Limits...
Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF- induced amphiregulin expression

View Article: PubMed Central - PubMed

ABSTRACT

Background: Increased expression of epidermal growth factor receptor (EGFR) and its ligands is associated with poor prognosis and chemoresistance in many carcinoma types, but its role in head and neck squamous cell carcinoma (HNSCC) is unclear. Our aim was to clarify whether mRNA expression of EGFR-ligands was linked to prognosis and cisplatin resistance, and if so, which ligand was most important and how was the expression regulated.

Methods: To examine the prognostic effect of EGFR-ligand expression, we analyzed tumorous mRNA expression in 399 HNSCC patients. The intracellular signaling pathways controlling epidermal growth factor (EGF)-induced amphiregulin (AREG) expression were examined in three oral squamous cell carcinoma (OSCC) cell lines. Effect of AREG on cisplatin resistance was examined by viability assays in four-, and by association in 11 OSCC cell lines.

Results: The patients were divided into five groups according to the median mRNA expression levels of four EGFR ligands, i.e. AREG, EGF, heparin-binding EGF-like growth factor (HBEGF) and beta-cellulin (BTC). The number of increased-expressed EGFR-ligands were progressively correlated to five-year survival, even in advanced TNM-stage IV patients, where five-year mortality increased from 26 % if tumor expressed none to one EGFR-ligand, to 45 % in three to four ligand expressing tumors. Thus, staging the tumor according to these EGFR-ligand mRNA expression pattern completely out performed TNM staging in predicting prognosis. Multivariate analysis identified AREG as the dominating predictor, and AREG was overexpressed in OSCC compared to tumors from other sites. Both EGF and HBEGF stimulation induced strong AREG increase in OSCC cell lines, which was partially mediated by the extracellular signal-regulated kinase 1/2 pathway, and negatively regulated by p38, c-Jun N-terminal kinase, and phosphoinositide-3 kinase. Although increased AREG mRNA expression predicted unfavorable prognosis in platinum treated HNSCC patients, AREG did not mediate cisplatin resistance in the OSCC cell lines.

Conclusions: Increased tumorous mRNA expression of four EGFR ligands was progressively associated with poor prognosis in HNSCC. Thus, EGFR-ligands mRNA expression pattern may be a new prognostic biomarker. The tightly regulated EGF-induced AREG mRNA expression was partly lost in the OSCC cell lines and restoring its regulation may be a new target in cancer treatment.

Trial registration: Not applicable as the clinical data of the 498 HNSCC patients and their mRNA expression profiles were collected from the open TCGA database: http://cancergenome.nih.gov/cancersselected/headandneck.

No MeSH data available.


Related in: MedlinePlus

High tumorous mRNA levels of EGFR-ligands predicted poor prognosis in HNSCC patients. HNSCC patients with higher than median tumorous AREG (a), EGF (b), HBEGF (c) or BTC (d) mRNA levels had lower five-year survival rate compared to patients with lower than median expression levels (Kaplan-Meier curve, Log rank test). The mRNA levels are measured as fragments per kilobase per million mapped reads (FPKM)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5037594&req=5

Fig1: High tumorous mRNA levels of EGFR-ligands predicted poor prognosis in HNSCC patients. HNSCC patients with higher than median tumorous AREG (a), EGF (b), HBEGF (c) or BTC (d) mRNA levels had lower five-year survival rate compared to patients with lower than median expression levels (Kaplan-Meier curve, Log rank test). The mRNA levels are measured as fragments per kilobase per million mapped reads (FPKM)

Mentions: A total of 399 patients, 284 (71 %) men and 115 (29 %) women, median 61 years (range from 19 to 90), were admitted in the study. The detailed patients’ information is shown in Table 1. Dividing patients using median mRNA expression levels as discriminators revealed that increased mRNA expression for four EGFR ligands (AREG, EGF, HBEGF and BTC) was associated with significantly reduced five-year survival compared to patients with lower expression (Fig. 1). Expression of the three other EGFR-ligands (EREG, EPGN and TGFA) was not linked to prognosis.Table 1


Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF- induced amphiregulin expression
High tumorous mRNA levels of EGFR-ligands predicted poor prognosis in HNSCC patients. HNSCC patients with higher than median tumorous AREG (a), EGF (b), HBEGF (c) or BTC (d) mRNA levels had lower five-year survival rate compared to patients with lower than median expression levels (Kaplan-Meier curve, Log rank test). The mRNA levels are measured as fragments per kilobase per million mapped reads (FPKM)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037594&req=5

Fig1: High tumorous mRNA levels of EGFR-ligands predicted poor prognosis in HNSCC patients. HNSCC patients with higher than median tumorous AREG (a), EGF (b), HBEGF (c) or BTC (d) mRNA levels had lower five-year survival rate compared to patients with lower than median expression levels (Kaplan-Meier curve, Log rank test). The mRNA levels are measured as fragments per kilobase per million mapped reads (FPKM)
Mentions: A total of 399 patients, 284 (71 %) men and 115 (29 %) women, median 61 years (range from 19 to 90), were admitted in the study. The detailed patients’ information is shown in Table 1. Dividing patients using median mRNA expression levels as discriminators revealed that increased mRNA expression for four EGFR ligands (AREG, EGF, HBEGF and BTC) was associated with significantly reduced five-year survival compared to patients with lower expression (Fig. 1). Expression of the three other EGFR-ligands (EREG, EPGN and TGFA) was not linked to prognosis.Table 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Increased expression of epidermal growth factor receptor (EGFR) and its ligands is associated with poor prognosis and chemoresistance in many carcinoma types, but its role in head and neck squamous cell carcinoma (HNSCC) is unclear. Our aim was to clarify whether mRNA expression of EGFR-ligands was linked to prognosis and cisplatin resistance, and if so, which ligand was most important and how was the expression regulated.

Methods: To examine the prognostic effect of EGFR-ligand expression, we analyzed tumorous mRNA expression in 399 HNSCC patients. The intracellular signaling pathways controlling epidermal growth factor (EGF)-induced amphiregulin (AREG) expression were examined in three oral squamous cell carcinoma (OSCC) cell lines. Effect of AREG on cisplatin resistance was examined by viability assays in four-, and by association in 11 OSCC cell lines.

Results: The patients were divided into five groups according to the median mRNA expression levels of four EGFR ligands, i.e. AREG, EGF, heparin-binding EGF-like growth factor (HBEGF) and beta-cellulin (BTC). The number of increased-expressed EGFR-ligands were progressively correlated to five-year survival, even in advanced TNM-stage IV patients, where five-year mortality increased from 26 % if tumor expressed none to one EGFR-ligand, to 45 % in three to four ligand expressing tumors. Thus, staging the tumor according to these EGFR-ligand mRNA expression pattern completely out performed TNM staging in predicting prognosis. Multivariate analysis identified AREG as the dominating predictor, and AREG was overexpressed in OSCC compared to tumors from other sites. Both EGF and HBEGF stimulation induced strong AREG increase in OSCC cell lines, which was partially mediated by the extracellular signal-regulated kinase 1/2 pathway, and negatively regulated by p38, c-Jun N-terminal kinase, and phosphoinositide-3 kinase. Although increased AREG mRNA expression predicted unfavorable prognosis in platinum treated HNSCC patients, AREG did not mediate cisplatin resistance in the OSCC cell lines.

Conclusions: Increased tumorous mRNA expression of four EGFR ligands was progressively associated with poor prognosis in HNSCC. Thus, EGFR-ligands mRNA expression pattern may be a new prognostic biomarker. The tightly regulated EGF-induced AREG mRNA expression was partly lost in the OSCC cell lines and restoring its regulation may be a new target in cancer treatment.

Trial registration: Not applicable as the clinical data of the 498 HNSCC patients and their mRNA expression profiles were collected from the open TCGA database: http://cancergenome.nih.gov/cancersselected/headandneck.

No MeSH data available.


Related in: MedlinePlus