搜索结果：proliferation

Hepatocellular carcinoma (HCC) involves abnormal alterations in cellular homeostasis regulation and molecular crosstalk between hepatic stellate cells (HSCs) and hepatocytes, and the underlying mechanisms are highly complex. Recent evidence suggests that HSCs exhibit obvious plasticity, are activated by stress stimuli such as carcinogens, and participate in HCC occurrence and progression through crosstalk with hepatocytes. MARVELD1 is a newly reported regulator of genomic stability closely associated with malignant tumors. However, the relationship between MARVELD1-mediated hepatocyte homeostasis and the crosstalk axis from HSCs remains unclear. Diethylnitrosamine (DEN)-induced HCC models were established using both systemic and hepatocyte-specific MarvelD1 knockout mice. Micro-CT scans were employed to track liver lesions after DEN treatment. RNA sequencing was used to analyze the molecular features of early liver injury after DEN treatment. H&E, immunohistochemistry, immunofluorescence, and qRT‒PCR were performed to evaluate HSC activation. Furthermore, an experimental procedure was used to obtain conditional medium (CM) from DEN-treated LX2 cells, and ELISA was used to determine the CCL5 concentration in CM. Antibody-blocking experiments were conducted to assess the interaction between CCL5 secreted by LX2 cells and CCR5 on hepatocytes during carcinogen-induced transformation of MarvelD1-deficient hepatocytes and its effect on cell proliferation and NF-κB pathway activation. CCK8 assays were used to evaluate the proliferation of MARVELD1-overexpressing HepG2 and MARVELD1-knockdown PLC/PRF/5 cells treated with CM from DEN-treated LX2 cells. Western blotting and qRT‒PCR were performed to evaluate the expression levels of the differentially expressed genes and proteins. Mouse primary HSCs and hepatocytes, either wild-type or MarvelD1 deficient, were used to validate the above findings and the expression patterns after DEN treatment. MarvelD1-deficient mice exhibited early-onset of HCC. In MarvelD1-deficient hepatocytes, metabolic, cancer and inflammatory response pathways, which represent early events, were upregulated in the context of early liver injury following DEN exposure. HSCs were activated early after DEN exposure and secreted active molecules that stimulate malignant proliferation of MarvelD1-deficient hepatocytes. The results of antibody-blocking experiments revealed that the interaction of CCL5 secreted by LX2 cells with CCR5 in hepatocytes is a crucial crosstalk axis for carcinogen-induced MarvelD1-deficient hepatocyte proliferation and canonical NF-κB signaling pathway activation. The expression patterns in HSCs and hepatocytes mediated by MarvelD1 involved the CCL5/CCR5-initiated NF-κB pathway and cancer-related factors after DEN treatment. The CCL5/CCR5 axis is involved in crucial crosstalk between activated hepatic stellate cells and MarvelD1-deficient hepatocytes during the early stages of DEN exposure. MarvelD1 plays an important regulatory role in maintaining NF-κB signaling homeostasis in hepatocytes to inhibit cell proliferation.

Intrahepatic cholangiocarcinoma (ICC) is known for its aggressive behavior and poor prognosis, but the role of dysregulated KMT2A in this cancer is not well understood. The study aimed to determine whether KMT2A functions as an oncogene in the development of ICC. The Cancer Genome Atlas (TCGA) provided the expression profiles of KMT2A in CHOL, which were then validated with clinical ICC samples from the Human Protein Atlas (THPA). The biological function of KMT2A was evaluated using plate colony formation and CCK8 assays. A joint analysis of public data, CHIP-PCR, Western Blotting, and RT-qPCR was carried out to provide mechanistic insights. The expression levels of KMT2A were notably elevated in tumor samples compared to healthy samples. When KMT2A was overexpressed in ICC cells, cell proliferation was significantly enhanced, while its knockdown resulted in the opposite outcome. Furthermore, KMT2A elevated H3K4me3 in the JAK2 promoter region, thereby promoting JAK2 expression. It was found that activating JAK2/STAT3 could lessen the suppression of ICC proliferation caused by KMT2A knockdown. In this study, a series of experiments was conducted. First, through public databases, we discovered that KMT2A expression was significantly higher in intrahepatic cholangiocarcinoma than in normal tissue. Furthermore, KMT2A promoted the proliferation of ICC cells. Finally, our findings indicate that KMT2A exerts its function, at least in part, by activating the JAK2/STAT3 signaling pathway via enhanced H3K4 trimethylation and increased JAK2 transcription. KMT2A was significantly upregulated in intrahepatic cholangiocarcinoma and elevated H3K4me3 levels at the JAK2 promoter, leading to higher JAK2 expression and activation of the JAK2/STAT3 pathway, which, in turn, stimulated ICC cell proliferation. This study offers novel insights into the potential of KMT2A as both a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by pathological bone formation. Synovial fibroblasts are key effector cells in this process, and their dysregulated osteogenic transformation is a critical event. The role of microRNA‑21 (miR‑21) and the mitogen-activated protein kinase (MAPK)/nuclear factor kappa-B‌ (NF‑κB) pathway in inflammation and bone metabolism is established; however, whether miR‑21 promotes AS fibroblast osteogenesis specifically via this pathway is unclear. This study aimed to determine whether miR-21 promotes osteogenic transformation and bone metabolism in AS synovial fibroblasts via the MAPK/NF‑κB pathway. Gain‑ and loss‑of‑function of miR‑21 was achieved in AS synovial fibroblasts by transfection with miR‑21 mimic or inhibitor, followed by evaluation of proliferation, osteogenic differentiation (alkaline phosphatase/alizarin red staining), and MAPK/NF‑κB pathway activity. In a proteoglycan‑induced arthritis (PGIA) mouse model, miR‑21 was inhibited by Antagomir to assess spinal pathology, serum inflammatory cytokines, bone metabolism markers, and MAPK/NF‑κB signaling. In vitro, miR-21 overexpression significantly promoted fibroblast proliferation, osteogenic differentiation, and activated the MAPK/NF-κB pathway, while its inhibition had opposite effects. In vivo, AntagomiR-21 treatment ameliorated spinal cartilage damage, reduced serum levels of inflammatory cytokines (IL-6, IL-1β, TNF-α) and bone metabolism markers (RANKL/OPG), and suppressed the MAPK/NF-κB pathway in PGIA mice. Our findings suggest that miR-21 is associated with synovial fibroblast proliferation and osteogenesis, potentially via the MAPK/NF‑κB pathway, and that its inhibition alleviates inflammatory arthritis phenotypes in mice. These observations indicate that miR‑21 may warrant further investigation as a candidate target in AS-related inflammation and cartilage pathology.

Hyaluronan (HA) is a key component of the pericellular and extracellular matrix and is synthesized by both non-hematopoietic and myeloid cells. In this study, we demonstrate that adaptive immune T cells not only respond to exogenously added high-molecular-weight HA by reducing proliferation but also generate an endogenous HA-rich glycocalyx in a stage-specific manner, as shown by fluorescence assisted carbohydrate electrophoresis and imaging studies. HA in the glycocalyx of naive CD4+ T cells, localized with the HA-binding proteoglycan, versican (VCAN). During differentiation into effector subsets, pericellular HA/VCAN is removed, with HA detected intracellularly, often co-localized with CD44. Hyaluronan synthase 3 (HAS3) is the predominant enzyme in naive CD4+ T cells, as HAS3-deficient T cells display minimal surface HA and exhibit extensive proliferation. We discuss the significance of the metabolic turnover of the HA/VCAN glycocalyx in T cells as a mechanism to regulate activation and proliferation.

Cancer therapies based on differentiation processes are strategies that try to induce the maturation of cancer cells into a differentiated and not proliferating state, aiming in this way to arrest the tumor growth. While conventional therapies often lack specificity and can harm normal cells, differentiation strategies have shown to be promising but they still remain limited in clinical application. Electrical stimulation (ES), which should not be confused with electroporation, has been shown to induce specific cellular responses, including differentiation. Here we showed that voltage-controlled biphasic pulses at 500 mV/mm and 100 Hz suppresses proliferation and promotes neuronal differentiation in the neuroblastoma cell line N2a, both in monolayer and 3D neurosphere cultures. The morphological changes induced by ES associated with neuronal differentiation, downregulated proliferation markers (H3S10ph and Ki-67), modulated neuronal differentiation markers (Neurod1 and SOX2) and reduced colony and neurosphere formation, all this without causing DNA damage. Therefore, ES represents a non-genotoxic mechanism to halt tumor cell growth, distinguishing it from standard cytotoxic therapies. These findings suggest that ES offers a means to suppress proliferation and induce differentiation in neuroblastoma cells, providing a potential foundation for less harmful therapeutic strategies targeting this pediatric cancer.

Laser treatments are widely applied in aesthetic and clinical dermatology to promote skin rejuvenation by inducing controlled tissue disruption, activating repair processes involving keratinocyte proliferation, fibroblast migration, and extracellular matrix remodeling. However, the cellular specialization and intercellular communication mechanisms, particularly in the early stages following laser treatment, remain poorly understood. Using single-cell RNA sequencing, we analyzed laser-treated and untreated skin, revealing significant differences in cell populations and functions. Keratinocytes and fibroblasts displayed the most prominent shifts in cell number and transcriptional diversity following laser exposure. In early-stage laser-induced skin remodeling, distinct keratinocyte subpopulations actively orchestrated skin repair, immune responses, and regenerative signaling. Cell-cell communication analysis uncovered a dynamic crosstalk between keratinocytes and fibroblasts. Functional validation through co-culture revealed this crosstalk was mediated by exosomes derived from laser-treated keratinocytes, which were enriched with CEBPA. Mechanistically, these exosomes enhanced keratinocyte proliferation through YAP/TAZ activation, while concurrently suppressing fibroblast activity by upregulating IGFBP3 expression during the early phase of laser-induced skin remodeling. Our findings provide new insights into how laser treatments modulate cellular behavior and intercellular signaling, emphasizing the therapeutic potential of exosome-based strategies for promoting skin regeneration and rejuvenation.

USP37 plays a pivotal role in cell cycle regulation, oncogenesis and metastasis. So far, the precise mechanisms and function of USP37 in hepatocellular carcinoma (HCC) remain unclear. In this study, we found USP37 expression was significantly elevated in HCC tissues compared to adjacent normal tissues and high expression was negatively correlated with patient prognosis. Functional assays including CCK-8, EdU staining, colony formation assays, patient derived organoids, transwell assays, wound healing, and in vivo models demonstrated that USP37 significantly promoted proliferation and migration of HCC cells. Mechanistically, USP37 interacted with RAF1, enhancing its protein stability and activating the ERK signaling pathway. This study identifies a novel mechanism by which USP37 promotes HCC cell proliferation through stabilizing RAF1 and activating the RAF-ERK signaling pathway. These findings highlight USP37 as a potential therapeutic target for HCC.

A 7-year-old male patient presented to Jinan Mingshui Eye Hospital (Jinan, China) in June 2025 with a 3-month history of a progressively enlarging mass on the right upper eyelid. The lesion was asymptomatic, with no associated pain, redness or discharge. Physical examination revealed a well-defined, smooth, yellow-red, round mass measuring ~6x5x5 mm at the medial canthus of the right upper eyelid, adjacent to the upper lacrimal punctum. Under general anesthesia, the tumor was completely excised in June 2025. Histopathological examination showed squamous epithelium overlying proliferations of small spindle cells, mitotic figures and scattered Touton-like giant cells. Immunohistochemistry revealed positive staining for CD68, CD163, S-100, CD1a, CD10 and anaplastic lymphoma kinase (ALK), with a Ki-67 proliferation index of ~10%. A diagnosis of ALK-positive epithelioid fibrous histiocytoma (EFH) was established. Postoperative recovery was uneventful, with no recurrence observed during a 6-month follow-up period. This case highlights an unusual presentation of EFH in a pediatric eyelid, where a rare tumor that occurred in the eyelid of a 7-year-old child was accurately diagnosed through a set of immunohistochemical panels containing tissue cell markers (CD68 and CD163), melanoma cell markers (S-100), dendritic cell markers (CD1a), mesenchymal cell markers (CD10) and ALK.

Prostate cancer (PCa) remains a major health challenge globally, necessitating the identification of novel therapeutic targets to improve patient outcomes. This study investigates the role of the SURF6 gene in PCa, focusing on its expression patterns, molecular mechanisms, and biological behaviours in vitro and in vivo. We employed a combination of bioinformatics analysis, gene expression profiling, Western blotting, and functional assays, including cell proliferation, migration, invasion, and stemness assays, to evaluate the impact of SURF6 modulation in PCa cell lines. Our findings demonstrate that SURF6 is significantly upregulated in PCa tissues compared to adjacent normal tissues, with elevated expression correlating with poor prognosis and advanced clinical stages. Functional assays revealed that silencing SURF6 inhibited PCa cell proliferation, migration, and invasion, while overexpression of SURF6 enhanced these malignant characteristics. Notably, we identified that SURF6 regulates CDK4 expression, which plays a pivotal role in cell cycle progression and maintenance of stem-like properties, as evidenced by the modulation of cancer stem cell markers such as CD44 and Nanog. Furthermore, we elucidated that METTL3 and YTHDF1 regulate SURF6 expression through m6A modification. In vivo experiments confirmed that knockdown of SURF6 inhibits tumour growth and reduces stemness features in xenograft models. Overall, our study underscores the critical role of SURF6 in promoting PCa progression and highlights its potential as a therapeutic target, paving the way for future research focused on targeting SURF6 in clinical settings to improve treatment strategies for PCa.

Fusobacterium nucleatum (F. nucleatum) is an oral commensal bacterium that acts as a pathobiont with pro-tumorigenic activity in various gastrointestinal cancers. However, its functional role, invasive capacity, and mechanistic contributions in cervical cancer remain largely unexplored. We identified F. nucleatum in cervical cancer tissues using bioinformatics and clinical 16S rRNA sequencing. Its spatial localization and intracellular presence were confirmed by fluorescence in situ hybridization (FISH) and transmission electron microscopy (TEM), respectively. Functional validation included in vitro assays for proliferation, migration, and apoptosis in cervical cancer cell lines, with bacterial invasion visualized by confocal microscopy, and in vivo tumor growth assessment in a xenograft model. The underlying mechanism involving high mobility group box 1 (HMGB1) and the NF-κB pathway was analyzed by western blot, qPCR, immunofluorescence, and ELISA. F. nucleatum was enriched in cervical cancer and correlated with poor patient survival. It invaded cervical cancer cells, promoted proliferation, migration, and invasion, suppressed apoptosis in vitro, and accelerated tumor growth in vivo. Mechanistically, infection triggered HMGB1 upregulation and specific activation of the canonical NF-κB pathway (via IκBα degradation, p65 phosphorylation/nuclear translocation), leading to selective secretion of IL-6/IL-8. Our study suggests that F. nucleatum is associated with cervical cancer malignancy, potentially acting through upregulation of HMGB1 and activation of the canonical NF-κB signaling pathway, thereby contributing to an altered tumor microenvironment. These findings reveal a previously unrecognized microbial-driven oncogenic mechanism in cervical cancer and highlight its potential as a prognostic marker and a therapeutic target. Not applicable in our manuscript.

Keloids are fibroproliferative dermal disorders characterized by excessive extracellular matrix deposition and a strong tendency to recur, yet the mechanistic links between inherited genetic variation, molecular phenotypes and disease risk remain incompletely understood. We integrated GTEx v8 skin expression quantitative trait loci (eQTL) data, pooled GWAS statistics for 338 cerebrospinal fluid (CSF) metabolites, and two independent European keloid GWAS datasets within a three-step Mendelian randomization (MR) framework to identify causal mediation pathways from skin gene expression through systemic metabolite levels to keloid susceptibility. Bulk RNA-seq, single-cell RNA-seq and in&#xa0;vitro fibroblast and smooth muscle cell experiments were then used to validate the functional roles of the prioritized genes and metabolites. Four CSF metabolites-sphingomyelin, 1-stearoyl-2-oleoyl-glycerophosphocholine (SOPC), N-acetylarginine and X-23593-were causally associated with increased keloid risk (OR >&#x2009;1) and replicated across both GWAS datasets. PARP14 emerged as a reproducible upstream risk gene (OR&#x2009;=&#x2009;1.17, 95% CI 1.02-1.34) coordinating effects across all four mediators, whereas ALDH2 was identified as a SOPC-mediated protective gene (OR <&#x2009;1). Single-cell profiling localized elevated PARP14 expression to smooth muscle cells and reduced ALDH2 expression to a disease-expanded mesenchymal fibroblast subset, with both signals embedded within canonical pro-fibrotic signaling programs (TGF-&#x3b2;, Wnt, Hippo, PI3K-Akt/mTOR, ECM-receptor interaction and focal adhesion). In&#xa0;vitro, SOPC and sphingomyelin produced dose-dependent fibroblast proliferation and induction of COL1A1, COL3A1, POSTN, and FN1, while modulation of PARP14 and ALDH2 by siRNA and lentiviral overexpression confirmed their roles in regulating proliferation and fibrotic marker expression. Together, these findings delineate a skin eQTL&#x2009;&#x2192;&#x2009;CSF&#x2009;metabolite&#x2009;&#x2192; cell-state axis in keloid pathogenesis, nominating PARP14, ALDH2 and SOPC-linked lipid remodeling as candidates for mechanistic study and therapeutic targeting.

Pancreatic cancer liver metastasis relies on crosstalk between pancreatic stellate cells (PSCs) and cancer cells, yet the role of transcriptional regulation in this interplay, particularly via macropinocytosis, remains unclear. Here, we aimed to explore a novel EGR1-driven pathway linking PSC function to cancer cell nutrient acquisition and liver metastasis. Single-cell RNA sequencing (scRNA-seq) was performed on human pancreatic cancer tissues to identify key regulators of PSC-cancer cell crosstalk. ChIP, EMSA, luciferase reporter assays, and western blotting were used to validate transcriptional regulation of GLUL by EGR1. Functional assays included cell proliferation, migration, invasion, and macropinocytosis analyses in co-culture systems. In vivo studies utilized a murine model of pancreatic cancer liver metastasis to assess the impact of the EGR1-GLUL/mTOR axis on metastasis. scRNA-seq identified EGR1 as a transcription factor enriched in PSCs, with strong co-expression of GLUL and mTOR pathway genes. EGR1 directly bound the GLUL promoter, promoting its transcription and activating mTOR signaling. This axis suppressed PSC activation (reduced &#x3b1;-SMA expression). EGR1 over-expressed PSCs inhibited pancreatic cancer cell macropinocytosis, leading to impaired nutrient uptake, reduced ATP production, and suppressed malignant behaviors (proliferation, migration, invasion). Additionally, the EGR1-GLUL/mTOR axis reduced liver metastasis in vivo. The EGR1-driven GLUL/mTOR axis in PSCs suppresses pancreatic cancer progression by inhibiting PSC activation, reducing cancer cell macropinocytosis, and restraining metastasis. This axis represents a promising therapeutic target for disrupting PSC-cancer cell crosstalk in pancreatic cancer.