Tumor Expression Research Articles

Relationship between inherited genetic variation and survival from colorectal cancer stratified by tumour location

The location of a patient’s colorectal cancer (CRC) influences their outcome but inherited factors may also be involved. We studied 1899 patients with advanced CRC (514 had proximal colonic, 493 distal colonic and 892 rectal tumours) and carried out genome-wide association studies for survival. Single nucleotide polymorphisms (SNPs) suggestive of association (P < 1.0 × 10–5) were tested for replication in 5078 CRC patients from the UK Biobank. We investigated the relationship between Phosphatidylinositol 4-Kinase Type 2 Beta (PI4K2B) expression in colorectal tumours and survival in 597 patients from The Human Protein Atlas (THPA). We also analysed 3 SNPs previously associated with survival by anatomical site. We found that SNPs at 54 independent loci were suggestive of an association with survival when stratified by tumour location. rs76011559 replicated in patients with proximal tumours (COIN, COIN-B and UK Biobank combined Hazard Ratio [HR] = 1.53, 95% Confidence Intervals [CI] = 1.19–1.86, P = 7.5 × 10–7) and rs12273047 replicated in patients with rectal tumours (combined HR = 1.27, 95% CI = 1.09–1.46, P = 4.1 × 10–7). In gene analyses, PI4K2B associated with survival in patients with distal cancers (P = 2.1 × 10–6) and increased PI4K2B expression in colorectal tumours was associated with improved survival (P = 9.6 × 10–5). No previously associated SNPs were replicated. Our data identify novel loci associated with survival when stratified by tumour location.

Aurora kinase A expression in pleomorphic adenoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma of salivary glands: an immunohistochemical study

BackgroundAurora kinase A (AurkA) plays a vital role in mitosis and is therefore critical in tumors development and progression. There are a few studies on AurkA expression in salivary gland tumors. The aim of the present study was to evaluate the expression pattern of AurkA in the most common benign and malignant salivary gland tumors by immunohistochemistry.MethodsIn this retrospective cross-sectional study, 68 cases including 25 pleomorphic adenomas (PAs), 21 adenoid cystic carcinomas (ADCa), 15 mucoepidermoid carcinomas (MEC), and 7 normal salivary glands (NSG) were enrolled from the archive of the Department of Pathology of Shiraz School of Dentistry, Iran. The expression of AurkA in the tissue samples was assessed by immunohistochemical method and was analyzed using statistical analysis (p < 0.05).ResultsOf total cases analyzed, the majority of benign and malignant tumors were found to involve minor salivary glands compared to major salivary glands (p < 0.001). In addition, all lesions studied expressed AurkA. More than half of the tumor tissues showed AurkA staining percentages between 26 and 50% and 76–100% compared to NSG (p = 0.08). In 44.1% of cases, cells had a weak staining score, 27.9% a moderate score and the rest (27.9%) a strong score (p = 0.64).ConclusionAlthough AurkA was observed to be expressed in all tumor tissues, further studies are needed to clearly understand the role of AurkA and the possibility of using it as a diagnostic, prognostic and therapeutic factor.

Value of [18F]AlF-NOTA-FAPI-04 PET/CT for predicting pathological response and survival in patients with locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant chemotherapy.

This study aimed to evaluate the predictive value of [18F]AlF-NOTA-FAPI-04 PET/CT for pathological response to neoadjuvant chemotherapy (NCT) and prognosis in patients with locally advanced pancreatic ductal adenocarcinoma (LAPDAC). This study included 34 patients with histopathologically and radiologically confirmed LAPDAC who received [18F]AlF-NOTA-FAPI-04 PET/CT scans before NCT. After 4-6 cycles of NCT, these patients underwent radical resection. Pathological response to NCT was assessed by pathological tumor regression grades (TRG) based on the Evans system. PET/CT parameters were evaluated for their association with TRG, recurrence-free survival (RFS) and overall survival (OS) after NCT, including the maximum standardized uptake value (SUVmax), FAPI-avid tumor volume (FTV), total lesion FAP expression (TLF) of primary tumor, total FAPI-avid pancreatic volume (FPV) and total pancreatic FAP expression (TPF) of total pancreas. Of 34 patients with LAPDAC, 14 patients had a pathologic good response (PGR, Evans III-IV), and 20 patients had a pathologic poor response (PPR, Evans I-II). Both the primary tumor SUVmax, FTV and TLF, and total pancreas FPV and TPF in the PGR groups were significantly lower than those in the PPR groups. Furthermore, SUVmax and TLF were higher in poorly differentiated LAPDAC than in well-moderately differentiated neoplasms. The FTV, TLF, FPV and TPF were closely associated with RFS and OS. On multivariate analysis, patients with FTV > 54.21 and TLF > 290.21 had a worse RFS and OS, respectively (HR = 3.24, P = 0.014 and HR = 3.35, P = 0.019) and OS (HR = 7.35, P = 0.002 and HR = 7.09, P = 0.004) in LAPDAC after NCT. The parameters of [18F]AlF-NOTA-FAPI-04 PET/CT had the excellent performance for predicting pathologic TRG after NCT in LAPDAC. FTV and TLF were independent postoperative prognostic factors for RFS and OS for LAPDAC.

Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models.

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited potent and specific cytotoxicity against uPAR-expressing PDAC cell lines, stromal and immune cells, and bystander killing of uPAR-negative cells. In vivo, the ADC induced remission or sustained tumor regression and extended survival in xenograft models. In syngeneic orthotopic models, the antitumor effect promoted immunomodulation by enhancing infiltrating immune effectors and decreasing immunosuppressive cells. This study lays grounds for further exploring FL1-PNU as a putative clinical ADC candidate, potentially providing a promising therapeutic avenue for PDAC as a monotherapy or in combinatorial regimens.

The role of OCT4 and CD44 in lower lip carcinogenesis.

Carcinogenesis is characterized by the transformation of normal cells into malignant cells. Concerning the lower lip, exposure to UV radiation is the main etiological factor associated with the development of epidermoid carcinomas and actinic cheilitis. According to the hierarchical model theory, cancer development is driven by populations of cancer stem cells. In this context, this study aimed to compare the expression of octamer-binding transcription factor 4 (OCT4) and CD44 in 40 lower lip epidermoid carcinoma (LLEC) and 40 actinic cheilitis (AC) cases. OCT4 and CD44 expressions were assessed semi-quantitatively according to the percentage of positive epithelial cells (PP) and intensity of expression (IE), resulting in a total immunolabeling score (PIT). No statistically significant differences were detected between OCT4 and CD44 immunoexpression and clinicopathological parameters, except for lymph node metastasis, in which a decrease in CD44 expression in the core tumor of cases with lymph node metastasis was observed. Furthermore, decreased CD44 expression was observed in LLEC cases when compared to AC cases. The findings reported herein suggest a higher participation of CD44 in early carcinogenesis stages. In addition, the imbalance between OCT4 and CD44 immunoexpressions suggests the presence of different neoplastic cell subpopulations.

DPP4, a potential tumor biomarker, and tumor therapeutic target: review.

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.

DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.

Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of paired box 3 (PAX3) and forkhead box O1 (FOXO1) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of Pax3::Foxo1, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low Pax3::Foxo1 expression: one subset enriched in Pax7 lineage tumours and a second subset enriched in myogenic factor 5 (Myf5) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Pan-cancer secreted proteome and skeletal muscle regulation: insight from a proteogenomic data-driven knowledge base.

Large-scale, pan-cancer analysis is enabled by data driven knowledge bases that link tumor molecular profiles with phenotypes. A debilitating cancer-related phenotype is skeletal muscle loss, or cachexia, which occurs partly from tumor products secreted into circulation. Using the LinkedOmicsKB knowledge base assembled from the Clinical Proteomics Tumor Analysis Consortium proteogenomic analysis, along with catalogs of human secretome proteins, ligand-receptor pairs and molecular signatures, we sought to identify candidate pan-cancer proteins secreted to blood that could regulate skeletal muscle phenotypes in multiple solid cancers. Tumor proteins having significant pan-cancer associations with muscle were referenced against secretome proteins secreted to blood from the Human Protein Atlas, then verified as increased in paired tumor vs. normal tissues in pan-cancer manner. This workflow revealed seven secreted proteins from cancers afflicting kidneys, head and neck, lungs and pancreas that classified as protein-binding activity modulator, extracellular matrix protein or intercellular signaling molecule. Concordance of these biomarkers with validated molecular signatures of cachexia and senescence supported relevance to muscle and cachexia disease biology, and high tumor expression of the biomarker set associated with lower overall survival. In this article, we discuss avenues by which skeletal muscle and cachexia may be regulated by these candidate pan-cancer proteins secreted to blood, and conceptualize a strategy that considers them collectively as a biomarker signature with potential for refinement by data analytics and radiogenomics for predictive testing of future risk in a non-invasive, blood-based panel amenable to broad uptake and early management.

Regulatory roles of eugenol in paraquat-altered SNCA/LZTS3/MAPT in the cerebellum of Wistar rats

BackgroundThe Microtubules-associated protein tau (MAPT), alpha-synuclein (SNCA), and leucine zipper tumor suppressor 3 (LZTS3) genes are implicated in neurodegeneration and tumor suppression, respectively. This study investigated the regulatory roles of eugenol on paraquat-altered genes.ResultsForty male Wistar rats divided into five groups of eight rats were used. The control group received normal saline; the Paraquat (PQ)-untreated group received only Paraquat. The low dose of eugenol was 200 mg/kg, the medium dose of eugenol was 400 mg/kg, and the high dose of eugenol was 600 mg/kg. All groups except the control group received 10 mg/kg of PQ orally for 14 days at one-day intervals, allowing PQ in the rats for 28 days. Eugenol treatment started on the 29th and lasted 14 days. Motor impairments were determined using wire string and beam-walk; biomarkers were estimated using cerebellar homogenates, while frozen cerebellum was used to study LZTS3, MAPT, and SNCA gene expression. LZTS3 was significantly suppressed in the PQ-untreated group and highly expressed in the eugenol-treated group. The MAPT and SNCA genes were overexpressed in the PQ-untreated group compared to the control group. Eugenol significantly decreased the expression of these genes compared to that in the PQ-untreated group. Antioxidants were reduced considerably, and oxidative stress markers were increased significantly, which could have caused increased protein fibrillation and reduced limb functionality. Histology revealed that eugenol mitigated the alterations caused by Paraquat.ConclusionsPQ can enhance tumor expression in addition to causing neurotoxicity, which decreases limb functionality, while eugenol, an antioxidant, can mitigate the effects of PQ.

KW2478 and Cisplatin Synergistically Anti-colorectal Cancer by Targeting PI3K/AKT/mTOR Pathway.

The objective of this study is to examine the impact of KW-2478 combined with DDP on colorectal cancer cells both in vitro and in vivo and to elucidate the molecular mechanism of KW-2478 in colorectal cancer. qRT-PCR and Western blot were employed to assess HSP90 mRNA and protein expression in normal intestinal epithelial and colorectal cancer cells. DLD-1 and HCT116 were selected for the experiment. CCK-8 was used to detect cytotoxicity; apoptosis rate was measured using flow cytometry; Western blot was employed to measure the expression levels of apoptotic and PI3K/AKT/mTOR pathway proteins. HCT116 was used to construct a subcutaneous tumor model in nude mice. After treatment with KW-2478 and DDP, the growth rate, volume, and weight of the tumor were observed. The expression of Ki67 was detected by immunohistochemistry. Apoptosis of tumor cells was detected using TUNEL. Western blot was employed to measure the expression levels of apoptotic and PI3K/AKT/mTOR pathway proteins. HSP90 mRNA and protein levels were elevated in colorectal cancer cells compared to normal colorectal epithelial cells. HSP90 mRNA and protein expression levels were also significantly elevated in HCT116 and DLD-1 cells compared to other colorectal cancer cells. In DLD-1 and HCT116 cells, KW2478 and DDP inhibited cell viability. The combination of KW2478 and DDP exhibited a significantly higher inhibitory effect compared to either KW2478 or DDP alone. DDP markedly triggered apoptosis in HCT116 and DLD-1. KW2478 at 3 μg/ml and 6 μg/ml induced apoptosis in HCT116 cells but not in DLD-1 cells. The combination of KW2478 and DDP induced a significantly higher apoptosis rate as compared to either KW2478 or DDP alone. Treatment of HCT116 and DLD-1 with KW2478 or DDP alone increased Bax, Caspase9, and Caspase3 protein expression, while decreasing BCL-2. The KW2478+DDP combined treatment group exhibited more significant changes. Phosphorylation of PI3k, AKT, and mTOR decreased in the KW2478 or DDP treatment groups, with more significant changes observed in the KW2478 + DDP combination group. The growth rate, volume, and weight of subcutaneous tumors in the KW2478 or DDP treatment groups were significantly lower than control, and the KW2478+DDP combination group was more affected. Ki67 expression in subcutaneous tumors was reduced in the KW2478 or DDP treatment groups compared to the vehicle control group, with the lowest expression observed in the KW2478 + DDP combination group. The fluorescence intensity of subcutaneous tumors was higher in both the KW2478 and DDP treatment groups compared to the vehicle control group, and the KW2478 + DDP combination group exhibited the strongest fluorescence intensity among them. The combination of KW2478 and cisplatin inhibits colorectal cancer cell proliferation and induces apoptosis by regulating the PI3K/AKT/mTOR pathway.

Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer

The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.

Comparative evaluation of PD-L1 expression and tumor immune microenvironment in molecular subtypes of muscle-invasive bladder cancer and its correlation with survival outcomes.

Immune checkpoint inhibitors have revolutionized treatment of platinum-refractory advanced bladder cancer, offering hope where options are limited. Response varies, however, influenced by factors such as the tumor's immune microenvironment and prior therapy. Muscle-invasive bladder cancer (MIBC) is stratified into molecular subtypes, with distinct clinicopathologic features affecting prognosis and treatment. This study assessed the expression of programmed cell death 1 ligand 1 (PD-L1) and other immune markers in MIBC, categorized by molecular phenotype. Using GATA3 and CK5/6 immunohistochemistry, 90 neoadjuvant chemotherapy-naive MIBC cases were classified into luminal andnon-luminalsubtypes. The immune microenvironment was characterized through immunostaining for PD-L1, CD4, and CD8. We applied PD-L1 positivity thresholds of 1% or greater for tumor cells and 5% or greater for immune cells. Tumors were examined for PD-L1 expression, histologic subtypes, and immune cell infiltration. Varied expression of PD-L1 and T-cell subtype densities were observed among MIBC subtypes. The double-negative subtype displayed the highest PD-L1 immune cell expression and stromal CD4 and CD8 T-cell densities, indicating an active immune profile. The basal subtype exhibited the highest PD-L1 positivity in tumor cells. In contrast, the luminal type showed the lowest PD-L1 tumor and immune cell expression, with high intratumoral CD4 T-cell density. Although PD-L1 expression in tumor or immune cells did not independently affect survival, patients with basal and double-negative tumors had poorer overall survival. This study highlighted the immune diversity of MIBC in the context of molecular subtypes. Distinct molecular and immune profiles could guide the development of predictive signatures for enhanced immunotherapy response in advanced bladder cancer.

Distribution Characteristics in Clinical Phenotype and Immunohistochemistry of STK11 Adnexal Tumors: Case Report and Narrative Synthesis.

STK11 adnexal tumors are recently named tumors of the female adnexal region, associated with Peutz-Jeghers syndrome (PJS). There is a lack of studies on the clinical phenotypes of PJS concerning the pathology and molecular characteristics of STK11 adnexal tumors. We searched for 781 relevant studies through PubMed and Web of Science, and preliminary statistical and grouping comparisons were made using the screened study data combined with our patient. A total of 25 patients with STK11 adnexal tumors (excluding tumors with no detectable STK11 alterations) were reported in 4 studies. The tumors were most common in middle-aged women (mean age of 39 years) and typically located at paratubal sites (76%). Nearly half of patients (45%) had PJS manifestations or molecular changes. Compared with sporadic (non-PJS) STK11 adnexal tumors, PJS-associated STK11 adnexal tumors were slightly larger in diameter (mean 12.6 cm vs 8.9 cm) and had a longer interval between first recurrences (median 19 months vs 7 months). Primary tumors with pelvic recurrence had a reduced keratin 7 positive rate and tended to grow in non-paratubal sites. However, overall, the clinicopathological characteristics of PJS-associated tumors and sporadic tumors were similar, as was the immunohistochemical expression of primary and recurrent tumors. More specimens and studies are needed to support these observations and further delineate the characteristics of STK11 adnexal tumors.

EZH2-mediated downregulation of miR-155-5p contributes to prostate cancer cell malignancy through SMAD2 and TAB2.

miR-155 exhibits variable expression in different tumors and fulfills diverse biological roles. However, specific molecular mechanisms by which miR-155-5p, which is under-expressed in prostate cancer (PCa), operates are yet to be elucidated. The role of the enhancer of zeste 2 (EZH2)/miR-155-5p axis in PCa was determined by using bioinformatics tools and performing luciferase reporter assay, chromatin immunoprecipitation PCR, CCK-8 assays, cell migration and invasion assays, RNA isolation, reverse transcription quantity (RT-qPCR) and Western blot. miR-155-5p expression would be reduced and promoter methylation would increase in PCa. After 5-Aza-CdR treatment and the integration of the upstream promoter of miR-155-5p into a pGL3-basic/luciferase construct, fluorescence reporter analysis showed that promoter hypermethylation mediated the suppression of miR-155-5p in PCa. Furthermore, EZH2 attached to the miR-155-5p promoter and modulated its expression. EZH2 facilitated the suppression of miR-155-5p through enhanced H3K27me3 methylation, considerably affecting its expression. Through dual-luciferase assays, SMAD2 and TAB2 were confirmed as downstream targets of miR-155-5p, regulating the PCa cellular phenotype governed by miR-155-5p. Lastly, 5-Aza-CdR regulated miR-155-5p expression by modulating its promoter methylation and influenced the malignant behavior of PCa cells. EZH2 promotes H3K27me3 methylation, repressing miR-155-5p expression, which subsequently upregulates the downstream targets SMAD2 and TAB2 and promotes PCa cell proliferation, epithelial-mesenchymal transition (EMT), migration and invasion.

Comparative Analysis of Transcriptomic and Proteomic Expression between Two Non-Small Cell Lung Cancer Subtypes.

Non-small cell lung cancer (NSCLC) is frequently diagnosed late and has poor survival. The two predominant subtypes of NSCLC, adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), are currently differentially diagnosed using immunohistochemical markers; however, they are increasingly recognized as very different cancer types suggestive of potential for new, more targeted therapies. There are extensive efforts to find more precise and noninvasive differential diagnostic tools. Here, we examined these two NSCLC subtypes for differences that may inform treatment and identify potential novel therapeutic pathways. We presented a comparative analysis of transcriptomic and proteomic expression in tumors from a cohort of 22 NSCLC patients: 8 LUSC and 14 LUAD. Comparing NSCLC subtypes, we found differential gene expression related to cell differentiation for LUSC and cellular structure and immune response regulation for LUAD. Differential protein expression between NSCLC subtypes was related to extracellular structure for LUSC and metabolic processes, including glucose metabolism for LUAD. This direct comparison was more informative about subtype-specific pathways than between each subtype and control (nontumor) tissues. Many of our observations between NSCLC subtypes support and inform existing observations and reveal differences that may aid research seeking to identify and validate novel subtype biomarkers or druggable targets.

Cabozantinib Selectively Induces Proteasomal Degradation of p53 Somatic Mutant Y220C and Impedes Tumor Growth.

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multi-kinase inhibitor currently used in clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting in the dissociation of p53Y220C protein from its binding with USP7 and subsequent ubiquitination and degradation mediated by CHIP (The carboxyl terminal of Hsp70-interacting protein). We also show that cabozantinib displays preferential cytotoxicity to p53Y220C-harboring cancer cells both in vitro and in vivo. This study demonstrates a novel, p53-Y220C mutant-targeted anticancer action and mechanism for cabozantinib, and provides the rationale for use of this drug in treatment of cancers that carry the p53-Y220C mutation.

Precision targeting of fat metabolism in triple negative breast cancer with a biotinylated copolymer.

Mitochondrial CPT1-mediated fatty acid β-oxidation (FAO) critically contributes to the accelerated metastatic expansion of triple negative breast cancer (TNBC). Hence, inhibition of FAO through active CPT1 targeting could be a promising therapeutic approach in anti-TNBC therapies. Herein, we strategically synthesized a pyrene chain end labelled copolymer bearing biotin pendants, CP4, that actively targets CPT1 and efficiently blocks FAO in metastatic TNBC. Following the comprehensive characterization and synthesis of CP4, in silico negative docking score and Ramachandran plot analyses confirmed its on-target binding potential to CPT1. As a result, CP4 disrupts mitochondrial membrane potential, generates excessive ROS, and restricts excessive ATP production by impairing mitochondrial respiration, glycolytic function, and FAO. Subsequently, CP4 suppressed FA uptake and regulated FAO-associated gene expressions, exhibiting successive metastatic growth inhibition and apoptosis induction. Also, in an animal model, CP4 demonstrated active binding to CPT1, as evidenced by the significant depletion of CPT1A expression in tumor and liver tissue, akin to the specific CPT1-targeted drug. This active targeting of CPT1 has further consolidated the healing of altered lipid and oxidative stress, resulting in remarkable tumor regression, highlighting CP4 as a promising anticancer therapy focused on mitochondrial FAO, advancing future breast cancer treatments.

Integration of eQTL and multi-omics comprehensive analysis of triacylglycerol synthase 1 (TGS1) as a prognostic and immunotherapeutic biomarker across pan-cancer.

An increasing number of expression quantitative trait loci (eQTLs) have been linked to tumorigenesis. In this study, we used Mendelian randomization (MR) to identify a novel cancer susceptibility gene, Trimethylguanosine Synthase 1 (TGS1). TGS1-induced hypermethylation at the 5' end of human telomerase RNA (hTR) impedes hTR accumulation, decreasing telomerase assembly factor levels and thus limiting telomere elongation, a crucial factor in tumor progression. Despite its significant role in cancer development, the TGS1-cancer relationship requires further experimental validation and bioinformatics analysis. To bridge this knowledge gap, we performed a comprehensive pan-cancer study using MR to evaluate TGS1's involvement in cancer progression. Leveraging data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we analyzed TGS1's role in 33 tumor types. The results indicated higher TGS1 expression in most tumors, with a significant correlation to patient prognosis. We also noted variations in TGS1 phosphorylation at different sites and a strong link between TGS1 expression and the infiltration of various immune cells. In addition, our enrichment analysis of TGS1-associated genes shed light on the molecular mechanisms involved. The study also highlighted TGS1's significant role in cellular apoptosis. Overall, our findings offer an in-depth analysis of TGS1's oncogenic roles across multiple tumor types and underscore its potential as an oncogene, biomarker, and gene therapy target in diverse cancers.

Hepatocyte nuclear factor 4α as a sensitive marker for uterine endocervical adenocarcinomas and their precursors.

Hepatocyte nuclear factor (HNF)-4α is a marker of gastrointestinal tumor differentiation; however, its expression in endocervical tumors remains unclear. We aimed to assess the utility of HNF4α expression as a marker for endocervical adenocarcinomas (ECAs) and adenocarcinoma in situs (AISs), and to establish a minimal panel for distinguishing them from nonneoplastic endocervical glandular lesions and metastases. HNF4α expression was analyzed immunohistochemically (positive, H-score ≥10) in 323 tissue samples: 57 endocervical neoplasms including 35 glandular neoplasms and 22 squamous neoplasms, 144 nonneoplastic endocervical lesions, and 122 tumors from other organs. The panel for distinguishing endocervical glandular neoplasms from nonneoplastic glands and from metastases comprised HNF4α, p16, CDX2, and SATB2; staining was assessed. HNF4α was expressed significantly in ECAs and AISs, both HPV-independent and -associated types, but not in nonneoplastic glandular and squamous lesions (p<0.05). The immunohistochemical detection sensitivity and specificity for endocervical ECA and AIS were 77% and 95%, respectively. For AIS alone, these were 79% and 94%, and for ECA alone, 75% and 94%, respectively. Either HNF4α(+) or p16(+) or double positive identified endocervical gland and squamous neoplasms (sensitivity, 96%; specificity, 76%). HNF4α(+) and SATB2(-) and CDX2(-) profiles suggested ECAs (sensitivity, 69%; specificity, 88%). HNF4α(+) and SATB2(+) or CDX2(+) profiles suggested adenocarcinomas of the gastrointestinal or genital tract (sensitivity, 81%; specificity, 88%). HNF4α is a promising marker for detecting both HPV-independent and -associated ECAs and AIS with high accuracy. Its combination with p16, CDX2, and SATB2 has potential use in diagnostic panels.

Activation of sphingosine-1-phosphate receptor 2 (S1PR2) upregulates dihydropyrimidine dehydrogenase (DPD) expression in colon cancer cells.

Dihydropyrimidine dehydrogenase (DPD) is a major determinant of cancer 5-fluorouracyl (5-FU) resistance via its direct degradation. However, the mechanisms of tumoral DPD upregulation have not been fully understood. This study aimed to explore the role of S1PR2 in the regulation of tumoral DPD expression, identifying S1PR2 as the potential target for reversing 5-FU resistance. Western blot was used to analyze S1PR2 expression in cultured cancer cells and human colorectal cancer (CRC) tissues. 5-FU resistance was estimated in mouse xenografts of HT-29sh-S1PR2 and SW480S1PR2 cells. HPLC-UV was used to measure 5-FU levels in the xenografts. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of YAP1/TEAD1 to the TWIST1 promoter. A luciferase reporter was used to analyze the binding of TWIST1 to the DPYD promoter. S1PR2 was highly expressed in cancer cell lines and human CRC tissues. Activation of S1PR2 upregulated DPD expression, leading to 5-FU resistance. Mechanistically, activated S1PR2 upregulated nuclear TWIST1 by activating the Hippo/TEAD1-TWIST1 pathway. Nuclear TWIST1 interacted with the JMJD3-RNA Pol II complex, resulting in the interaction of TWIST1 with the DPYD promoter, thus increasing H3K27me3-enriched DPYD transcription. These findings were confirmed in xenografted human colon cancer cells in nude mice. Transfection with an S1PR2 expression vector led to the upregulation of DPD, blunting the sensitivity of SW480S1PR2 cells to 5-FU by 45.14 %. Conversely, knockdown of S1PR2 resulted in a decrease of DPD, thus increasing the sensitivity of HT-29sh-S1PR2 cells to 5-FU by 62.12 %. Molecular analysis of these xenografts confirmed the role of S1PR2 in upregulating DPD expression by activating the Hippo/TEAD1-JMJD3 pathway. Activation of S1PR2 upregulated DPD expression by activating the Hippo/TWIST1-JMJD3 pathway. S1PR2 is therefore a potential target for novel inhibitors that may reverse 5-FU resistance in cancer therapy.