Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis

Li, Yuejuan; Liang, Jiurong; Yang, Ting; Mena, Jessica E. Monterrosa; Huan, Caijuan; Xie, Ting; Kurkciyan, Adrianne; Liu, Ningshan; Jiang, Dianhua; Noble, Paul W.

doi:10.1016/j.matbio.2016.03.004

Cited by 80 publications

(66 citation statements)

References 61 publications

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“…The progressive loss of dermal hyaluronan is a hallmark of skin aging. A major factor that contribute to this loss is the aging-associated downregulation of HAS2 and HAS3 [8, 9]. Moreover, we measured the expression of the senescence-associated genes p53 [10], p21 upregulation [11], maspin[12], and IL-6 [13].…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of skin aging induced by EGFR inhibitors

Gerber

Buhren

Schrumpf

et al. 2016

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BACKGROUND The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes. OBJECTIVE To evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs. PATIENTS AND METHODS Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (< 25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro. RESULTS Progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA β-Gal activity. There was significantly decreased baseline expression in EGFR-density in aged skin, when compared to young controls. CONCLUSIONS EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.

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Section: Methodsmentioning

confidence: 99%

Mechanisms of skin aging induced by EGFR inhibitors

Gerber

Buhren

Schrumpf

et al. 2016

Support Care Cancer

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“…Recent studies by Paul Noble’s group have demonstrated that overexpression of HAS2 in murine mesenchymal cells regulates the invasiveness of fibroblasts and promotes pulmonary fibrosis [210]. Furthermore, this same group has shown that HAS2 controls fibroblast senescence [211] and that targeting HAS2 could be an attractive therapeutic approach to resolve tissue fibrosis. These studies however have been further complicated by studies from our own group [212] which showed that removal of hyaluronan from TGF-β-stimulated myofibroblasts promotes the fibrotic phenotype by increasing, rather than inhibiting, the expression and accumulation of collagen I and fibronectin (Figure 6).…”

Section: Dynamic Ecm Remodeling Of Hyaluronan and Versican: From Provmentioning

confidence: 99%

Provisional matrix: A role for versican and hyaluronan

2017

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Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular “coats” and “open space” that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican-enriched provisional matrix to collagen-rich matrix is a “hallmark” of tissue fibrosis .Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention.

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“…As one member of the HAS family, HAS-2 is also involved in synthesizing hyaluronan and cell proliferation, cell differentiation and even cellular inflammation [16]. In particular, the inhibition of HAS-2 in tumor cells would influence the cell cycle to further control cell proliferation [17]. HAS-2 has been reported to be over-expressed in breast cancer, and HAS-2 was demonstrated to be involved in the migration and invasion of breast cancer cells, suggesting that it might play a role in breast cancer metastasis [18,19].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Effects of HAS-2 Gene Silencing on the Proliferation and Apoptosis of the MCF-7 Human Breast Cancer Cell Line

Zhang¹,

Feng²,

Wang³

et al. 2016

Cell Physiol Biochem

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Background: Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. This study is aimed to investigate the effects of silencing the HAS-2 gene on the proliferation and apoptosis of human breast cancer cells. Methods: MCF-7 cells were collected and assigned into control, scrambled siRNA and HAS-2- siRNA groups. After transfection, the morphological changes in the MCF-7 cells were observed using phase contrast microscopy. qRT-PCR and Western blot assays were used to detect the mRNA and protein expression of apoptosis-related proteins. CCK-8 and flow cytometry were performed to evaluate cell proliferation, the cell cycle and apoptosis. Results: In the control and the scrambled siRNA groups, cells grew adhered to the wall and mainly showed a spindle shape with a clear nucleolus. Compared with the control and scrambled siRNA groups, increases in the number of cells in early apoptosis and metaphase cells in apoptosis were observed in the HAS-2-siRNA group. The HAS-2-siRNA group showed decreased expression of HAS-2 relative to that in the control and scrambled siRNA groups. No significant differences in cell proliferation, cell cycle distribution or apoptosis were noted between the control and scrambled siRNA groups. In the HAS-2-siRNA group, the cell proliferation ability decreased significantly, but the number of cells in the G0/G1 stage, the number of apoptotic cells and the expression of caspase-3 and caspase-9 increased significantly. Conclusion: Our findings indicate that HAS-2 gene silencing may inhibit proliferation and promote apoptosis in the MCF-7 human breast cancer cell line.

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Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis

Cited by 80 publications

References 61 publications

Mechanisms of skin aging induced by EGFR inhibitors

Mechanisms of skin aging induced by EGFR inhibitors

Provisional matrix: A role for versican and hyaluronan

In Vitro Effects of HAS-2 Gene Silencing on the Proliferation and Apoptosis of the MCF-7 Human Breast Cancer Cell Line

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