Decorin impeded the advancement of thyroid papillary carcinoma by thwarting the EGFR/ FER/ SHP2 signaling-induced sustenance of early endosomes

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Abstract

Objective

This study explores the inhibition of papillary thyroid carcinoma proliferation by Decorin via the EGFR/SHP2/FER pathway.

Method

ology: Thirty-two pairs of papillary thyroid carcinoma tissues and adjacent normal tissues were collected for immunohistochemical analysis. Thyroid cancer cell lines with overexpressed or silenced Decorin were employed in subcutaneous tumor formation experiments in nude mice. Cell membrane proteins were extracted for Western blot and immunofluorescence analyses.

Results

Reduced Decorin expression in human papillary thyroid carcinoma was associated with inhibited formation of the EGFR/SHP2/FER complex. Immunohistochemical analysis revealed lower Decorin levels in carcinoma tissues compared to adjacent normal tissues, corroborated by decreased Decorin and PTEN levels in carcinoma as shown by Western Blot. Overexpression of Decorin in mouse models diminished tumor growth, an effect reversed by Decorin silencing and mitigated by FER inhibition. Decorin modulated Rab5-GTP and Rab7-GTP levels, impacting endosome transition and subsequent signaling pathways.

Conclusion

Decorin inhibits papillary thyroid carcinoma proliferation by disrupting the EGFR/SHP2/FER pathway and modulating endosomal transport.

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Most cited references 53

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Emerging functions of the EGFR in cancer

Sara Sigismund, Daniele Avanzato, Letizia Lanzetti (2017)

The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

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PTEN modulates EGFR late endocytic trafficking and degradation by dephosphorylating Rab7

Swapnil Shinde, Subbareddy Maddika (2016)

Tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase that negatively regulates growth factor-induced survival signalling. Here, we demonstrate that PTEN attenuates epidermal growth factor receptor (EGFR) signalling by promoting late endosome maturation by virtue of its protein phosphatase activity. Loss of PTEN impairs the transition of ligand-bound EGFR from early to late endosomes. We unveil Rab7, a critical GTPase for endosome maturation, as a functional PTEN interacting partner. PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. Thus, our findings reveal PTEN-dependent endosome maturation through phosphoregulation of Rab7 as an important route of controlling EGFR signalling.

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Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition

Tero Järvinen, Stuart Prince (2015)

Decorin (DCN) is the best characterized member of the extracellular small leucine-rich proteoglycan family present in connective tissues, typically in association with or “decorating” collagen fibrils. It has substantial interest to clinical medicine owing to its antifibrotic, anti-inflammatory, and anticancer effects. Studies on DCN knockout mice have established that a lack of DCN is permissive for tumor development and it is regarded as a tumor suppressor gene. A reduced expression or a total disappearance of DCN has been reported to take place in various forms of human cancers during tumor progression. Furthermore, when used as a therapeutic molecule, DCN has been shown to inhibit tumor progression and metastases in experimental cancer models. DCN affects the biology of various types of cancer by targeting a number of crucial signaling molecules involved in cell growth, survival, metastasis, and angiogenesis. The active sites for the neutralization of different growth factors all reside in different parts of the DCN molecule. An emerging concept that multiple proteases, especially those produced by inflammatory cells, are capable of cleaving DCN suggests that native DCN could be inactivated in a number of pathological inflammatory conditions. In this paper, we review the role of DCN in cancer.

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Author and article information

Contributors

Xiaoling Shang

Journal

Journal ID (nlm-ta): Heliyon

Journal ID (iso-abbrev): Heliyon

Title: Heliyon

Publisher: Elsevier

ISSN (Electronic): 2405-8440

Publication date PMC-release: 20 June 2024

Publication date Collection: 15 July 2024

Publication date (Electronic): 20 June 2024

Volume: 10

Issue: 13

Electronic Location Identifier: e33358

Affiliations

[a ]Otorhinolaryngology, Head and Neck Surgery, Hebei North University.Medical Insurance Office, The Fourth Hospital of Hebei Medical University, Zhangjiakou, Hebei, China

[b ]Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China

[c ]Otorhinolaryngology, Head and Neck Surgery, Hebei North University, Zhangjiakou, Hebei, China

Author notes

[* ]Corresponding author. liuyaping6298@ 123456163.com

Article

Publisher Item ID: S2405-8440(24)09389-7 Publisher ID: e33358

DOI: 10.1016/j.heliyon.2024.e33358

PMC ID: 11259844

PubMed ID: 39035505

SO-VID: b24e2c19-83f6-4f87-a0d3-5e6d374686a1

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 8 April 2024

Date revision received : 19 June 2024

Date accepted : 19 June 2024

Decorin impeded the advancement of thyroid papillary carcinoma by thwarting the EGFR/ FER/ SHP2 signaling-induced sustenance of early endosomes

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Abstract

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Neuronal Signaling

Most cited references 53

Emerging functions of the EGFR in cancer

PTEN modulates EGFR late endocytic trafficking and degradation by dephosphorylating Rab7

Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition

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