Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma

Prokopios P. Argyris; Zachary Slama; Chris Malz; Ioannis G Koutlas; Betty Pakzad; Ketan Patel; Deepak Kademani; Ali Khammanivong; Mark C Herzberg

doi:10.1016/j.oraloncology.2019.05.027

Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma

Prokopios P. Argyris, Zachary Slama, Chris Malz, Ioannis G Koutlas, Betty Pakzad, Ketan Patel, Deepak Kademani, Ali Khammanivong, Mark C Herzberg

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13 Scopus citations

Abstract

Objectives: Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims: (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods: Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results: In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions: In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.

Original language	English (US)
Pages (from-to)	1-10
Number of pages	10
Journal	Oral Oncology
Volume	95
DOIs	https://doi.org/10.1016/j.oraloncology.2019.05.027
State	Published - Aug 2019

Bibliographical note

Funding Information:
The project was supported by NIH/NIDCR R01DE021206 to MCH and R90DE023058 to PPA. We thank Rachel Isaksson Vogel, PhD for assistance with our statistical analyses. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR or the NIH.

Publisher Copyright:
© 2019

Keywords

Calprotectin
Caspase-3/7
EGFR
Epithelial differentiation
Head and neck squamous cell carcinoma
NGF
P16+ squamous cell carcinoma
Premalignant epithelial dysplasia
S100A8/A9
VEGF-A
VEGF-C

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title = "Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma",

abstract = "Objectives: Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims: (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods: Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results: In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions: In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.",

keywords = "Calprotectin, Caspase-3/7, EGFR, Epithelial differentiation, Head and neck squamous cell carcinoma, NGF, P16+ squamous cell carcinoma, Premalignant epithelial dysplasia, S100A8/A9, VEGF-A, VEGF-C",

author = "Argyris, {Prokopios P.} and Zachary Slama and Chris Malz and Koutlas, {Ioannis G} and Betty Pakzad and Ketan Patel and Deepak Kademani and Ali Khammanivong and Herzberg, {Mark C}",

note = "Funding Information: The project was supported by NIH/NIDCR R01DE021206 to MCH and R90DE023058 to PPA. We thank Rachel Isaksson Vogel, PhD for assistance with our statistical analyses. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR or the NIH. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = aug,

doi = "10.1016/j.oraloncology.2019.05.027",

language = "English (US)",

volume = "95",

pages = "1--10",

journal = "Oral Oncology",

issn = "1368-8375",

publisher = "Elsevier Limited",

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TY - JOUR

T1 - Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma

AU - Argyris, Prokopios P.

AU - Slama, Zachary

AU - Malz, Chris

AU - Koutlas, Ioannis G

AU - Pakzad, Betty

AU - Patel, Ketan

AU - Kademani, Deepak

AU - Khammanivong, Ali

AU - Herzberg, Mark C

N1 - Funding Information: The project was supported by NIH/NIDCR R01DE021206 to MCH and R90DE023058 to PPA. We thank Rachel Isaksson Vogel, PhD for assistance with our statistical analyses. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR or the NIH. Publisher Copyright: © 2019

PY - 2019/8

Y1 - 2019/8

N2 - Objectives: Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims: (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods: Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results: In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions: In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.

AB - Objectives: Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims: (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods: Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results: In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions: In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.

KW - Calprotectin

KW - Caspase-3/7

KW - EGFR

KW - Epithelial differentiation

KW - Head and neck squamous cell carcinoma

KW - NGF

KW - P16+ squamous cell carcinoma

KW - Premalignant epithelial dysplasia

KW - S100A8/A9

KW - VEGF-A

KW - VEGF-C

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UR - http://www.scopus.com/inward/citedby.url?scp=85066449694&partnerID=8YFLogxK

U2 - 10.1016/j.oraloncology.2019.05.027

DO - 10.1016/j.oraloncology.2019.05.027

M3 - Article

C2 - 31345374

AN - SCOPUS:85066449694

SN - 1368-8375

VL - 95

SP - 1

EP - 10

JO - Oral Oncology

JF - Oral Oncology

ER -

Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma

Abstract

Bibliographical note

Keywords

UN SDGs

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