Paradoxical Roles of Desmosomal Components in Head and Neck Cancer

Liu, Yin-Qiao; Zou, Hai-Ying; Xie, Jian‐Jun; Fang, Wang‐Kai

doi:10.3390/biom11060914

Cited by 21 publications

(15 citation statements)

References 160 publications

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“…Despite recent advances in treatment technology, the survival rate for HNC patients remains roughly 50% [ 23 ]. The carcinogenesis of HNC involves numerous molecular events such as the sequential activation of oncogenes and the inactivation of tumor suppressor genes [ 24 ]. Although epidermal growth factor receptor (EGFR) inhibitors have been approved as targeted agents for HNC, they are not effective for everyone, and once resistance develops, there are few suitable alternative target drugs for HNC patients [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop

Jin

Jung

Lim

et al. 2021

IJMS

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Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGF-β) superfamily, has been reported to be overexpressed in different kinds of cancer types. However, the function and mechanism of GDF15 in head and neck cancer (HNC) remains unclear. The Cancer Genome Atlas (TCGA) data show that the expression of GDF15 is significantly associated with tumor AJCC stage, lymph vascular invasion and tumor grade in HNC. In this study, we confirmed that knockdown of GDF15 attenuated: cell proliferation, migration and invasion via regulation of EMT through a canonical pathway; SMAD2/3 and noncanonical pathways; PI3K/AKT and MEK/ERK in HNC cell lines. Furthermore, we found that early growth response 1 (EGR1) was a transcription factor of GDF15. Interestingly, we also demonstrated that GDF15 could regulate the expression of EGR1, which meant a positive feedback loop occurred between these two factors. Moreover, combined inhibition of both GDF15 and EGR1 in a HNC mouse xenograft model showed significantly decreased tumor volume compared to inhibition of EGR1 or GDF15 alone. Our study showed that the GDF15–EGR1 signaling axis may be a good target in HNC patients.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop

Jin

Jung

Lim

et al. 2021

IJMS

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“…161 In addition to desmoglein-3, the tumor-promoting functions of several other desmosomal components were recently summarized elsewhere. 162 This evidence suggest that desmosomes might not be simply regarded as tumor suppressive molecules, but rather multifunctional structure during tumor development.…”

Section: Altered Junctional Componentsmentioning

confidence: 98%

“…For instance, desmoglein‐3 is overexpressed in human head and neck cancer and associated with advanced tumor stage, and inhibition of desmoglein‐3 is sufficient to mitigate tumor progression both in vitro and in vivo 161 . In addition to desmoglein‐3, the tumor‐promoting functions of several other desmosomal components were recently summarized elsewhere 162 . This evidence suggest that desmosomes might not be simply regarded as tumor suppressive molecules, but rather multifunctional structure during tumor development.…”

Section: Reorganization Of Cell Junctions and Cytoskeleton: Key Chara...mentioning

confidence: 99%

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

Huang

Zhang

Zhou

et al. 2022

MedComm

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Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.

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“…Thus, differential expression of desmosomal cadherins enables the tissue to spatially tune EGFR signaling. Accordingly, the presence of Dsg2/3 but loss of Dsg1 is associated with cancer progression and in some cases poor prognosis ( Brown and Wan, 2015 ; Liu et al, 2021 ; Muller et al, 2021 ).…”

Section: Basal Cell Commitmentmentioning

confidence: 99%

The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

Green

Niessen

Rübsam

et al. 2022

Front. Cell Dev. Biol.

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While classic cadherin-actin connections in adherens junctions (AJs) have ancient origins, intermediate filament (IF) linkages with desmosomal cadherins arose in vertebrate organisms. In this mini-review, we discuss how overlaying the IF-desmosome network onto the existing cadherin-actin network provided new opportunities to coordinate tissue mechanics with the positioning and function of chemical signaling mediators in the ErbB family of receptor tyrosine kinases. We focus in particular on the complex multi-layered outer covering of the skin, the epidermis, which serves essential barrier and stress sensing/responding functions in terrestrial vertebrates. We will review emerging data showing that desmosome-IF connections, AJ-actin interactions, ErbB family members, and membrane tension are all polarized across the multiple layers of the regenerating epidermis. Importantly, their integration generates differentiation-specific roles in each layer of the epidermis that dictate the form and function of the tissue. In the basal layer, the onset of the differentiation-specific desmosomal cadherin desmoglein 1 (Dsg1) dials down EGFR signaling while working with classic cadherins to remodel cortical actin cytoskeleton and decrease membrane tension to promote cell delamination. In the upper layers, Dsg1 and E-cadherin cooperate to maintain high tension and tune EGFR and ErbB2 activity to create the essential tight junction barrier. Our final outlook discusses the emerging appreciation that the desmosome-IF scaffold not only creates the architecture required for skin’s physical barrier but also creates an immune barrier that keeps inflammation in check.

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Paradoxical Roles of Desmosomal Components in Head and Neck Cancer

Cited by 21 publications

References 160 publications

Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop

Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

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