Induction of premature senescence and a less-fibrogenic phenotype by programmed cell death 4 knockdown in the human hepatic stellate cell line Lieming Xu-2

Although programmed cell death 4 (PDCD4) was initially reported as a tumor suppressor and has been shown to inhibit cancer cell growth and metastasis, recent studies have demonstrated that loss of PDCD4 expression also induces growth inhibition by inducing apoptosis and/or cellular senescence. At pr...

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Published in:Human cell : official journal of Human Cell Research Society 2023-03, Vol.36 (2), p.583-601
Main Authors: Perveen, Rasheda, Ozaki, Iwata, Manirujjaman, M., Mine, Keiichiro, Murata, Yuzo, Tanaka, Kenichi, Xia, Jinghe, Takahashi, Hirokazu, Anzai, Keizo, Matsuhashi, Sachiko
Format: Article
Language:English
Subjects:
Actin
Apoptosis
Apoptosis Regulatory Proteins - genetics
Biomedical and Life Sciences
Cell Biology
Cell death
Collagen (type III)
Collagen (type IV)
Collagen - metabolism
Fibrosis
Gelatinase B
Genotype & phenotype
Gynecology
Hepatic Stellate Cells
Humans
Interstitial collagenase
Life Sciences
Liver
Matrix metalloproteinase
Metalloproteinase
Metastases
Oncology
Phenotype
Phenotypes
Reproductive Medicine
Research Article
RNA-Binding Proteins - genetics
Senescence
Smooth muscle
Stem Cells
Surgery
Tissue inhibitor of metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1 - genetics
Tissue Inhibitor of Metalloproteinase-1 - metabolism
Tumor suppressor genes
β-Galactosidase
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Summary:Although programmed cell death 4 (PDCD4) was initially reported as a tumor suppressor and has been shown to inhibit cancer cell growth and metastasis, recent studies have demonstrated that loss of PDCD4 expression also induces growth inhibition by inducing apoptosis and/or cellular senescence. At present, the roles of PDCD4 in the activation and profibrogenic properties of myofibroblasts, which are critically involved in organ fibrosis, such as that in the liver, are unclear. We, therefore, investigated the roles of PDCD4 in myofibroblasts using human hepatic stellate cell line Lieming Xu-2 (LX-2). PDCD4 knockdown inhibited LX-2 proliferation and induced a senescent phenotype with increased β-galactosidase staining and p21 expression in a p53-independent manner together with downregulation of the notch signaling mediator RBJ-κ/CSL. During PDCD4 knockdown, alpha smooth muscle actin (α-SMA; an activation marker of myofibroblasts), matrix metalloproteinases MMP-1 and MMP-9, and collagen IV were upregulated, but the expression of collagen1α1 and collagen III was markedly downregulated without any marked change in the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). These results demonstrated that knockdown of PDCD4 induced the cellular senescence phenotype and activated myofibroblasts while suppressing the profibrogenic phenotype, suggesting roles of PDCD4 in cellular senescence and fibrogenesis in the liver.
ISSN:1749-0774
0914-7470
1749-0774
DOI:10.1007/s13577-022-00844-9