Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.

Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

Guanylate-binding proteins(GBPs) are interferonstimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma(CRC) and inflammatory bowel diseases(IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong antiangiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.

Tamoxifen Treatment in Correlation with Increased ET-1 Levels Is Associated with the Development of Breast Cancer Metastases

Background: In breast cancer patients, a correlation between endothelin-1 (ET-1) and lymph node metastasis was found. While breast cancer with a positive ER status can be treated with Tamoxifen, several studies describe increasing Tamoxifen resistance in patients. We analyzed the relationship between Tamoxifen, ET-1 overexpression, and ER leading to Tamoxifen resistance. Methods: Breast cancer cell lines were treated with Tamoxifen, ET-1, estrogen and combinations. Using qRT-PCR, immune-precipitation, Western blot, EMSA and immunohistology target gene expression and ER complex partners were investigated. Human biopsies and mastectomy specimens were immunohistologically studied for Vimentin 3, and ERβ. Results: Breast cancer cells stimulated with a combination of Tamoxifen and ET-1 downregulate ERα, while upregulating intracellular ET-1, and ERβ. Immunoprecipation of nuclear extracts with ET-1, ERα or ERβ agarose conjugated antibodies reveals a complex formation change replacing ERα by ERβ once Tamoxifen forms a complex with ET-1. ERβand ET-1 migrate into the nucleus. ET-1 stimulation upregulates metastases promoting target genes (IL-6, Wnt11), including a novel one, Vimentin 3. Tissue analyses show Vim3 and ERβ expression in metastases of ERα positive breast cancer, and in ERα negative biopsies/mastectomy specimens. Conclusion: We are the first to describe a complex consisting of Tamoxifen, ERβ and ET-1, whose nuclear transmigration causes an overexpression of target genes. This mechanism may explain Tamoxifen resistance. Future pathologic analyses should include estrogen beta receptor status as well as the ET-1 expression. This concept presents a new treatment approach for individualized medicine in breast cancer patients with increased ET-1 levels.

MET fusions and splicing variants convergently defne a subgroup of glioma sensitive to MET inhibitors

Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets.Methods:Totally,1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas(CGGA)and published data.All kinds of MET fusions and/or splicing variants(MET F/SVs)were identifed by bioinformatical methods.Single-cell RNA sequencing(scRNA-seq)were used for validation.In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment.Results:MET F/SVs but not genomic amplifcation,were highly enriched in the secondary glioblastomas(sGBM)and marked worse prognosis.Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression.Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors.Conclusion:Our fndings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may beneft from MET-targeted therapy.

Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome

Dear Editor,Tumor microenvironment(TME)-dependent stromal cell plasticity governs tumor development and therapy response.Tumor endothelial cells(TECs)are a major cellular component in this context[1].In colorectal carcinoma(CRC),the stromal cell-dependent impact of the TME is illustrated by an improved survival depending on an interferon(IFN)-γ-dominated Th1-like TME associated with high T-cell density[2]and suppressed angiogenesis[3,4].Cellular transcriptional memory is reported in cell lines after repeated exposure to IFN-γin vitro[5],suggesting that a Th1-like TME may also exert stable imprinting effects in vivo.Here,we investigated whether TME-dependent transcriptional imprinting in TECs from CRC patients can be exploited to retrieve clinically relevant signatures predicting outcomes.