Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion

Brochu-Gaudreau, Karine; Charbonneau, Martine; Harper, Kelly; Dubois, Claire M.

doi:10.3390/cancers14112751

Cited by 3 publications

(3 citation statements)

References 106 publications

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“…SMAD2 can promote the development of CRC by regulating the polarization of tumor macrophages [24]. In this study, SMAD2 expression in CRC was low, which was SMAD3 plays the dual role of oncogene and tumor suppressor gene in tumor formation, and can be used as a prognostic marker for tumors [22]. SMAD4 is a tumor suppressor gene that plays a central role in TGF-β signaling pathway transduction [25].…”

Section: Discussionmentioning

confidence: 71%

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Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Ding

Luo

et al. 2023

International Journal of Analytical Chemistry

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Background. In recent years, the incidence and mortality of colorectal cancer (CRC) are increasing, and the 5-year survival rate of advanced metastatic CRC is poor. Small mothers against decapentaplegic (SMAD) superfamily are intracellular signal transduction proteins associated with the development and prognosis of a variety of tumors. At present, no study has systematically analysed the relationship between SMADs and CRC. Methods. Here, R3.6.3 was used to analyse the expression of SMADs in pan-cancer and CRC. Protein expression of SMADs were analysed by Human Protein Atlas (HPA). Gene expression profiling interactive analysis (GEPIA) was used to evaluate the correlation between SMADs and tumor stage in CRC. The effect of R language and GEPIA on prognosis was analysed. Mutation rates of SMADs in CRC were determined by cBioPortal, and potentially related genes were predicted using GeneMANIA. R analysis was used to correlate immune cell infiltration in CRC. Results. Both SMAD1 and SMAD2 were found to be weakly expressed in CRC and correlated with the immune invasion level. SMAD1 was correlated with patient prognosis, and SMAD2 was correlated with tumor stage. SMAD3, SMAD4, and SMAD7 were all expressed at low levels in CRC and associated with a variety of immune cells. SMAD3 and SMAD4 proteins were also expressed at low levels, and SMAD4 had the highest mutation rate. SMAD5 and SMAD6 were overexpressed in CRC, and SMAD6 was also associated with patient overall survival (OS) and CD8+ T cells, macrophages, and neutrophils. Conclusions. Our results reveal innovative and strong evidence that SMADs can be used as biomarkers for the treatment and prognosis of CRC.

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Section: Discussionmentioning

confidence: 71%

“…SMAD2 plays diferent roles in diferent stages of cancer by regulating various biological processes [22]. In colorectal cancer, the tumor suppressor gene NIT1 is realized by activating the SMAD2/3 signaling pathway [23].…”

Section: Discussionmentioning

confidence: 99%

Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Ding

Luo

et al. 2023

International Journal of Analytical Chemistry

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“…Transforming growth factor-beta (TGFβ), a multifunctional cytokine expressed in the intestinal epithelium, regulates cell differentiation, proliferation, angiogenesis, and immune response [14]. TGFβ triggers downstream signaling pathways by activating serine/threonine kinase transmembrane receptors type I (TGFβ R1) and type II (TGFβ R2), leading to the phosphorylation of the intracellular mediators SMAD2 and SMAD3 [14][15][16][17]. Phosphorylated SMAD2 or SMAD3 forms a complex with SMAD4, translocating into the nucleus to regulate the transcription of target genes [17].…”

Section: Introductionmentioning

confidence: 99%

Involucrasin B Inhibits the Proliferation of Caco-2 Cells by Regulating the TGFβ/SMAD2-3-4 Pathway

Wang,

Lin,

Shi

et al. 2024

Molecules

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(1) Background: Colorectal cancer (CRC) is the third most common malignant tumor worldwide and the second most common cause of cancer death. However, effective anti-CRC drugs are still lacking in clinical settings. This article investigated the anti-proliferative effect of involucrasin B on CRC Caco-2 cells. (2) Methods: This study employed a sulforhodamine B (SRB) method, colony formation experiments, flow cytometry, FastFUCCI assay, dual luciferase assay, and Western blot analysis for the investigation. (3) Results: The SRB method and colony formation experiments showed that involucrasin B exhibited an inhibitory effect on the Caco-2 cells cultured in vitro. Subsequently, the flow cytometry, FastFUCCI assay, and Western blotting results showed that involucrasin B induced cell cycle arrest in the G1 phase dose-dependently. Involucrasin B significantly enhanced the TGFβ RII protein level and SMAD3 phosphorylation, thus inhibiting the expression of CDK4 and cyclin D1 and causing G1 cell cycle arrest. (4) Conclusion: This study shows that involucrasin B exerts its anti-proliferative effect by regulating the TGFβ/SMAD2-3-4 pathway to cause G1 cycle arrest in Caco-2 cells.

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Hypoxia Promotes Invadosome Formation by Lung Fibroblasts

Lebel,

Cliche,

Charbonneau

et al. 2024

Cells

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Lung parenchymal hypoxia has emerged as a cardinal feature of idiopathic pulmonary fibrosis (IPF). Hypoxia promotes cancer cell invasion and metastasis through signaling that is dependent upon the lysophosphatidic acid (LPA) receptor, LPA1 (LPAR1). Abundant data indicate that LPA1-dependent signaling also enhances lung fibrogenesis in IPF. We recently reported that fibroblasts isolated from the lungs of individuals with IPF have an increased capacity to form subcellular matrix-degradative structures known as invadosomes, an event that correlates with the degree of lung fibrosis. We therefore hypothesized that hypoxia promotes invadosome formation in lung fibroblasts through LPA1-dependent signaling. Here, it is demonstrated that invadosome formation by fibroblasts from the lungs of individuals with advanced IPF is inhibited by both the tyrosine receptor kinase inhibitor nintedanib and inhibition of LPA1. In addition, exposure of normal human lung fibroblasts to either hypoxia or LPA increased their ability to form invadosomes. Mechanistically, the hypoxia-induced invadosome formation by lung fibroblasts was found to involve LPA1 and PDGFR-Akt signaling. We concluded that hypoxia increases the formation of invadosomes in lung fibroblasts through the LPA1 and PDGFR-Akt signaling axis, which represents a potential target for suppressing lung fibrosis.

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Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion

Cited by 3 publications

References 106 publications

Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Involucrasin B Inhibits the Proliferation of Caco-2 Cells by Regulating the TGFβ/SMAD2-3-4 Pathway

Hypoxia Promotes Invadosome Formation by Lung Fibroblasts

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