Translational cancer research最新文献

Background: The causal relationship between percentage of fat in milk consumption and cancer risk lacks sufficient investigation. The purpose of this study was to explore whether the percentage of fat in milk consumption is a factor that affects the risk variation of several common types of cancer.

Methods: Mendelian randomization (MR) was performed to estimate the unconfounded causal relationship between the percentage of fat in milk consumption and the risk of six cancers related to milk intake, as well as to assess the associations between body fat percentage and these cancers. Data corresponding to the percentage of fat in milk consumption (n=411,503), body fat percentage (n=401,772), breast cancer (n=139,274), ovarian cancer (n=66,450), endometrial cancer (n=121,885), colorectal cancer (n=32,072), prostate cancer (n=140,254), and bladder cancer (n=373,295) were obtained from the Integrative Epidemiology Unit (IEU) or the genome-wide association study (GWAS) Catalog databases. The primary analytical strategy employed the inverse-variance weighted (IVW) method. Sensitivity analysis, including assessments of heterogeneity and pleiotropy, was conducted to assess the robustness of the findings.

Results: The percentage of fat in milk consumption only exhibited a causal relationship with breast cancer (β=2.993, P=0.01). The study identified significant causal effects of body fat percentage on the risk of several cancers, including ovarian cancer (β=0.225, P=0.002), endometrial cancer (β=0.669, P<0.001), and colorectal cancer (β=0.344, P<0.001), as well as a protective effect on prostate cancer (β=-0.104, P=0.046). Sensitivity analysis demonstrated that the findings were robust.

Conclusions: Our study findings indicated that a higher percentage of fat in milk consumption was associated with an increased risk of breast cancer, providing valuable insights for cancer prevention strategies among the European population.

Background: Invasive breast cancer (BC) is a highly life-threatening disease affecting women world-wide. While its early identification may benefit the provision of more effective therapies, several BC-associated factors may influence BC patients' therapeutic outcomes. Therefore, identifying novel prognostic and therapeutic targets for invasive BC can help with accurate prognosis and therapy-related decisions. The BRI3 binding protein (BRI3BP) gene was found to be a principal gene in invasive BC cohorts using artificial neural network (ANN) techniques. Thus, this study aimed to evaluate the clinicopathological significance of BRI3BP at the transcriptomic and proteomic levels in invasive BC.

Methods: Two transcriptomic BC cohorts, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1,980) and The Cancer Genome Atlas (TCGA; n=854), were used to evaluate BRI3BP expression at the mRNA level. Formalin-fixed paraffin-embedded (FFPE) tissues from an invasive BC cohort (n=100) were also used to evaluate BRI3BP expression at the protein level via immunohistochemistry. The association between BRI3BP expression, clinicopathological characteristics, and patient outcomes was evaluated.

Results: In both METABRIC and TCGA cohorts, high expression of BRI3BP was significantly associated with aggressive tumor features such as high histological grade, large tumor size, and lymph vascular invasion (LVI) positivity. At the protein level, high BRI3BP expression was associated with high histological grade, hormone receptor negativity, high expression of Ki67, and poor outcome.

Conclusions: This study revealed the prognostic significance of BRI3BP in invasive BC patients. Further functional assessment is needed to confirm the biological role of BRI3BP in BC.

Background: Many cancer cells exhibit aberrant metabolic reprogramming through abnormal mitochondrial respiration. Protein tyrosine phosphatase mitochondrial 1 (PTPMT1) is a protein tyrosine phosphatase localized to the mitochondria and linked to mitochondrial respiration. However, the expression and role of PTPMT1 in regulating the biological characteristics of small cell lung cancer (SCLC) has not yet been explored. The aim of this study was to evaluate the role of PTPMT1 on SCLC cell survival and mitochondrial function.

Methods: SCLC and adjacent normal tissues were obtained from surgery. The expression level of PTPMT1 in the SCLC tissues and cell lines was determined by immunohistochemical staining, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). PTPMT1 knockdown was induced by lentivirus-mediated short-hairpin RNA (shRNA) transduction and PTPMT1 inhibition (alexidine dihydrochloride). The biological characteristics of the cells were measured by cell counting kit 8 (CCK-8), colony formation assay, and cell migration assay. The mitochondrial function of the cells was measured by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining. The H69 cells were treated with alexidine dihydrochloride, after which transcriptome sequencing and an untargeted metabolomic analysis were performed. The transcriptome differentially expressed genes were measured by qRT-PCR.

Results: PTPMT1 was upregulated in the SCLC tissues compared to the adjacent normal tissues. PTPMT1 inhibition by lentiviral shRNA transduction or specific inhibition resulted in significant growth arrest and apoptosis. The transcriptome sequencing analysis revealed that pathways related to the respiration chain and mitochondrial member protein were disrupted. Several mitochondrial metabolism-related genes, such as FGF21, GDF-15, APLN, and MT-DN6, were dysregulated. Further, PTPMT1 inhibition was found to downregulate Glut expression and disturb mitochondrial function.

Conclusions: PTPMT1 was shown to play a critical role in the survival and growth of SCLC cells, and may become a potential therapeutic target.

Background: Esophageal cancer (EC) is one of the most common malignant tumors worldwide, which has severely threatened human health. This study aims to evaluate the prognostic factors and predictors of survival in patients diagnosed with advanced lower third esophageal carcinoma (aLEC). Based on the Surveillance, Epidemiology, and End Results (SEER) database, we developed a model (nomogram) to provide accurate and individualized survival prediction for the patients who have lost the opportunity to undergo radical surgery.

Methods: Using SEER database, the basic information and Medicare data of patients diagnosed with aLEC from 2010 to 2015 were collected. The patients were randomly divided into the training and validation set according to an 8:2 ratio. Univariate and multivariate Cox analyses were used to investigate variables significantly correlated with disease-specific survival (DSS). A nomogram was constructed to predict the prognosis of EC patients. We used the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the evaluation of performance. Furthermore, calibration curves were used to evaluate the accuracy of the model. The clinical utility was also assessed via decision curve analysis (DCA). Differences in clinicopathological characteristics between T1NanyM1 and T2-4NanyM1 stages were evaluated using the Chi-squared test. Cox regression analysis was performed and Kaplan-Meier curves were plotted to evaluate the impact of T-stage, chemotherapy, and radiotherapy on the survival time of EC patients.

Results: Results of multivariate regression analysis demonstrated that histology type, T stage, and chemotherapy were independent prognostic factors for predicting survival time in patients with aLEC. Notably, the constructed nomogram suggested that patients with stage T2 or T3 had a higher survival rate at 6 months, 1 year, and 2 years compared with those with stage T1. DCAs showed that the predictive nomogram was clinically useful. There were fewer patients with stage T1NanyM1 receiving chemotherapy (P=0.004) or radiotherapy (P<0.001) than patients with stage T2-4NanyM1. Moreover, patients with stage T1NanyM1 who underwent chemotherapy had a better prognosis than those who did not [hazard ratio (HR) 3.15, 95% confidence interval (CI): 2.58-3.83; P<0.001]. For patients with stage T1NanyM1, radiotherapy did not improve outcomes (HR 0.98, 95% CI: 0.82-1.17; P=0.80).

Conclusions: A prognostic nomogram integrating three clinicopathological factors was constructed to predict survival in aLEC patients. Chemotherapy improves outcomes of patients with stage T1NanyM1 aLEC.

Background: Chromosome segregation 1 like (CSE1L) overexpression can promote proliferation and migration in cancer. In previous study, we found that CSE1L expression was higher in gastric cancer (GC) tissues compared to normal tissues. However, the biological function and molecular mechanism of CSE1L in GC remains unclear. In this study, we investigate the function of CSE1L in GC biology and its related molecular mechanisms and therapeutic potentials.

Methods: Transcriptome data from public databases were used to assess CSE1L messenger RNA (mRNA) expression levels in GC. A total of 83 pairs of GC surgical samples were evaluated to determine CSE1L protein expression levels. CSE1L was knocked out in MGC-803 and overexpressed in BGC-823 to evaluate its biological function in GC cells. RNA sequencing (RNA-seq) was used to identify the signaling pathways regulated by CSE1L and the underlying molecular mechanisms, and the transcriptome data were validated. Western blotting and immunofluorescence were used to clarify the regulatory effect of CSE1L on phosphorylated focal adhesion kinase (p-FAK).

Results: CSE1L mRNA was increased in patients with GC, and the high expression of CSE1L was associated with poor prognosis in these patients. Protein levels of CSE1L were also increased in GC surgical samples. CSE1L promoted cell proliferation, cell migration, cell invasion, clone formation, and adhesion ability in GC cells. RNA-seq results suggested that CSE1L upregulated the focal adhesion pathway, which was verified at the mRNA level and protein level. Moreover, CSE1L upregulated p-FAK tyrosine 397 [p-FAK (Y397)] and enhanced the efficacy of defactinib. After the knockout of CSE1L, the killing effect of defactinib on GC cells was intensified.

Conclusions: CSE1L is a potential biomarker for evaluating the prognosis of patients with GC. Knockdown of CSE1L can enhance the efficacy of defactinib by inhibiting p-FAK (Y397), which may be a synergistic target of defactinib.

Dipeptidase 1 (DPEP1), initially identified as a renal membrane enzyme in mature human kidneys, plays a pivotal role in various cellular processes. It facilitates the exchange of materials and signal transduction across cell membranes, contributing significantly to dipeptide hydrolysis, glucose and lipid metabolism, immune inflammation, and ferroptosis, among other cellular functions. Extensive research has delineated the complex role of DPEP1 in oncogenesis and tumor progression, with its influence being context dependent. DPEP1 has been observed to promote oncogenic activities in hepatocellular carcinoma, non-small cell lung cancer, colorectal cancer, and lymphoblastic malignancies and is hypothesized to participate in multiple biological processes, including tumor cell invasion, metastatic spread, cellular signaling pathways, cell-matrix interactions, and evasion of immune surveillance. Conversely, DPEP1 has been identified as a tumor suppressor in pancreatic adenocarcinoma, lobular breast carcinoma, and Wilms tumor. Moreover, the role of DPEP1 in colorectal cancer has been increasingly recognized in recent research. Emerging evidence suggests that DPEP1 substantially augments the metastatic and invasive potential of colorectal cancer cells, facilitates immune evasion, and confers resistance to chemotherapeutic agents. Despite these findings, the precise molecular mechanisms remain to be fully characterized. This systematic review endeavors to elucidate the structural and functional attributes of the DPEP1 protein, with the aim to clarify its regulatory mechanisms and assess its clinical relevance in oncology. Gaining a thorough understanding of the physiological role and molecular underpinnings of DPEP1 is critical to informing the diagnostic, therapeutic, and prognostic paradigms of related pathologies. It is anticipated that these insights will facilitate the discovery of novel therapeutic targets and generate new investigative trajectories, particularly in the clinical management of colorectal cancer.

Background: In the clinic, the primary conventional treatments of advanced non-small cell lung cancer (NSCLC) are surgery, radiation therapy, and chemotherapy. In recent years, immune checkpoint inhibitors (ICIs) have shown promise in optimizing therapeutic benefits when combined with other immunotherapies or standard therapies. However, effective biomarkers for distant metastasis or recurrence have yet to be identified, making it difficult to determine the best therapeutic approaches. The effect of tumor immunotherapy, as well as metastasis and recurrence, are thought to be significantly affected by the tumor immunosuppressive microenvironment. Transcription factor interferon regulatory factor 5 (IRF5) is a critical regulator of the immune response. It has been found to play an important role in malignant tumor transformation, immune regulation, clinical prognosis, and the treatment response. Nevertheless, its precise role in the advancement of NSCLC, including lung adenocarcinoma (LUAD) remains poorly understood. This study sought to investigate the expression of IRF5 in LUAD and its effect on patient prognosis, and examine the biological function of IRF5. Additionally, the study aimed to examine the association between IRF5 expression and immune cell infiltration, as well as its correlation with key immune checkpoint genes relevant to NSCLC.

Methods: LUAD RNA-sequencing data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and analyzed. A tissue microarray (TMA) analysis was conducted to detect IRF5 expression, and immunofluorescence staining was performed to determine immune infiltration. Bioinformatics and TMA analyses, including a differential expression analysis, prognosis prediction analysis, correlation analysis, immune infiltration analysis, and gene set enrichment analysis (GSEA), were conducted using the TCGA dataset.

Results: The results showed that the expression levels of IRF5 were lower in the LUAD tissues than the normal lung tissues. Patients with high IRF5 expression had longer survival times than those with low IRF5 expression. IRF5 was also found to be correlated with lymph node metastasis. Nine distinct types of immune cells were identified between the groups with high and low IRF5 expression levels. Eight major immune checkpoint genes were found to be upregulated in LUAD patients with high IRF5 expression levels. The enrichment analyses showed that various immune pathways were enriched in the LUAD samples with IRF5, including T cell activation, lymphocyte activation, and T cell receptor activation.

Conclusions: IRF5 expression is closely related to tumor immunity and immunotherapy in LUAD patients. IRF5 may be indicative of prognosis in LUAD patients.

Background: N6-methyladenosine (m⁶A)-mediated epitranscriptomic pathway has been shown to contribute to chemoresistance and radioresistance. Our previous work confirmed the defense of lycorine against tamoxifen resistance of breast cancer (BC) through targeting HOXD antisense growth-associated long non-coding RNA (HAGLR). Whereas, the precise regulation among them remains to be elucidated. The aim of this study was to investigate the role of IGF2BP2-mediated m⁶A methylation in the regulation of HAGLR and its impact on lycorine's effect on tamoxifen resistance in BC.

Methods: m⁶A status was detected via methylated RNA immunoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR). Relative expression of HAGLR and IGF2BP2 were tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell viability, proliferation and apoptosis were estimated via Cell Counting Kit-8 (CCK-8), colony formation and flow cytometer analysis. Interplay among IGF2BP2 and HAGLR was tested by RNA immunoprecipitation (RIP) assay. IC₅₀ value of BC cells to tamoxifen was determined by 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay.

Results: Total m⁶A level in tamoxifen-resistant BC cells (TAMR/MCF-7 and TAMR/T47D) was elevated relative to corresponding parental cells and normal mammary epithelial cell line, MCF10A, either with the presence of m⁶A modifications within HAGLR sequence. Moreover, IGF2BP2-mediated m⁶A methylation drove the upregulation and stability of HAGLR in TAMR BC cells. IGF2BP2 served as a key downstream target mediating the anti-tumors of lycorine on TAMR BC. Knockdown of IGF2BP2 or HAGLR could reduce the IC₅₀ value of TAMR/MCF-7 and TAMR/T47D cells to tamoxifen.

Conclusions: Our results demonstrated that lycorine inhibits tamoxifen-resistant BC by repressing IGF2BP2-mediated m⁶A methylation of HAGLR.