Escape from TGF‐β‐induced senescence promotes aggressive hallmarks in epithelial hepatocellular carcinoma cells

Molecular Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Transforming growth factor‐β (TGF‐β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. Despite provoking senescence‐associated arrest in epithelial HCC cells, elevated TGF‐β activity paradoxically correlates with increased aggressiveness poor prognosis advanced tumors. Whether the transition between these dichotomous functions involves modulation phenotype during disease progression remains elusive. Exploiting cell line Huh7 as a robust model, we demonstrate that chronic exposure to prompts escape from Smad3‐mediated senescence, leading development resistance. This altered state is characterized by an optimal proliferation rate acquisition molecular functional traits less‐differentiated mesenchymal coinciding differential capacity 2D 3D culture conditions, epithelial‐to‐mesenchymal (EMT), invasiveness vitro , metastasis vivo . Mechanistically, resistant cells exhibit defective activation nuclear trafficking Smad molecules, particularly Smad3, ectopic TGF‐β/Smad3 axis able reinstate sensitivity. An integrated transcriptomic landscape reveals both shared distinct gene signatures associated senescent states. Importantly, genetic ablation studies identify microtubule affinity regulating kinase 1 (MARK1) glutamate metabotropic receptor 8 (GRM8) critical modulators resistance phenomenon, potentially impairing spatiotemporal dynamics activity. Our findings unveil novel phenomenon wherein may exploit plasticity mechanism oppose anti‐tumor responses progress towards more aggressive phenotypes.

Language: Английский

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Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword

Cancer Cell International, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 26, 2025

Abstract Multiple myeloma (MM) is a hematological malignancy defined by the abnormal proliferation and accumulation of plasma cells (PC) within bone marrow (BM). While multiple impacts bone, it not classified as primary cancer. The microenvironment significantly influences progression its treatment response. Mesenchymal stromal (MSCs) in this environment engage with other components via direct contact secretion soluble factors. This review examines established roles MSCs facets MM pathology, encompassing their pro-inflammatory functions, contributions to tumor epigenetics, effects on immune checkpoint inhibitors (ICIs), influence reprogramming, chemotherapy resistance, senescence. investigates role development MM.

Language: Английский

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The Landscape of lncRNAs in Multiple Myeloma: Implications in the “Hallmarks of Cancer”, Clinical Perspectives and Therapeutic Opportunities

Cancers, Journal Year: 2022, Volume and Issue: 14(8), P. 1963 - 1963

Published: April 13, 2022

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that not translated into proteins. Nowadays, lncRNAs gaining importance as key regulators of gene expression and, consequently, several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role pathogenesis multiple myeloma (MM). We focus on their ability to regulate processes identified “hallmarks cancer” enable malignant cell transformation, early tumor onset progression. The aberrant MM suggests potential use clinical biomarkers for diagnosis, patient stratification, management. Moreover, they represent ideal candidates therapeutic targeting.

Language: Английский

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Residual Foci of DNA Damage Response Proteins in Relation to Cellular Senescence and Autophagy in X-Ray Irradiated Fibroblasts

Cells, Journal Year: 2023, Volume and Issue: 12(8), P. 1209 - 1209

Published: April 21, 2023

DNA repair (DNA damage) foci observed 24 h and later after irradiation are called “residual” in the literature. They believed to be sites for complex, potentially lethal double strand breaks. However, features of their post-radiation dose-dependent quantitative changes role processes cell death senescence still insufficiently studied. For first time one work, a simultaneous study association number residual key damage response (DDR) proteins (γH2AX, pATM, 53BP1, p-p53), proportion caspase-3 positive, LC-3 II autophagic SA-β-gal senescent cells was carried out 24–72 fibroblast with X-rays at doses 1–10 Gy. It shown that an increase from 72 h, positive decrease, while cells, on contrary, increases. The highest noted 48 irradiation. In general, results obtained provide important information understanding dynamics development cellular populations irradiated fibroblasts.

Language: Английский

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Senescence in head and neck squamous cell carcinoma: relationship between senescence-associated secretory phenotype (SASP) mRNA expression level and clinicopathological features

Clinical & Translational Oncology, Journal Year: 2024, Volume and Issue: 26(4), P. 1022 - 1032

Published: Jan. 4, 2024

Abstract Background Cellular senescence is a state characterized by cell-cycle arrest and apoptotic resistance. Senescence in cancer may be induced oncogenes or therapy. While cellular might play an important role protection against development, elevated uncontrolled senescent cells accumulation promote carcinogenesis secreting collection of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Material methods We determined gene expression at mRNA level selected markers (p16 LMNB1) SASP factors (IL-6, IL-1b, CXCL-1 TNF-α) 72 cancerous tissues 64 normal obtained from patients with head neck squamous cell carcinoma (HNSCC) correlated this data patients’ clinical follow-up. Results Our results indicate higher levels compared to tissues. presented relationship between transcript progression disease. Moreover, we proposed CXCL1 as candidate biomarker differentiating ones IL1b molecular factor related increased TNM stage. Conclusion primary study indicates that associated some clinicopathological features. However, more detailed needed present specific senescence-related mechanism SASPs especially tumor therapy response relation patient’s immune system condition.

Language: Английский

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