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Results for “tissue microarray”

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At least 19 recordsLinked to original sources

PubMed2025

GATA2 promotes cervical cancer progression under the transcriptional activation of TRIP4.

The continued rise in recurrence and mortality rates of cervical cancer suggests the need to find novel therapeutic targets. Previous studies suggest that TRIP4 acts as a transcription factor to regulate cervical carcinogenesis and progression. Our aim was to explore whether the key downstream genes of TRIP4 functions same as TRIP4 in promoting cervical cancer development. We analyzed and confirmed the downstream targets of TRIP4 by RNA sequencing in cervical cancer cells with TRIP4 knockdown. The expression correlation between TRIP4 and GATA2 and the effect of GATA2 on cervical cancer cell growth were determined respectively by Western Blot, Scratch, Spheroid, and MTT analyses. Pulldown and ChIP experiments were performed to analyze the binding of TRIP4 to the promoter of GATA2. The clinical significance of GATA2 and TRIP4 expression in cervical cancer patients was analyzed by tissue microarray staining. GATA2 was highly expressed in cervical cancer tissues. Knockdown of GATA2 inhibited the growth, metastasis and stemness of cervical cancer cells and sensitized cervical cancer cells to radiation therapy. The inhibitory effect of TRIP4 knockdown on cervical cancer cells was rescued by GATA2 overexpression. Furthermore, TRIP4 could bind to the specific GATA2 promoter region, thereby activating its transcription. Clinical tissue microarray analysis indicated that the expression of TRIP4 and GATA2 was positively correlated, and high expression of both predicted a poor prognosis in cervical cancer patients. Our study demonstrated that GATA2 functions as the key downstream target of TRIP4 to promote cervical cancer progression and effective intervention of TRIP4/GATA2 signaling is expected to be developed as potential cervical cancer therapeutic strategy.

Humans↗

PubMed2026

Profiling Dectin-2-Positive Tumor-Associated Macrophages Across Human Cancers by Immunohistochemistry.

PURPOSE: To characterize the prevalence and distribution of Dectin-2-positive macrophages across human tumors and develop a research immunohistochemistry (IHC) assay to assess Dectin-2 in cancer tissues. MATERIALS AND METHODS: C-type lectin domain family 6 member A (CLEC6A), the gene encoding Dectin-2, was evaluated across 38 tumor types using The Cancer Genome Atlas. A fit-for-purpose Dectin-2 IHC assay was developed using a monoclonal antibody selected from screening 11 anti-Dectin-2 antibodies. Assay performance was supported by Dectin-2-expressing and parental cell line controls, macrophage-associated staining patterns, and comparison with an orthogonal CLEC6A in situ hybridization method using RNAscope. Dectin-2 expression was assessed in tissue microarrays (n = 553 samples) across 6 cancer types and whole tissue sections (n = 137) across 7 cancer types. RESULTS: The Cancer Genome Atlas analysis identified enriched CLEC6A expression in several tumor types, including non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and subsets of head and neck cancer (HNC) and colorectal cancer (CRC). By IHC, Dectin-2-positive macrophages were detected across tumor types, with notable heterogeneity within and across cancer types. In tissue microarrays, NSCLC showed the highest frequency of Dectin-2-positive macrophage infiltration, with 38% of cases with staining ≥1% of tumor area. Whole tissue section analysis confirmed and expanded these findings, with ≥50% of NSCLC, melanoma, HNC, TNBC, and CRC samples showing Dectin-2-positive macrophages in ≥1% tumor area. CONCLUSIONS: Dectin-2 expression was observed in subsets of tumor-associated macrophages across multiple human cancers, with relatively enriched expression in NSCLC, melanoma, HNC, TNBC, and CRC. To our knowledge, this study represents the first broad protein-level characterization of Dectin-2 across multiple human tumor types, identifies cancers with relatively enriched Dectin-2-positive macrophage infiltration, and provides a foundation for future translational studies of Dectin-2-targeted therapies.

Humans↗

PubMed2026

Integrated multi-omics analysis and functional experiments reveals PPAP2C as a potential prognostic biomarker and therapeutic target in breast cancer.

BACKGROUND: This study aims to systematically elucidate the clinical significance and biological function of the phospholipid phosphatase (PLPP) family member (PPAP2C) phosphatidic acid phosphatase type 2C in breast cancer, and to evaluate its potential as a prognostic biomarker and therapeutic target. METHODS: Gene expression data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were integrated to characterize the expression profile of PLPP family members, focusing on PPAP2C in breast cancer. The prognostic value of PPAP2C, initially identified at the mRNA level (TCGA, (METABRIC) Molecular Taxonomy of Breast Cancer International Consortium, Gene Expression Omnibus (GEO)), was confirmed at the protein level by immunohistochemistry (IHC) on tissue microarrays (TMA). The oncogenic functions of PPAP2C were investigated in triple-negative breast cancer (TNBC) cells through CRISPR-Cas9-mediated knockout and ectopic overexpression, with assessment of key phenotypes including proliferation, colony formation, migration, and invasion. In vivo validation was subsequently performed using an MDA-MB-231 xenograft model. RESULTS: PPAP2C exhibits the most significant overexpression pattern across 33 cancer types (upregulated in 16 cancers, downregulated in only 3). Compared with normal tissues, PPAP2C showed specific overexpression in breast cancer tissues and was significantly associated with advanced clinical stages and aggressive subtypes (HER2+ and TNBC). Survival analysis demonstrated that high PPAP2C expression correlated with significantly shorter overall survival and disease-free survival, which was further validated in METABRIC and GEO cohorts. Tissue microarray analysis confirmed higher PPAP2C protein positivity in tumor tissues (94.7%) than in adjacent normal tissues (59.7%), with worse OS and RFS in high-expression groups. Multivariate analysis identified PPAP2C as an independent prognostic factor for OS. Functional experiments revealed that PPAP2C knockout (via 5-bp/1-bp frameshift mutations) suppressed TNBC cell proliferation, colony formation, migration, and invasion, while overexpression enhanced these phenotypes. In vivo studies further demonstrated complete tumor regression in MDA-MB-231 xenografts upon PPAP2C knockout. CONCLUSION: This study identifies PPAP2C as a key oncogenic driver and a robust independent prognostic biomarker in breast cancer. The findings provide compelling evidence that PPAP2C represents a promising therapeutic target, offering a new strategic avenue for precision therapy, particularly for aggressive breast cancer subtypes.

PLPP2↗

PubMed2024

Integrated bioinformatics analysis and experimental validation reveal the relationship between ALOX5AP and the prognosis and immune microenvironment in glioma.

BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.

Humans↗

PubMed2026

Integrin α3 (ITGA3) expression across breast cancer subtypes: Prognosis and therapeutic relevance.

BACKGROUND: Integrin α3 (ITGA3), which heterodimerizes with integrin β1, has emerged as a potential biomarker and therapeutic target in several epithelial malignancies; however, its clinical relevance in breast cancer remains incompletely characterized. This study evaluated ITGA3 expression across breast cancer molecular subtypes and assessed its prognostic and predictive significance. METHODS: Immunohistochemistry (IHC) was performed on archival breast cancer specimens using tissue microarrays (n = 148) and whole-tissue sections (n = 21). Complete clinicopathologic and outcome data were available for 108 patients, including hormone receptor-positive/human epidermal growth factor receptor 2-negative, HER2-positive, and triple-negative breast cancer (TNBC) subtypes. ITGA3 expression was quantified using H-scores and correlated with clinicopathologic features and survival outcomes. Independent transcriptomic analyses were conducted using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and the Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohorts to evaluate ITGA3 mRNA expression, co-expressed signaling pathways, and associations with therapeutic response. RESULTS: ITGA3 protein expression was detected in 85.2% of breast cancer specimens and was significantly higher in HR-positive/HER2-negative and HER2-positive tumors compared with TNBC (p < 0.0050). High ITGA3 expression was associated with shorter recurrence-free survival (p < 0.0001). In the METABRIC cohort, tumors with ITGA3 alterations demonstrated significantly worse relapse-free survival (p < 0.0001) and overall survival (p < 0.0500). Transcriptomic analyses revealed that ITGA3 co-expressed with estrogen receptor 1(ESR1), erb-b2 receptor tyrosine kinase 2 (ERBB2), and luminal markers, along with enrichment of estrogen receptor and phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathways. ITGA3 expression was not predictive of response to tamoxifen or trastuzumab. CONCLUSION: Elevated ITGA3 expression is associated with breast cancer recurrence and poor clinical outcomes, supporting its potential role as a prognostic biomarker and candidate therapeutic target.

Biomarkers↗

PubMed2026

Profibrogenic Gremlin-1 expression in prostate cancer and the clinicopathologic association.

BACKGROUND: Gremlin-1 (GREM1) is a profibrogenic molecule involved in TGF-β signaling. Recent studies have implicated GREM1 in androgen receptor (AR)-independent signaling and castration resistance in advanced prostate cancer. However, its compartment expression patterns and clinicopathologic significance in primary prostate cancer remain unclear. METHODS: GREM1 mRNA expression and clinicopathologic associations were analyzed in the Cancer Genome Atlas (TCGA) prostate adenocarcinoma (TCGA-PRAD), the Memorial Sloan Kettering Cancer Center (MSKCC), and the German Cancer Research Center (DKFZ) primary prostate cancer cohorts. Correlations between GREM1 and genes related to TGF-β signaling, extracellular matrix organization, fibroblast activation, and AR signaling were evaluated by Spearman analysis. GREM1 protein expression was examined by immunohistochemistry in commercial human prostate cancer tissue microarrays (TMAs) using compartment-specific QuPath-based H-scores. RESULTS: GREM1 expression was relatively elevated in prostate and bladder cancers. Across the three prostate cancer cohorts, higher GREM1 expression was associated with adverse pathologic features and was most consistently correlated with FAP. Inverse correlations were observed with selected AR-related genes, whereas no significant correlation was found with AR itself. Higher GREM1 expression was associated with shorter disease-free survival only in MSKCC but was not an independent prognostic factor after clinicopathologic adjustment. Quantitative immunohistochemistry in 43 patients showed higher epithelial than stromal GREM1 H-scores (median, 3.10 vs 1.41; P < 0.0001), with heterogeneous staining in both compartments. Neither epithelial nor stromal H-scores were associated with Gleason score or pathologic T stage. CONCLUSIONS: GREM1 mRNA expression in primary prostate cancer was associated with adverse clinicopathologic features, and a fibroblast-associated transcriptional context but did not demonstrate independent prognostic value. At the protein-level, GREM1 expression was heterogeneous in both epithelial and stromal compartments, with higher epithelial H-scores on average. These findings support further investigation of the biological significance of GREM1 expression in primary prostate cancer.

TCGA↗

PubMed2025

NME2 modulates HCC progression through 4EBP1 phosphorylation and autophagy regulation independent of mTOR.

BACKGROUND: To investigate the role of nucleoside diphosphate kinase 2 (NME2) in HCC progression, assessing its therapeutic potential. METHODS: Utilizing transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of tissue microarrays, we analyzed NME2 expression in HCC tumor tissues. The effects of NME2 on HCC cell proliferation and autophagy flux were assessed through knockdown and overexpression experiments. Additionally, the relationship between NME2 and 4EBP1 phosphorylation was explored through specific site mutation analysis. RESULTS: NME2 overexpression in HCC correlated with poor prognosis. NME2 knockdown significantly hindered HCC cell proliferation and induced autophagy flux. Notably, NME2 modulates 4EBP1 phosphorylation (Thr37/46) independently of mTOR, unveiling a novel axis in HCC pathogenesis. Additionally, NME2 modulates eukaryotic translation initiation factor 4F (eIF4F) complex formation and autophagy flux. CONCLUSIONS: NME2 plays a crucial role in HCC development by modulating 4EBP1 phosphorylation and autophagy through an mTOR-independent pathway. Our research underscores NME2's significance as a potential therapeutic target in HCC, meriting further exploration of its underlying mechanisms and clinical applicability.

Humans↗

PubMed2023

Bovine meat and milk factor protein expression in tumor-free mucosa of colorectal cancer patients coincides with macrophages and might interfere with patient survival.

Bovine milk and meat factors (BMMFs) are plasmid-like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co-markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor-adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low-/high-grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co-immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor-adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD-adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC-specific death were increased for higher Rep expression (TMA), with high tumor-adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF-specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.

Humans↗

PubMed2026

Development and Validation of a Prognostic Signature Based on Transcription Factors Associated with Endoplasmic Reticulum Stress in Pancreatic Adenocarcinoma.

BACKGROUND: Endoplasmic reticulum stress (ER stress) plays a crucial role in influencing the malignant behaviors of various tumors. Targeting the expression or degradation of transcription factors (TFs) offers a promising avenue for cancer treatment. However, a detailed understanding of how ER stress affects TF function and their interactions remains limited. This study aims to develop a prognostic model and identify TFs associated with ER stress in pancreatic ductal adenocarcinoma (PDAC). METHODS: We obtained gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA). To develop a prognostic signature, we performed several analyses, including unsupervised clustering, enrichment analysis, immune infiltration assessment, as well as univariate, LASSO, and multivariate Cox regression analyses. Four transcription factors-STAT1, IRF6, NRF1, and RXRA-were incorporated into a risk model, which was subsequently validated using the GSE dataset. Additionally, we examined IRF6 through quantitative PCR, western blotting, flow cytometry, and immunohistochemistry in vitro using pancreatic cancer cell lines and a tissue microarray. RESULTS: The high-risk group identified by the model exhibited significant associations with immune cell infiltration and poorer survival outcomes, though there was no significant correlation with tumor purity (p = 0.19). Furthermore, IRF6 downregulation in vitro was found to inhibit pancreatic cancer cell proliferation and promote apoptosis. IRF6 depletion also increased the expression of key molecules involved in ER stress at both the transcriptional and translational levels. Immunohistochemical analysis revealed marked differences in IRF6 expression between tumor and adjacent non-tumor tissues (59.29±29.88 vs. 95.22±40.80, p<0.001). CONCLUSION: This study provides evidence that the constructed risk model can effectively predict prognosis in PDAC patients. Transcription factors related to ER stress, such as IRF6, show promise as both prognostic biomarkers and potential therapeutic targets for PDAC.

Humans↗

PubMed2026

CTGF/CCN2 Promotes Invasive Growth in Cervical Cancer Spheroids and Is Associated With Metastatic Cervical Cancer Tissue.

BACKGROUND/AIM: Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS: CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS: Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) ≥ 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION: In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.

Humans↗

PubMed2026

LDHC4 promotes ovarian cancer progression through H4K12 lactylation to regulate PGK1 expression and modulate glycolysis.

OBJECTIVE: Ovarian cancer (OC) pathogenesis involves metabolic and epigenetic alterations, yet the underlying mechanisms remain unclear. Here, we sought to investigate the role and regulatory mechanism of lactate dehydrogenase C4 (LDHC4) in OC progression. METHODS: Multi-omics approaches were employed, including analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts, tissue microarrays, molecular biology experiments, and in vivo mouse models. LDHC4 expression was modulated in OC cell lines (A2780 and ES-2) to assess its effects on proliferation, migration, invasion, and metastasis. Lactylproteomic profiling, cleavage under targets and tagmentation (CUT&Tag), and chromatin analyses were conducted to explore epigenetic mechanisms. The functional role of the downstream glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was examined using pharmacological inhibition. Molecular docking and xenograft models were used to evaluate the therapeutic potential of targeting H4K12lac (lactylation of histone H4 at lysine 12). RESULTS: LDHC4 was significantly overexpressed in OC tissues and associated with poor overall survival (OS) (hazard ratio [HR] = 4.017, 95% confidence interval [CI]: 2.308–6.989, P < 0.0001). It promoted proliferation, migration, invasion, and metastasis in vitro and in vivo. LDHC4 overexpression increased global lactylation, notably upregulating H4K12lac, which was enriched at the PGK1 promoter. Inhibition of PGK1 with CBR-470-1 (half-maximal inhibitory concentration [IC₅₀] = 14.56 µM) suppressed OC growth and metastasis. Importantly, Elbasvir, identified as a high-affinity H4K12lac inhibitor, significantly reduced tumor burden in mouse xenografts across multiple doses (10–20 mg·kg⁻¹) and downregulated H4K12lac and Ki-67 expression. CONCLUSION: We conclude that LDHC4 promotes OC progression via lactylation-mediated epigenetic upregulation of PGK1. Targeting this pathway through H4K12lac inhibitors such as Elbasvir thus emerges as a viable therapeutic approach for OC.

Female↗

PubMed2026

Profiling tumor immune microenvironment of epithelial ovarian carcinoma.

BACKGROUND: Epithelial ovarian carcinoma (EOC) comprises five main histological subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), mucinous (MOC), and endometrioid (ENOC). Each histotype harbors specific genomic alterations and clinical outcome. Few studies systematically compared the tumor immune microenvironment across the five subtypes. METHODS: We performed 7-plex (CD45, CD8, CD68, CD163, FoxP3, CD20, and cytokeratin) sequential immunohistochemistry on a clinically annotated tissue microarray including 139 EOC representing the five subtypes and 26 borderline tumors (serous and mucinous). Digital pathology was used to quantify immune cell abundance, their spatial distribution (stroma vs tumor core), and correlation with survival. RESULTS: Immune cells were dominated by macrophages and more abundant in the stroma than tumor core across the five subtypes, consistent with immune excluded pattern. Compared to HGSOC, CCOC displayed the highest infiltration by CD45+ leukocytes and CD68+ macrophages, particularly M2-like CD163+ cells, suggesting a macrophage-rich, immunosuppressive phenotype. LGSOC exhibited the highest infiltration by intraepithelial FoxP3+ regulatory T cells. Comparison of borderline tumors with invasive carcinoma (LGOSC and MOC) revealed that malignant progression is accompanied by loss of CD8+ T cells, enrichment in regulatory T cells and increase of CD163+/CD68+ ratio, consistent with immune evasion during tumorigenesis. There was a trend toward better survival in HGSOC highly infiltrated by lymphocytes, either intraepithelial (CD8+ and FoxP3+) or stromal (FoxP3+ and CD20+). CONCLUSIONS: EOC is characterized by histotype-specific immune milieux defined by macrophage dominance, epithelial immune exclusion and dynamic immune remodeling during progression from borderline tumors to invasive carcinomas.

Humans↗

PubMed2026

Integrated expression profiling of trophoblast cell-surface antigen 2 (TROP2), folate receptor alpha (FRα), and human epidermal growth factor receptor 2 (HER2) in endometrial Cancer across molecular classes, genomic alterations, and histologic subtypes.

OBJECTIVE: Antibody-drug conjugates (ADCs) are expanding treatment options in endometrial carcinoma, but the distribution of actionable surface targets across histologic, molecular, and genomic subgroups remains incompletely defined. METHODS: This single-institution retrospective tissue microarray (TMA) study included 312 endometrial carcinomas: 158 endometrioid and 154 serous tumors. Trophoblast cell-surface antigen 2 (TROP2) was quantified by histochemical score (H-score); human epidermal growth factor receptor 2 (HER2) was assessed using endometrial carcinoma-specific and gastric/DESTINY-PanTumor02 criteria; and folate receptor alpha (FRα) positivity was defined as ≥75% viable tumor cells with ≥2+ membranous staining. Molecular class was assigned using a hierarchical DNA polymerase epsilon (POLE)-mutant, microsatellite instability/mismatch repair-deficient (MSI/MMRd), p53-abnormal, and no specific molecular profile (NSMP) classifier. Tumor mutational burden (TMB) and recurrent genomic alterations were analyzed in relation to biomarker expression. RESULTS: TROP2 was broadly expressed, with median H-scores of 280 in endometrioid and 200 in serous carcinomas. HER2 gastric-score 2+/3+ expression and FRα positivity were enriched in serous versus endometrioid carcinoma (22.5% vs 8.9% and 20.1% vs 4.4%), restricted to FIGO grade 3 tumors, and concentrated in p53-abnormal disease. FRα positivity was absent in POLE-mutant and MSI/MMRd tumors. HER2 2+/3+ expression correlated with erb-b2 receptor tyrosine kinase 2 (ERBB2) alterations, whereas FRα-positive tumors were enriched for TP53 alterations and showed lower frequencies of ARID1A and PTEN alterations. Triple-negative TROP2/HER2/FRα tumors were uncommon (6/308, 1.9%). CONCLUSIONS: TROP2 is broadly expressed in endometrial carcinoma, whereas HER2 and FRα define a more restricted high-grade, serous/serous-like, p53-abnormal compartment, supporting biomarker-informed ADC development.

Humans↗

PubMed2026

Sex Hormone Receptors, HBV Integrations and Their Prognostic Predictive Value Among Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) infection predominantly affects males, yet few studies have investigated the association between sex hormones and HBV integrations, and their involvement in HCC prognosis. We assessed estrogen receptor alpha (ERα) and androgen receptor (AR) expression via immunohistochemistry on tissue microarrays constructed from 426 HBV-related HCC samples. HBV integration features were determined using HBV-captured sequencing data. Logistic regression models were utilized to evaluate the association between sex hormone receptor expression level and HBV integration features. Cox regression models, combined with machine learning (ML) methods, were implemented to investigate the prognostic value of sex hormone receptors and HBV integrations concerning overall survival. We found high AR expression level was significantly associated with higher HBV integration levels (adjusted odds ratio [aOR] = 1.84, 95% confidence interval [CI]: 1.09-3.11, P for trend = 0.012), TERT integration (aOR = 2.34, 95% CI: 1.16-4.74, P for trend = 0.047), intergenic integration (aOR = 2.25, 95% CI: 1.20-4.24, P for trend = 0.021), and promoter integration (aOR = 1.81, 95% CI: 1.00-3.31, P for trend = 0.034). The inclusion of sex hormone receptors and HBV integrations in the predictive models led to improvements across all performance metrics in the Cox regression analyses (AUC improvement: 0.014 [Training], 0.026 [Validation]) and the ML (AUC improvement: 0.022 [Training]), although a slight deterioration in performance was noted in the ML validation set. The results suggested a relationship between AR expression level and HBV integration events, as well as the potential utility of HBV integration biomarkers and sex hormone receptor profiles in assessing post-surgical prognosis among HCC patients.

Humans↗

PubMed2025

HnRNPR promotes non-small cell lung cancer progression by protecting XB130 mRNA from XRN1- and DIS3L2-mediated degradation.

The adaptor protein XB130 is critically implicated in tumorigenesis. However, the mechanisms regulating its expression in tumors are not well understood. Our previous studies have identified hnRNPR as a potential binding protein of XB130 3'UTR in non-small cell lung cancer (NSCLC). This study aimed to clarify hnRNPR's role in NSCLC progression and its specific mechanisms regulating XB130 expression. The expression of hnRNPR in NSCLC and normal tissues was assessed using NSCLC tissue microarray and the TCGA database. Subsequently, in vitro and in vivo experiments were conducted to investigate the impact of hnRNPR on NSCLC cell proliferation and epithelial-mesenchymal transition (EMT) by modulating XB130 expression. The underlying molecular mechanisms of hnRNPR regulating XB130 expression were explored utilizing a range of molecular biology techniques including Western blotting, Real-time quantitative PCR, Immunohistochemistry, Dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation. We identified the overexpression of hnRNPR in NSCLC, with heightened hnRNPR levels significantly associated with poor prognosis in patients with lung adenocarcinoma. Functionally, hnRNPR overexpression promoted NSCLC cell proliferation and EMT and activated the Akt signaling pathway. Mechanistically, hnRNPR protected XB130 mRNA from XRN1- and DIS3L2-mediated degradation by binding to specific regions within XB130 3'UTR, consequently elevating XB130 expression. Lastly, XB130 overexpression counteracted the effects of hnRNPR silencing on NSCLC cells. Overall, our study unveils the potential of targeting the hnRNPR/XB130 axis as a promising therapeutic strategy for NSCLC.

Humans↗

PubMed2024

Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

Humans↗

PubMed2026

Genome-scale CRISPR screening uncovers SRSF6 as a target to sensitize hepatocellular carcinoma to radiotherapy.

BACKGROUND & AIMS: Radiotherapy confers clinical benefits to patients with hepatocellular carcinoma (HCC) across all stages, yet its clinical efficacy is limited by radioresistance. This study aimed to identify key regulators of HCC radiosensitivity through genome-wide functional screening. METHODS: A genome-wide CRISPR-Cas9 screen in Huh7 cells identified radiosensitivity regulators, with SRSF6 validated by siRNA knockdown and γ-H2AX assessment. Stable shRNA-mediated SRSF6 knockdown was established in Huh7 and HepG2 cells, followed by clonogenic, EdU incorporation, apoptosis, micronucleus, and comet assays. Mechanistically, RNA-seq, Western blotting, mRNA stability assays, RIP-qPCR, and RAD51 overexpression rescue assays were performed. The therapeutic potential of the SRSF6 inhibitor indacaterol was evaluated using MTS assays, HCC xenograft mouse models (BALB/c-nu/nu, n = 28), and HCC patient-derived organoids (PDOs) (n = 3). In addition, SRSF6 expression and its correlation with patient survival were analyzed using data from The Cancer Genome Atlas and a tissue microarray (n = 14 HCC and 14 paired adjacent non-tumorous liver samples). RESULTS: We identified the RNA-binding protein SRSF6 as a driver of HCC radioresistance. SRSF6 depletion enhanced the radiosensitivity of HCC cells (p <0.05-0.0001) by post-transcriptionally destabilizing the mRNAs of critical DNA repair genes (p <0.05-0.0001), thereby impairing radiation-induced DNA damage repair. The radiosensitizing effect of SRSF6 depletion was partially abrogated by ectopic overexpression of the core DNA repair protein RAD51 (p <0.05-0.001). Indacaterol exhibited cytotoxic effects on HCC cells (p <0.05-0.0001) and enhanced the antitumor efficacy of radiation in vivo (p <0.05-0.0001), as further validated across multiple HCC patient-derived organoids (p <0.05-0.0001). CONCLUSIONS: SRSF6 is a key regulator of HCC radioresistance through its post-transcriptional control of DNA repair capacity, and represents a novel therapeutic target to sensitize HCC to radiotherapy. IMPACT AND IMPLICATIONS: In this study, we performed a genome-wide CRISPR-Cas9 knockout library screen to dissect the molecular determinants governing HCC radiosensitivity, and identified RNA-binding protein SRSF6 as a driver of HCC radioresistance. We demonstrate that SRSF6 depletion disrupts the post-transcriptional stability of key DNA repair gene mRNAs and enhances HCC radiosensitivity. These findings are important for radiation oncologists and translational researchers, as they identify SRSF6-dependent RNA regulation as a critical determinant of radiotherapy response in HCC. Practically, we show that the clinically approved bronchodilator indacaterol suppresses SRSF6 function and enhances the antitumor efficacy of radiotherapy, offering a readily repurposable pharmacological strategy to overcome radioresistance. These implications are based on preclinical evidence across multiple models; however, future clinical trials are needed to validate the safety and efficacy of indacaterol-based radiosensitization in patients with HCC.

DNA repair↗

PubMed2026

Proteomics in environmental pollution research: Advances, challenges, and future directions.

Environmental proteomics has emerged as a powerful approach for elucidating the molecular mechanisms underlying pollutant-induced biological effects. Although this field has developed rapidly, the systematic review of recent proteomics applications in environmental pollution research remains limited. This review explored the emerging roles of toxicoproteomics in biomarker discovery and mechanistic elucidation, as well as ecotoxicoproteomics in ecological risk assessment and bioremediation strategies. Here, we review the field, highlighting recent trends such as the integration of proteomics with genomics, transcriptomics, and metabolomics to provide a comprehensive view of biological responses to environmental stressors. We further discuss the growing application of artificial intelligence in improving proteomics data interpretation and accelerating biomarker discovery. In addition, recent technological advances in environmental proteomics are highlighted, including next-generation tissue microarray proteomics, nanoscale proteomics, single-cell proteomics, and spatial proteomics. Despite its potential, proteomics faces challenges, such as high operational costs, computational complexity in analysis, and technical limitations in low-abundance protein detection. We propose that the convergence of proteomics with artificial intelligence and multi-omics approaches offers promising solutions to these challenges, enhancing the practical application of proteomics in environmental monitoring and risk assessment.

Proteomics↗