Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

Moses, Michael A.; George, Andrea L.; Sakakibara, Nozomi; Mahmood, Kanwal; Ponnamperuma, Roshini M.; King, Kathryn E.; Weinberg, Wendy C.

doi:10.3390/ijms20143590

Cited by 77 publications

(63 citation statements)

References 137 publications

(194 reference statements)

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“…In animal studies, p63 knockout led to severe anomalies in the development of epithelia and their derivatives, and even death at birth (25,50). p63 is also widely recognized as being involved in tumorigenesis, especially epithelial tumors, such as those associated with prostate, bladder, and colorectal cancer (26,27). In addition, p63 is a speci c marker of basal cells and serves a vital role in helping maintain self-renewal potential and inhibit apoptosis in various epithelial cells, including those in the mouse trachea and human airways (21,22,24).…”

Section: Discussionmentioning

confidence: 99%

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Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

Peng

Chang

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) may contribute to repair in severe diseases including acute lung injury (ALI). However, applications with MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced to pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form.Methods: Intratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was delivered as a treatment. Histopathological assessment was achieved by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively. Plasma lipid profiles were detected by performing lipidomics analysis.Results: Here, we found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited signaling through the interleukin 6–phosphorylated signal transducer and activator of transcription pathway to activate tumor protein 63–jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and relieve inflammatory responses. Furthermore, MSC SLP significantly reversed changes in plasma lipid profiles caused by bleomycin.Conclusions: MSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and acute respiratory distress syndrome. Our findings also suggest that phosphatidylserine has potential for serving as a pharmaceutical or dietary supplement for alleviating ALI.

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Section: Discussionmentioning

confidence: 99%

“…Similarly, p63 has been shown to be a vital mediator of the normal development, maintenance, and homeostasis of the epithelium (23,25). In addition, p63 has been widely documented in various epithelial tumors, including squamous cell carcinomas of the lungs, prostate, and bladder (26,27).…”

Section: Introductionmentioning

confidence: 99%

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

Peng

Chang

et al. 2020

Preprint

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“…10,13 The OM-SCMs involved in molecular signalling pathways include keratins 5/14, 15, 19, α 6 β 4 -integrin + CD71 − , β 1 -integrin, collagen IV, p75 NGFR , stage-specific embryonic antigen 1 (SSEA1), CD24, CD44 (CD44H), CD71, CD117 (c-kit), CD133, melanomaassociated chondroitin sulfate proteoglycan (MCSP), Nestin, p63, octamer-binding transcription factor-3/4 (Oct-3/4), Nanog, SOX2, ABCG-2, ALDH1 and Bmi-1 (Supplementary Information (SI)). 22,[55][56][57][58][59][60][61][62][63][64][65] The crucial role of keratins 5, 14, 19, CD44, β1-integrin, p63, SOX2, Oct-4, c-MYC, Bmi-1 and ALDH1 in potentiating stem cell behaviour in OSF is further discussed in sections "β1-integrin as a stem cell marker in OSF and its malignant evolution", "p63 as a stem cell marker in OSF and its malignant transformation", "c-MYC as a stem cell marker in OSF and its malignant evolution", "Bmi-1 is a stem cell marker in OSF and its malignant evolution", "Keratin 5/14 as a stem cell marker in OSF and its malignant evolution" and "Keratin-19 as a stem cell marker in OSF and its malignant evolution".…”

Section: Alterations In the Expression Pattern Of Om-scms In Osf Opmmentioning

confidence: 99%

Loss of oral mucosal stem cell markers in oral submucous fibrosis and their reactivation in malignant transformation

Sharma¹,

Fonseca

Hunter

et al. 2020

Int J Oral Sci

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The integrity of the basal stem cell layer is critical for epithelial homoeostasis. In this paper, we review the expression of oral mucosal stem cell markers (OM-SCMs) in oral submucous fibrosis (OSF), oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) to understand the role of basal cells in potentiating cancer stem cell behaviour in OSF. While the loss of basal cell clonogenicity triggers epithelial atrophy in OSF, the transition of the epithelium from atrophic to hyperplastic and eventually neoplastic involves the reactivation of basal stemness. The vacillating expression patterns of OM-SCMs confirm the role of keratins 5, 14, 19, CD44, β1-integrin, p63, sex-determining region Y box (SOX2), octamer-binding transcription factor 4 (Oct-4), c-MYC, B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi-1) and aldehyde dehydrogenase 1 (ALDH1) in OSF, OPMDs and OSCC. The downregulation of OM-SCMs in the atrophic epithelium of OSF and their upregulation during malignant transformation are illustrated with relevant literature in this review.

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“…P63 and P73 mutations are rare in human tumors, but they can be overexpressed. P63 plays a critical role in development of squamous epithelium and is overexpressed in squamous cell carcinoma [145]. Metformin inhibited p63 protein expression in squamous carcinoma cell, resulting in decreased cell viability and xenographic tumor growth [146].…”

Section: Metformin Inhibits the Nuclear Entry Of Chrebp And Foxo1 Fromentioning

confidence: 99%

New Insight into Metformin Mechanism of Action and Clinical Application

Yan¹,

Kover²,

Moore³

2020

Metformin [Working Title]

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Metformin is the first-line medication for Type 2 diabetes (T2D) treatment, and it is the only US FDA approved oral antidiabetic medication for pediatric patients with T2D 10 years and older. Metformin is also used to treat polycystic ovary syndrome (PCOS), another condition with underlying insulin resistance. The clinical applications of metformin are continuing to expand into other fields including cancer, aging, cardiovascular diseases, and neurodegenerative diseases. Metformin modulates multiple biological pathways. Its novel properties and effects continue to evolve; however, its molecular mechanism of action remains incompletely understood. In this chapter, we focus on the recent translational research and clinical data on the molecular action of metformin and the evidence linking the effects of metformin on insulin resistance, prediabetes, diabetes, aging, cancer, PCOS, cardiovascular diseases, and neurodegenerative diseases. Metformin 2 Mechanisms of actionThe potential mechanisms of metformin action involve several pathways. The AMPK-pathway plays an important role in metformin actions [2, 3]. Metformin inhibits the mitochondrial respiratory chain (complex I), which increases the AMP to ATP ratio, leading to the phosphorylation of AMP-activated protein kinase (AMPK) at Thr-172. We have demonstrated that metformin treatment increases protein level of phosphorylated AMPK in high-glucose-treated endothelial cells [4]. The phosphorylated AMPK subsequently phosphorylates multiple downstream effectors to regulate cellular metabolism and energy homeostasis [5]. These downstream effectors include thioredoxin interacting protein (TXNIP) and TBC1D1, a RAB-GTPase activating protein and a member of the tre-2/BUB2/cdc1 domain family. Phosphorylated TXNIP and TBC1D1 increase the plasma membrane localization of glucose transporter 1 (GLUT1) and GLUT4, respectively [6, 7], and regulate glycogen synthases (GYS1 and GYS2) to prevent the storage of glycogen [8]. Some actions of metformin have been found to be AMPK-independent [9].In diabetic mice, metformin has an effect on gut microbiota by inducing a profound shift in the gut microbial community profile, resulting in an increase in the Akkermansia spp. population [10] and cAMP-induced agmatine production [11], which may decrease absorption of glucose from the gastrointestinal tract and increase lipid metabolism respectively. In addition, metformin decreases insulin-induced suppression of fatty acid oxidation and lowers lipid content of hepatic cells [12].New Insight into Metformin Mechanism of Action and Clinical Application DOI: http://dx.doi.org/10.5772/intechopen.91148 association with insulin resistance. Metformin decreases the level of circulating branched-chain amino acids and reduces insulin resistance in a high-fat diet mouse model [22]. Metformin treatment lowers plasma ADMA which is associated with improved glycemic control in patients with T2D [23].Recent studies indicate that phosphatidylinositol-3-kinase/protein kinase B protein (PI3K/PKB, also known as ...

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Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

Cited by 77 publications

References 137 publications

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

Loss of oral mucosal stem cell markers in oral submucous fibrosis and their reactivation in malignant transformation

New Insight into Metformin Mechanism of Action and Clinical Application

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