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PubMed2025

Cyclin D1 Overexpression Predicts Poor Disease-Specific Survival in Human Papillomavirus-Independent Vulvar Squamous Cell Carcinoma.

The amplification of CCND1 is associated with the development and progression of various cancers. In a recent study, we showed that almost all adverse outcomes in vulvar squamous cell carcinomas (VSCC) occurred in patients with human papillomavirus (HPV)-independent, TP53-mutated tumors harboring CCND1 gains. In this study, we analyzed the association between CCND1 gain, cyclin D1 immunohistochemistry (IHC), and disease-specific survival (DSS) in a series of patients with HPV-independent VSCC. All patients who underwent primary surgery for VSCC at the Hospital Clínic of Barcelona, Spain, from 1975 to 2023 were recruited ("overall" cohort, n = 139). IHC for p53 and cyclin D1 was performed in all cases. In a subset of patients, we performed DNA sequencing to evaluate CCND1 copy number variations ("sequencing" cohort, n = 54). Cyclin D1 IHC overexpression (≥50% of tumor cells) had 94% sensitivity and 67% specificity as a surrogate marker of CCND1 gain. In the "sequencing" cohort, only CCND1 gains were significantly associated with impaired DSS in the multivariate analysis (hazard ratio [HR], 4.15; 95% CI, 1.08-5.40; P = .032), whereas stage or mutant TP53 status did not reach statistical significance. In the "overall" cohort, advanced stage (HR, 2.41; 95% CI, 1.08-5.39; P = .032) and cyclin D1 IHC overexpression (HR, 4.89; 95% CI, 1.77-18.5; P = .001) were associated with worse DSS in the multivariate analysis, whereas abnormal p53 IHC was not (HR, 5.06; 95% CI, 0.68-647; P = .138). In conclusion, cyclin D1 overexpression is an acceptable surrogate for CCND1 gain and has a much stronger adverse prognostic impact than altered p53 IHC in patients with HPV-independent VSCC.

Humans↗

PubMed2026

Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.

Animals↗

PubMed2026

Spatial Proteomic Profiling, a Novel Method for Detecting Diagnostic and Prognostic Proteins in Pediatric Sarcoma.

Pediatric sarcomas comprise approximately 10% of all childhood solid malignancies and are characterized by distinct genetic and proteomic alterations that have potential diagnostic, prognostic, and therapeutic significance. We have utilized digital spatial profiling (DSP) to identify protein expression in pediatric Ewing sarcoma (ES), Osteosarcoma (OS), Alveolar rhabdomyosarcoma (ARMS), and Embryonal rhabdomyosarcoma (ERMS), in association with clinical outcomes. Formalin-fixed, paraffin-embedded sections from a tissue microarray block containing eight ES, eight OS, five ARMS, and three ERMS cases were subjected to proteomic DSP on a GeoMx NanoString platform yielding information on expression of 580 proteins. Proteins related to epigenetic regulation, signaling pathways, and mesenchymal differentiation were broadly expressed across all tumor types. Tumor-specific protein profiles were defined based on highly expressed proteins. Differentially expressed proteins include Cyclin D1 in ES, S100A4 in OS and IKKi/IKKe in ARMS and ERMS. Immunohistochemical validation confirmed variable expression of H3K27me3 across the tumors, and elevated expression of Cyclin D1 in ES and S100 in OS. These findings underscore the utility of DSP as a high-resolution proteomic tool for the identification of clinically relevant biomarkers in pediatric sarcomas. The results provide a foundation for further investigation of candidate proteins with potential diagnostic, prognostic, and therapeutic applications.

Humans↗

PubMed2019

Network pharmacology exploration reveals the bioactive compounds and molecular mechanisms of Li-Ru-Kang against hyperplasia of mammary gland.

Li-Ru-Kang (LRK) has been commonly used in the treatment of hyperplasia of mammary gland (HMG) as a cipher prescription and achieved obvious therapeutic effects. However, the bioactive compounds and underlying pharmacological mechanisms remain unclear. This study aims to decipher the bioactive compounds and potential action mechanisms of LRK in the treatment of HMG using an integrated pharmacology approach. The ingredients of LRK and the corresponding drug targets were retrieved through drug target databases and were used to construct the "compound-target-disease" network and function-pathway network. Ultimately, 89 compounds and 2150 drug targets were collected. Gene ontology enrichment analysis revealed that mammary gland alveolus development and mammary gland lobule development were the key biological processes and were regulated simultaneously by three direct targets, including androgen receptor (AR), estrogen receptor (ER) and cyclin-D1. Moreover, 14 compounds of LRK were directly involved in the regulation of the three aforementioned targets. KEGG pathway enrichment analysis found that five signaling pathways and seven direct targets were closely related with HMG treatment by LRK. The results of animal experiments showed that LRK significantly improved the histopathological status of HMG in rats. Additionally, LRK markedly regulated the protein expressions of AR, cyclin-D1, MMP2, MMP3 and MMP9. But interestingly, the effect of LRK on ER was not obvious. This study demonstrated that LRK exerted its therapeutic efficacy based on multi-components, multi-targets and multi-pathways. This research confirms the advantages of network pharmacology analyses and the necessity for experimental verification.

Animals↗

PubMed2026

Multi-cohort integration and machine learning identify CPVL as a novel oncogenic driver in gastric cancer.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, and the prognosis of advanced GC remains poor. Systematic identification of robust biomarkers through multi-cohort integration and computational prioritization may facilitate the discovery of novel therapeutic targets. AIM: To identify key genes associated with gastric cancer progression through integrative multi-omics analysis and to elucidate the biological functions and molecular mechanisms of the top-prioritized candidate gene. METHODS: Comprehensive bioinformatics analyses integrating The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets were performed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), Cox regression, and eight machine-learning algorithms to systematically identify and prioritize GC-associated hub genes. Among the identified candidates, CPVL was selected for further validation based on its diagnostic and prognostic performance. CPVL expression and clinical relevance were validated by independent datasets and immunohistochemistry. Lentiviral constructs were used to overexpress or silence CPVL in GC cell lines. Functional assays were performed, including CCK-8, colony formation, EdU incorporation, and flow cytometry, to assess cell proliferation and cell-cycle distribution. Western blotting and JAK2 inhibitor (AZD1480) rescue experiments were performed to elucidate the underlying mechanisms, and a nude mouse xenograft model was used to evaluate tumorigenicity in vivo. RESULTS: Multi-cohort screening identified five hub genes (CPVL, AADAC, BCAT1, CPXM1, and FBN1). Among them, CPVL exhibited the highest diagnostic accuracy (AUC = 0.895) and the strongest correlation with poor overall survival, and was therefore selected for mechanistic investigation. CPVL expression was markedly upregulated in GC tissues and cell lines. Functional assays demonstrated that CPVL promotes GC cell proliferation and accelerates G1/S-phase transition. Mechanistically, CPVL activated the JAK2/STAT3 signaling pathway, upregulating Cyclin D1 and CDK4 while downregulating p27. Treatment with the JAK2 inhibitor AZD1480 partially reversed these effects. In vivo, CPVL knockdown significantly inhibited tumor growth. CONCLUSION: Through systematic multi-cohort integration and machine-learning prioritization, CPVL was identified as a novel oncogenic driver in gastric cancer. CPVL promotes tumor growth via activation of the JAK2/STAT3 pathway and regulation of the Cyclin D1/CDK4/p27 axis, highlighting its potential as a diagnostic biomarker and therapeutic target.

Biomarker↗

PubMed2025

Exploring the Genetic Landscape of Primary Marginal Zone Lymphoma of the Urinary Bladder.

Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 women and 6 men) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed the literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a and negative for CD5 (except 1), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ and 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of 1 patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B, and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a point mutation-driven disease rather than gene fusion-driven disease and that E coli is present in approximately one-third of tumor biopsies. These tumors frequently harbor pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which was unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma; however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.

Humans↗

PubMed2025

Uterine Sarcomas With Recurrent KDM2B Gene Fusions: Three Cases of a Possible Novel Subtype of High-Grade Endometrial Stromal Sarcoma.

The advent of widespread genomic testing of uterine mesenchymal tumors has led to novel insights into the biology of these diverse tumors, and many genomically defined entities have been described in recent years. During a larger study of endometrial stromal sarcomas and unclassified uterine sarcomas, we identified 3 tumors harboring KDM2B gene fusions. Patients were 32, 61, and 67 years old, and all initially underwent incomplete sampling via laparoscopic myomectomy (n = 1), laparoscopic biopsy (n = 1), or hysteroscopic myomectomy (n = 1). One patient's tumor was densely adherent to the pelvic sidewall; she was treated with chemotherapy and died of widely metastatic disease at 29 weeks. Another underwent a subsequent recent hysterectomy with the tumor confined to the uterus and minimal follow-up to date. The final patient refused further treatment and was alive at 28 weeks, although the status of the disease progression was unknown. On microscopic examination, 2 tumors showed infiltrative borders, whereas interface with the myometrium was not present in the third. The tumors were variably cellular with alternating hypercellular and hypocellular zones in a myxoid to loosely collagenous stroma. The hypercellular areas contained round to ovoid cells in diffuse (n = 3) and sex cord-like arrangements, including cords (n = 3), nests (n = 2), and tubules (n = 1); 2 also contained occasional spindled cells arranged in vague fascicles. These cells showed moderate atypia with open chromatin, numerous mitoses (8, 24, and 25 per 10 high-power fields), and frequent apoptosis. The hypocellular areas contained sparse, ovoid-to-spindled cells with minimal atypia. All tumors were diffusely positive for cyclin D1, whereas BCL6 corepressor was diffusely positive in 1 and negative in 2; desmin and caldesmon were negative in all 3 neoplasms. All harbored KDM2B gene fusions; partner genes included EPC1, EP400, and CITED1. MDM2 amplification was also noted in 2. Clustering analysis based on RNA expression profiling revealed tight clustering of all 3 tumors within the broad group of high-grade endometrial stromal sarcomas. Based on the overall clinicopathologic and genomic features, we suggest that these tumors may represent a novel subtype of uterine sarcoma and may be best classified as high-grade endometrial stromal sarcoma, although additional confirmatory studies are needed.

Humans↗

PubMed2026

Uterine Leiomyomas Presenting During Pregnancy and Delivery: Comprehensive Characterization of Features Helpful in the Distinction From Malignant Mimics.

A subset of uterine leiomyomas becomes clinically apparent during pregnancy/delivery and is typically excised during Cesarean section. Although benign, these leiomyomas excised during pregnancy and/or delivery (LEPs) can pose diagnostic challenges due to morphologic changes that mimic malignant mesenchymal neoplasms, such as leiomyosarcoma. This study analyzed 97 LEPs to characterize their histopathologic and immunohistochemical features. Histologic examination revealed predominantly low mitotic activity (mean: 0.5 mitoses/10 HPFs) and mild (87.6% of tumors) to at most focal moderate (9.3% of tumors) nuclear atypia. Ischemic necrosis occurred in 57.7% of tumors. Features attributed to coagulative necrosis were common, including sharp viable-nonviable transition (22.7%), perivascular tumor preservation (9.3%), and ghost outlines of tumor cell nuclei (50.5%). Focal myxoid changes, affecting ≤30% of tumor volume, were seen in 42.3% of tumors. Rare, bizarre cells were identified in 48.5% of tumors. Immunohistochemistry demonstrated the absence of estrogen receptor staining in 65% of tumors, with focal staining in 35.2%, and progesterone receptor expression in 97.7%. Caldesmon (98.9%) and desmin (100%) were positive, with the majority diffuse. CD10 (100%) showed variable staining intensity. Wild-type p53 expression was seen in all tumors tested. Expression of ATRX, MTAP, RB1, and PTEN was predominantly retained with equivocal staining in 35.3% (ATRX) and 3.4% (RB1) of tumors. Although Cyclin D1 expression was common (97.4%), it was always focal, with no diffuse (≥70%) strong nuclear staining. FH loss occurred in 3.2% of tumors. All tumors were negative for MelanA, and 92.4% were negative for HMB45. Calretinin expression was observed in 39% of tumors, typically focal and strong, while only 1 tumor showed positive inhibin staining in <5% of cells. ALK expression was focally positive or equivocal in 9.6% of cases, but no gene rearrangements were identified by in situ hybridization. Follow-up data were available for 71 patients (mean: 56 mo), with no malignant transformation or recurrence. These findings confirm that LEPs exhibit distinct morphologic and immunophenotypic alterations, including features typically attributed to coagulative tumor cell necrosis. However, given benign clinical outcomes, low mitotic activity, and lack of significant atypia, such a finding does not warrant designation as leiomyosarcoma or smooth muscle tumor of uncertain malignant potential in the context of concurrent pregnancy.

Female↗

PubMed2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

Journal Article↗

PubMed2026

Establishment of Stable Immortalized Human Choroidal Melanocytes for Ocular Research.

PURPOSE: The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. METHODS: NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. RESULTS: NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. CONCLUSIONS: NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.

Humans↗

PubMed2026

The role of miRNA-32 in non-small cell lung cancer.

BACKGROUND: This study aimed to investigate whether miRNA-32 affects the proliferation and migration of non-small cell lung cancer (NSCLC) cells by regulating the expression of myocyte enhancer factor 2D (MEF2D). METHODS: Quantitative real-time polymerase chain reaction was utilized to evaluate the expression levels of miRNA-32 in clinical NSCLC tissue specimens and cell lines. Western blotting was employed to detect the protein expression levels of MEF2D, E-cadherin, N-cadherin, and CyclinD1, as well as to verify transfection efficiency. Cell proliferation and migration were assessed using Cell Counting Kit-8 and Transwell assays, respectively. Additionally, a dual-luciferase reporter gene assay was performed to validate the targeted regulatory relationship between miRNA-32 and MEF2D. RESULTS: miRNA-32 was significantly downregulated in lung cancer tissues and cell lines, whereas MEF2D exhibited significant upregulation. High miRNA-32 expression correlated with poor clinical outcomes in NSCLC across both our in-house cohort and the TCGA cohort. The stable overexpression of miRNA-32 in lung cancer cells markedly inhibited their proliferation and migratory capabilities. Mechanistically, miRNA-32 inhibited the translation of MEF2D by directly binding to its 3'UTR region. Crucially, the overexpression of MEF2D significantly reversed the inhibitory effects of miRNA-32 on lung cancer cell proliferation and migration. CONCLUSION: The miRNA-32/MEF2D signaling axis plays a pivotal role in the proliferation and metastasis of NSCLC, highlighting its potential as a diagnostic biomarker and prognostic indicator for the disease.

Humans↗