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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalOral Oncology
Volume95
DOIs
StatePublished - Aug 1 2019

Fingerprint

Leukocyte L1 Antigen Complex
Caspases
Epidermal Growth Factor Receptor
Caspase 7
Caspase 3
Epithelium
Carcinoma, squamous cell of head and neck
Cell Nucleus
Fluorescence Microscopy
Small Interfering RNA
Neoplasms
Cell Survival
Carcinogenesis
Cytoplasm
Survival Rate
Western Blotting
Immunohistochemistry
Carcinoma

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

Cite this

Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma. / Argyris, Prokopios P.; Slama, Zachary; Malz, Chris; Koutlas, Ioannis G; Pakzad, Betty; Patel, Ketan; Kademani, Deepak; Khammanivong, Ali; Herzberg, Mark C.

In: Oral Oncology, Vol. 95, 01.08.2019, p. 1-10.

Research output: Contribution to journalArticle

@article{5d428dd6c7674690b523bc0796e0f1be,
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}",
year = "2019",
month = "8",
day = "1",
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",

}

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

PY - 2019/8/1

Y1 - 2019/8/1

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

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

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

VL - 95

SP - 1

EP - 10

JO - Oral Oncology

JF - Oral Oncology

SN - 1368-8375

ER -