GATA6 triggers fibroblast activation and tracheal fibrosis through the Wnt/β-catenin pathway

Li, Anmao; Gu, Lei; Mu, Junhao; Li, Yishi; Wang, Xiaohui; Jiang, Jinyue; Bai, Yang; Yang, Mingjin; He, Chunyan; Xiao, Rui; Liao, Jiaxin; Jin, Xingxing; Xiao, Meiling; Xiao, Yang; Zhang, Xia; Tan, Tairong; Peng, Mingyu; Xu, Li; Guo, Shuliang

doi:10.1016/j.cellsig.2023.110593

Cited by 4 publications

(3 citation statements)

References 35 publications

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“…Numerous perturbations altered the expression of this gene program in both directions. Strong inducers included PLAGL1, PLAG1, GATA6, and EGR3, with the latter two being previously reported as possible mediators of fibrogenic responses 87,88 . Conversely, strong suppressors included NEUROD2, FOXE1, FOXA3, and KLF5.…”

Section: Transcription Factor Perturbations Driving Markers Of In Viv...mentioning

confidence: 86%

Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states

Southard,

Ardy,

Tang

et al. 2024

Preprint

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SummaryCell atlas projects have nominated recurrent transcriptional states as drivers of biological processes and disease, but their origins, regulation, and properties remain unclear. To enable complementary functional studies, we developed a scalable approach for recapitulating cell statesin vitrousing CRISPR activation (CRISPRa) Perturb-seq. Aided by a novel multiplexing method, we activated 1,836 transcription factors in two cell types. Measuring 21,958 perturbations showed that CRISPRa activated targets within physiological ranges, that epigenetic features predicted activatable genes, and that the protospacer seed region drove an off-target effect. Perturbations recapitulatedin vivofibroblast states, including universal and inflammatory states, and identifiedKLF4andKLF5as key regulators of the universal state. Inducing the universal state suppressed disease-associated states, highlighting its therapeutic potential. Our findings cement CRISPRa as a tool for perturbing differentiated cells and indicate thatin vivostates can be elicited via perturbation, enabling studies of clinically relevant statesex vivo.

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Section: Transcription Factor Perturbations Driving Markers Of In Viv...mentioning

confidence: 86%

Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states

Southard,

Ardy,

Tang

et al. 2024

Preprint

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“…Multiple studies have reported that the Wnt/β‐catenin pathway exerted essential functions in cell apoptosis, differentiation, and proliferation 40 . Wnt/β‐catenin pathway was proved to be the regulator in types of diseases, such as in hepatocellular carcinoma regulated by AQP9, 41 in tracheal fibrosis regulated by GATA6, 42 and in prostate cancer regulated by GPX2 43 . It was reported that impairment of the Wnt/β‐catenin pathway contributed to tumor invasion and metastasis 44 .…”

Section: Discussionmentioning

confidence: 99%

Baicalein targets STMN1 to inhibit the progression of nasopharyngeal carcinoma via regulating the Wnt/β‐catenin pathway

Li,

Cai

2024

Environmental Toxicology

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BackgroundsNasopharyngeal carcinoma is a common malignancy in the head and neck. Baicalein has been reported to exert the anticancer effects on various cancers. In this study, our aim was to explore the function of baicalein in the development of nasopharyngeal carcinoma and further investigate the potential underlying mechanisms.MethodsCell Counting Kit (CCK)‐8 assay, EdU assay, sphere formation assay, flow cytometry, and transwell invasion assay were conducted to determine cell proliferation, stemness, apoptosis, and invasion, respectively. Western blot was performed to examine the protein levels of PCNA, MMP9, STMN1, β‐catenin, and Wnt3A. The mRNA level of STMN1 was assessed using real‐time quantitative polymerase chain reaction (RT‐qPCR). Xenograft tumor model was carried out to evaluate the effects of baicalein on tumor growth in vivo. Immunohistochemistry (IHC) assay was used to detect the levels of PCNA, MMP9, and STMN1 in tumor tissues from mice.ResultsBaicalein significantly induced cell apoptosis and impeded cell proliferation, invasion, and stemness of nasopharyngeal carcinoma cells. STMN1 was highly expressed in nasopharyngeal carcinoma, and baicalein could directly downregulate STMN1 expression. STMN1 knockdown hampered the progression of nasopharyngeal carcinoma cells. Moreover, the effects of baicalein on cell proliferation, stemness, invasion, and apoptosis in nasopharyngeal carcinoma cells were harbored by STMN1 overexpression. Baicalein regulated STMN1 to inhibit the activation of the Wnt/β‐catenin pathway. SKL2001, an agonist of the Wnt/β‐catenin pathway, could reverse the effects of STMN1 knockdown on the progression of nasopharyngeal carcinoma. In addition, baicalein markedly impeded tumor growth in vivo.ConclusionBaicalein regulated the STMN1/Wnt/β‐catenin pathway to restrain the development of nasopharyngeal carcinoma.

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“…It has been reported that GATA6 upregulates the expression of LYPD1 in cardiac fibroblasts. Another study suggested that tracheal fibroblast activation by transforming growth factor-β (TGF-β) upregulates the mRNA and protein expression of GATA6 23 . Thus, considering that TGF-β is a critical cytokine in fibrosis and in particular SSc 24 , we speculate that LYPD1 might be downstreamly regulated by TGF-β through GATA6 in SSc pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Association of serum Ly6/PLAUR domain-containing protein 1 levels with skin sclerosis in systemic sclerosis

Sugimori,

Omori,

Iwasawa

et al. 2024

Sci Rep

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Systemic sclerosis (SSc) is a connective tissue disease characterized by aberrant immune activation, vascular injury, and fibrosis of the skin and internal organs. Ly6/PLAUR domain-containing protein 1 (LYPD1) was reported to be secreted and to have various physiological functions such as anti-angiogenic effects. Here we investigated serum LYPD1 levels in SSc patients and the association of serum LYPD1 levels with clinical features of SSc. Serum samples were obtained from 75 SSc patients and 22 healthy individuals as controls. We measured serum LYPD1 levels using enzyme-linked immunosorbent assay kits. Then, the relationship between serum LYPD1 levels and clinical features of SSc was analyzed. Serum LYPD1 levels in diffuse cutaneous SSc (dcSSc) patients were significantly higher than those in the limited cutaneous SSc (lcSSc) patients (median [25–75th percentiles], 1693.43 [1086.61–1917.57] vs. 904.55 [714.356–1285.56] pg/mL), while there were no significant differences in the serum LYPD1 levels between lcSSc and healthy controls (904.55 [714.356–1285.56] vs. 750.71 pg/mL [544.00–912.14]). Further analysis revealed that serum LYPD1 levels in patients correlated with skin thickness scores and serum interleukin (IL)-6 levels, which were known to reflect the extent of skin thickening in SSc. Moreover, serum LYPD1 levels showed a decrease with improvement in skin thickness after treatment, along with a decrease in serum IL-6 levels. These results indicate that LYPD1 might be a potential marker for monitoring skin sclerosis and evaluating the efficacy of skin fibrosis treatment in SSc patients.

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GATA6 triggers fibroblast activation and tracheal fibrosis through the Wnt/β-catenin pathway

Cited by 4 publications

References 35 publications

Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states

Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states

Baicalein targets STMN1 to inhibit the progression of nasopharyngeal carcinoma via regulating the Wnt/β‐catenin pathway

Association of serum Ly6/PLAUR domain-containing protein 1 levels with skin sclerosis in systemic sclerosis

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