Cellular Senescence as a Brake or Accelerator for Oncogenic Transformation and Role in Lymphatic Metastasis

Banerjee, Priyanka; Gaddam, Niyanshi; Pandita, Tej K.; Chakraborty, Sanjukta

doi:10.3390/ijms24032877

Cited by 10 publications

(5 citation statements)

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“…Meanwhile, since zinc finger proteins have been implicated as transcription factors in cellular senescence and senescence is also associated with changes in ECM components and the role of senescent cells in invasiveness and lymphangiogenesis [ 23 , 24 ], we examined the expression patterns of the ZNF334 (a member of the C2H2 zinc finger family) and TINAGL1 (a new member of the matricellular ECM proteins family) genes in the lung SCC senescence state [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

Khashei Varnamkhasti,

Moghanibashi,

Naeimi

2024

J Transl Med

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Background The primary goal of this work is to identify biomarkers associated with lung squamous cell carcinoma and assess their potential for early detection of lymph node metastasis. Methods This study investigated gene expression in lymph node metastasis of lung squamous cell carcinoma using data from the Cancer Genome Atlas and R software. Protein-protein interaction networks, hub genes, and enriched pathways were analyzed. ZNF334 and TINAGL1, two less explored genes, were further examined through in vitro, ex vivo, and in vivo experiments to validate the findings from bioinformatics analyses. The role of ZNF334 and TINAGL1 in senescence induction was assessed after H2O2 and UV induced senescence phenotype determined using β-galactosidase activity and cell cycle status assay. Results We identified a total of 611 up- and 339 down-regulated lung squamous cell carcinoma lymph node metastasis-associated genes (FDR < 0.05). Pathway enrichment analysis highlighted the central respiratory pathway within mitochondria for the subnet genes and the nuclear DNA-directed RNA polymerases for the hub genes. Significantly down regulation of ZNF334 gene was associated with malignancy lymph node progression and senescence induction has significantly altered ZNF334 expression (with consistency in bioinformatics, in vitro, ex vivo, and in vivo results). Deregulation of TINAGL1 expression with inconsistency in bioinformatics, in vitro (different types of lung squamous cancer cell lines), ex vivo, and in vivo results, was also associated with malignancy lymph node progression and altered in senescence phenotype. Conclusions ZNF334 is a highly generalizable gene to lymph node metastasis of lung squamous cell carcinoma and its expression alter certainly under senescence conditions.

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Section: Resultsmentioning

confidence: 99%

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

Khashei Varnamkhasti,

Moghanibashi,

Naeimi

2024

J Transl Med

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“…Gene enrichment analysis revealed enrichment of pathways related to cellular senescence, oxidative stress, and other biological processes. Cellular senescence is commonly recognized as a tumor-suppressing mechanism; however, senescent cells also exhibit heightened invasiveness and lymphangiogenic capabilities attributed to the development of a senescence-associated secretory phenotype [ 34 ]. Recent studies report that cellular senescence is associated with the spatial evolution of colorectal cancer toward a more metastatic phenotype [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of metastasis-related genes for predicting prostate cancer diagnosis, metastasis and immunotherapy drug candidates using machine learning approaches

Wang,

Ji,

Zhang

et al. 2024

Biol Direct

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Background Prostate cancer (PCa) is the second leading cause of tumor-related mortality in men. Metastasis from advanced tumors is the primary cause of death among patients. Identifying novel and effective biomarkers is essential for understanding the mechanisms of metastasis in PCa patients and developing successful interventions. Methods Using the GSE8511 and GSE27616 data sets, 21 metastasis-related genes were identified through the weighted gene co-expression network analysis (WGCNA) method. Subsequent functional analysis of these genes was conducted on the gene set cancer analysis (GSCA) website. Cluster analysis was utilized to explore the relationship between these genes, immune infiltration in PCa, and the efficacy of targeted drug IC50 scores. Machine learning algorithms were then employed to construct diagnostic and prognostic models, assessing their predictive accuracy. Additionally, multivariate COX regression analysis highlighted the significant role of POLD1 and examined its association with DNA methylation. Finally, molecular docking and immunohistochemistry experiments were carried out to assess the binding affinity of POLD1 to PCa drugs and its impact on PCa prognosis. Results The study identified 21 metastasis-related genes using the WGCNA method, which were found to be associated with DNA damage, hormone AR activation, and inhibition of the RTK pathway. Cluster analysis confirmed a significant correlation between these genes and PCa metastasis, particularly in the context of immunotherapy and targeted therapy drugs. A diagnostic model combining multiple machine learning algorithms showed strong predictive capabilities for PCa diagnosis, while a transfer model using the LASSO algorithm also yielded promising results. POLD1 emerged as a key prognostic gene among the metastatic genes, showing associations with DNA methylation. Molecular docking experiments supported its high affinity with PCa-targeted drugs. Immunohistochemistry experiments further validated that increased POLD1 expression is linked to poor prognosis in PCa patients. Conclusions The developed diagnostic and metastasis models provide substantial value for patients with prostate cancer. The discovery of POLD1 as a novel biomarker related to prostate cancer metastasis offers a promising avenue for enhancing treatment of prostate cancer metastasis.

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“…The molecular coordination of the autophagy process involves five key stages ( 45 ) ( 1 ): the formation of a phagophore, also known as nucleation, is inhibited by mTOR. Factors such as hypoxia, low energy, and DNA damage can lead to a reduction in mTOR activity, inducing autophagy ( 2 ).…”

Section: Molecular Mechanisms Of Cgas-sting-mediated Inflammation Met...mentioning

confidence: 99%

“…In terms of viral infections, DNA viruses can directly activate cGAS, whereas RNA viruses can indirectly activate cGAS through mitochondria ( 68 ), which is beyond the scope of this article. Endogenous dsDNA can be further categorized into three types ( 1 ): nuclear DNA ( 2 ), mitochondrial DNA (mtDNA), and ( 3 ) retrotransposons. There are various mechanisms that lead to the accumulation of cytoplasmic DNA, such as telomere shortening, chromosomal damage, decreased nuclear membrane stability, mitochondrial dysfunction, and cytoplasmic DNA degradation obstacles.…”

Section: Production and Accumulation Of Ligands That Activate The Cga...mentioning

confidence: 99%

“…At the cellular level, the aging process involves the aging of related cells, the accumulation of senescent cells, the buildup of inflammatory factors, and metabolic imbalances. Cellular aging, represented by irreversible cell cycle arrest, can be classified into replicative senescence triggered by telomere shortening after a certain number of cell divisions (Hayflick limit) and premature senescence caused by various stressors (e.g., radiation, oxidative stress, activation of oncogenes) before reaching the Hayflick limit, also known as accelerated aging ( 1 , 2 ). Telomere shortening and stress-related DNA damage not only trigger cellular aging but also lead to cytoplasmic DNA accumulation and activation of cGAS-STING signaling.…”

Section: Introductionmentioning

confidence: 99%

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STING signaling in inflammaging: a new target against musculoskeletal diseases

Song

et al. 2023

Front. Immunol.

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Stimulator of Interferon Gene (STING) is a critical signaling linker protein that plays a crucial role in the intrinsic immune response, particularly in the cytoplasmic DNA-mediated immune response in both pathogens and hosts. It is also involved in various signaling processes in vivo. The musculoskeletal system provides humans with morphology, support, stability, and movement. However, its aging can result in various diseases and negatively impact people’s lives. While many studies have reported that cellular aging is a leading cause of musculoskeletal disorders, it also offers insight into potential treatments. Under pathological conditions, senescent osteoblasts, chondrocytes, myeloid cells, and muscle fibers exhibit persistent senescence-associated secretory phenotype (SASP), metabolic disturbances, and cell cycle arrest, which are closely linked to abnormal STING activation. The accumulation of cytoplasmic DNA due to chromatin escape from the nucleus following DNA damage or telomere shortening activates the cGAS-STING signaling pathway. Moreover, STING activation is also linked to mitochondrial dysfunction, epigenetic modifications, and impaired cytoplasmic DNA degradation. STING activation upregulates SASP and autophagy directly and indirectly promotes cell cycle arrest. Thus, STING may be involved in the onset and development of various age-related musculoskeletal disorders and represents a potential therapeutic target. In recent years, many STING modulators have been developed and used in the study of musculoskeletal disorders. Therefore, this paper summarizes the effects of STING signaling on the musculoskeletal system at the molecular level and current understanding of the mechanisms of endogenous active ligand production and accumulation. We also discuss the relationship between some age-related musculoskeletal disorders and STING, as well as the current status of STING modulator development.

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Cellular Senescence as a Brake or Accelerator for Oncogenic Transformation and Role in Lymphatic Metastasis

Cited by 10 publications

References 170 publications

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

Identification of metastasis-related genes for predicting prostate cancer diagnosis, metastasis and immunotherapy drug candidates using machine learning approaches

STING signaling in inflammaging: a new target against musculoskeletal diseases

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