC. An anti-tumor compound, Agkistrodon acutus venom component I (AAVC-I), purified from Agkistrodon acutus venom, has demonstrated anticancer activity both in vitro and in vivo. However, the mechanism of AAVC-I's anticancer activity in cancer cells has yet to be established. This study aimed to investigate the mechanism of AAVC-I-induced apoptosis in HSC-3 OSCC cells and explore its regulatory effect on oxidative stress.

Methods: Survival rates of human OSCC cell HSC-3 were detected by Cell Counting Kit-8 (CCK-8). The reactive oxygen species (ROS) level was analyzed by flow cytometry and fluorescence microscopy. The mitochondrial membrane potential was analyzed by cytometry and fluorescent microplate reader. Apoptosis of HSC-3 cells was analyzed using flow cytometry. The oxidative stress level was evaluated using glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) kits. In addition, the target proteins were analyzed by western blot.

Results: AAVC-I reduced HSC-3 cells' survival rates in a dose-dependent manner with a 50% inhibiting concentration (IC₅₀) of 8.86 µg/mL. It induced apoptosis of HSC-3 cells and the expression of cleaved caspase-3, cleaved caspase-9, and Cyt-c increased significantly, whereas the expression level of Bcl-2 decreased in AAVC-I-treated HSC-3 cells. Thus, AAVC-I caused apoptosis of HSC-3 via the activation of the intrinsic apoptotic pathway. In addition, AAVC-I reduced the mitochondrial membrane potential in HSC-3, enhanced intracellular ROS, and increased intracellular oxidative stress levels in comparison to that of untreated control cells. Furthermore, AAVC-I increased the expression of Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) levels.

Conclusions: These findings demonstrate the inhibitory effects and associated mechanisms of AAVC-I on the HSC-3 OSCC cell line. This insight could be valuable for investigating AAVC-I as a potential therapeutic option for patients with OSCC.

Background: With improving prognosis in upper-tract urothelial carcinoma (UTUC), an increasing number of second primary malignancies (SPMs) are being identified. However, there is limited research on SPMs following UTUC. This study aims to evaluate the risk of SPMs in UTUC patients and create a nomogram to predict their survival rates.

Methods: Utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the risk of SPMs among UTUC patients. Additionally, we developed and validated an overall survival (OS) nomogram for SPM patients post-UTUC diagnosis.

Results: The prevalence of SPMs among UTUC patients was 30.23%, with solid tumors being the most prevalent type of second malignancy, constituting 95.30% of all SPMs. The overall risk of SPMs was significantly elevated across all subgroups. Univariate and multivariate Cox regression analyses identified age, race, gender, UTUC SEER historic stage, surgery, SPM site, histologic type, grade, and SEER historic stage as independent prognostic factors for SPM OS. Subsequently, we developed a nomogram for predicting SPM OS. The C-index for the training and validation sets were 0.72 [95% confidence interval (CI): 0.70-0.74] and 0.71 (95% CI: 0.67-0.75), respectively. The area under the curve (AUC) demonstrated good performance of our model in predicting the 3-year (0.73 and 0.737) and 5-year (0.723 and 0.733) OS of SPMs in both sets.

Conclusions: This study represents the first comprehensive analysis of SPM incidence in UTUC patients and introduces a nomogram for predicting SPM prognosis.

Background: The recently identified carcinogenic long non-coding RNA (lncRNA) MIR4435-2HG has been validated to contribute to the initiation and progression of several malignancies. Nonetheless, its specific mechanistic function in pancreatic cancer (PC) is yet to be determined. This study aims to investigate the expression and functional role of MIR4435-2HG in PC and to elucidate its potential mechanism.

Methods: This study employed The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx)-Pancreas datasets for the analysis of MIR4435-2HG expression in PC and normal pancreatic tissues and its relations with prognosis in PC. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was employed for analyzing MIR4435-2HG, miR-128-3p, and ABHD17C expressions within cells and tissues. Cell proliferation and apoptosis were detected in vitro through Cell Counting Kit 8 (CCK-8) assay and flow cytometry while utilizing transwell and wound healing assays to assess cell migration and invasion. Predicting miR-128-3p binding sites with MIR4435-2HG or ABHD17C was conducted via the online tool starBase and validated through a dual-luciferase reporter (DLR), RNA pull-down and RNA binding protein immunoprecipitation (RIP) assays. Herein, we deployed Western blot to assess protein expression levels. The in vivo role of MIR4435-2HG was studied using tumor xenografts.

Results: MIR4435-2HG overexpression exhibited a correlation with poor prognosis in PC. Knocking down MIR4435-2HG significantly hindered the proliferative, invading, and migrating PC cell abilities, accompanied by apoptosis induction, counteracted via a miR-128-3p inhibitor. Moreover, MIR4435-2HG could directly bind to miR-128-3p. Additionally, miR-128-3p directly targeted ABHD17C. Furthermore, in vitro as well as in vivo experiment results elucidated that knocking down MIR4435-2HG hindered PC progression by suppressing ABHD17C expression via miR-128-3p upregulation.

Conclusions: MIR4435-2HG can serve as a dependable target for PC diagnosis and treatment by modulating the miR-128-3p/ABHD17C axis to promote its progression.