The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging

Ghosh, Kanad; Capell, Brian C.

doi:10.1016/j.jid.2016.06.621

Cited by 119 publications

(99 citation statements)

References 91 publications

(105 reference statements)

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“…Emerging evidence has demonstrated that the cross‐talk between monocyte‐macrophage‐osteoclasts and bone marrow stromal cells (BMSCs)‐osteoblasts plays a vital role in the pathology of osteoporosis (Cao et al., 2005; Yu, & Wang, 2016). With organismal aging, molecules of the senescence‐associated secretory phenotype (SASP) are secreted into the bone microenvironment by senescent cells (Ghosh, & Capell, 2016; Lim, Park, Shin, Kwon, & Kim, 2017). These molecules attenuate osteogenic differentiation as well as promote adipogenic differentiation and senescence of BMSCs, which is considered to be the primary cause of osteoporotic bone loss (Riminucci, Remoli, Robey, & Bianco, 2015; Tsai, & Li, 2017).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

et al. 2018

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The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.

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Section: Introductionmentioning

confidence: 99%

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

et al. 2018

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“…However, we find that skin cancer induced elevation in the gene and protein expression of NFκB, TNF‐α and IL‐1β. It has been reported that skin cancer induced upregulation of NFκB pathway, which creates a permissive tumor microenvironment that helps the development of drug‐resistance . In addition, resistance to MAPK inhibitors takes place in tumors associated with transcriptional upregulation of NFκB‐driven inflammatory genes .…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that skin cancer induced upregulation of NFκB pathway, which creates a permissive tumor microenvironment that helps the development of drug-resistance. [36] In addition, resistance to MAPK inhibitors takes place in tumors associated with transcriptional upregulation of NFκB-driven inflammatory genes. [37] On the other hand, treatment of skin cancer with sulforaphane significantly reduced skin cancer-induced elevation in the gene and protein expression of the inflammatory pathway.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase‐2

Alyoussef

Taha

2018

Experimental Dermatology

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Although there are many treatment options for skin cancer, the chemotherapeutic agents for skin cancer are linked with many adverse effects as well as the development of multidrug resistance. Sulforaphane is an isothiocyanate, which is found in cruciferous vegetables. Consumption of sulforaphane‐rich diet has been linked to inhibition of UV‐exposed skin carcinogenesis. Therefore, the goal of this study was to determine the ability of sulforaphane to reduce skin cancer in mice through inhibition of sulfatase‐2 enzyme. Epicutaneous application of 7,12‐dimethylbenz (a) anthracene was performed on the shaved dorsal skin of mice followed by croton oil. Sulforaphane (9 μmol/mouse/day) was administered to mice orally. Skin was removed from the dorsal area for assessment of sulfatase‐2, glypican‐3, heparan sulphate proteoglycans (HSPGs), nuclear factor (NF)κB, nuclear factor E2‐related factor 2 (Nrf2), tumor necrosis factor (TNF)‐α, IL‐1β and caspase‐3. In addition, skin sections were stained with haematoxylin/eosin, Mallory and cytokeratin immunostaining. We found that, sulforaphane blocked sulfatase‐2 activity, leading to significant elevation in HSPGs as well as significant reduction in glypican‐3. In addition, sulforaphane significantly activated Nrf2 and reduced both the gene and protein expression of NFκB, TNF‐α, IL‐1β and caspase‐3. In parallel, stained sections obtained from skin cancer mice treated with sulforaphane showed significant reduction in hyperkeratosis, acanthosis and epithelial dysplasia. The collective results indicate that sulforaphane suppresses skin cancer via blocking sulfatase‐2 with subsequent elevation in HSPGs and reduction in glypican‐3. Moreover, sulforaphane attenuated skin cancer‐induced activation of inflammatory and apoptotic pathways.

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“…When a telomere reaches a critically short length, the cell stops dividing and reaches a state of cellular senescence, often referred to as the 'Hayflick limit' (16). The Hayflick limit has been demonstrated in a variety of adult cell types in vitro, including fibroblasts (10), endothelial cells (17) and lymphocytes (18), whereby cells exhibit progressively shorter telomeres over increasing passages (or "population doublings"), a gradual reduction in their ability to proliferate, a reduced propensity to undergo programmed cell death, and a maladaptive proinflammatory phenotype (19). The reduced replicative capacity of ageing cells is hypothesized to contribute to age-related tissue-level pathology in vivo; as old, damaged cells, can no longer be replaced with new, healthy cells (20).…”

Section: Introductionmentioning

confidence: 99%

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

Palmos

Duarte

Smeeth

et al. 2020

Preprint

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Telomere shortening is one hallmark of cell ageing that can limit the proliferative capacity of cell populations and increase risk for age-related disease. It has been hypothesized that short telomeres, and subsequently a limited proliferative capacity of hippocampal progenitor cells, could contribute to smaller hippocampal volumes and impaired cognition, amongst psychiatric disorder patients. The current study employed a systematic, multidisciplinary approach which aimed to model the effects of telomere shortening on human hippocampal neurogenesis, and to explore its relationship with cognition and psychiatric disorder risk. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Aged progenitors demonstrated shorter telomeres (p<0.05), and reduced rates of cell proliferation, as marked by bromodeoxyuridine staining (p<0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNAsequencing and gene set enrichment analysis revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts showed a significant overlap with genes regulating cognitive function and risk for schizophrenia and bipolar disorder. Collectively, our results suggest that reductions in adult hippocampal neurogenesis, caused by telomere shortening, could represent a cellular mechanism contributing to age-related cognitive impairment and psychiatric disorder risk.

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The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging

Cited by 119 publications

References 91 publications

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase‐2

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

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