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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

EGFR-ligands-based molecular staging outperforms the TNM system in predicting patient prognosis. a The TNM staging was unable to predict patients five-year survival (Kaplan-Meier curve, Log rank test, p = 0.08). b Expressing more than median mRNA levels of either none, one, two, three or four of the EGFR ligands (i.e. AREG, EGF, HBEGF and BCT) was significantly linked to reduced five-year survival (Kaplan-Meier curve, Log rank test, p < 0.001). Whereas only 14 % of the patients (4/29) with tumors that expressed less than median mRNA levels of the four EGFR ligands died within five years, the number of death increased as the number of higher-than-median expressing ligands increased to one (25 %, 25/100), two (31 %, 44/142), three (35 %, 34/97) or four (45 %, 14/31). c EGFR-ligand mRNA expression predicted patient survival with TNM stage IV disease (Kaplan-Meier curve, Log rank test, p = 0.004). Whereas only 26 % (14/54) of patients died within five years if the OSCCs expressed increased mRNA for none or one of the EGFR-ligands, it increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two, or three to four EGFR-ligands, respectively. d Patients with over-median-AREG-expressing tumors had worse prognosis than patients expressing any of the other three ligands in the single-ligand-expressing group (Kaplan-Meier curve, Log rank test, p = 0.04)
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Fig2: EGFR-ligands-based molecular staging outperforms the TNM system in predicting patient prognosis. a The TNM staging was unable to predict patients five-year survival (Kaplan-Meier curve, Log rank test, p = 0.08). b Expressing more than median mRNA levels of either none, one, two, three or four of the EGFR ligands (i.e. AREG, EGF, HBEGF and BCT) was significantly linked to reduced five-year survival (Kaplan-Meier curve, Log rank test, p < 0.001). Whereas only 14 % of the patients (4/29) with tumors that expressed less than median mRNA levels of the four EGFR ligands died within five years, the number of death increased as the number of higher-than-median expressing ligands increased to one (25 %, 25/100), two (31 %, 44/142), three (35 %, 34/97) or four (45 %, 14/31). c EGFR-ligand mRNA expression predicted patient survival with TNM stage IV disease (Kaplan-Meier curve, Log rank test, p = 0.004). Whereas only 26 % (14/54) of patients died within five years if the OSCCs expressed increased mRNA for none or one of the EGFR-ligands, it increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two, or three to four EGFR-ligands, respectively. d Patients with over-median-AREG-expressing tumors had worse prognosis than patients expressing any of the other three ligands in the single-ligand-expressing group (Kaplan-Meier curve, Log rank test, p = 0.04)

Mentions: Standard algorithms for TNM staging in HNSCC patients did not predict prognosis, and patients in stage II and III had similar five-year survival (Fig. 2a). Since the mRNA expression levels of these four EGFR-ligands predicted patients outcome separately, we examined if the number of EGFR ligands with above-median mRNA expression level predicted the prognosis even better. Patients were divided into five groups according to number of ligands with increased tumorous mRNA expression levels. This revealed a dose-effect pattern with decreased survival as a function of the number of ligands that were expressed above median level. Thus, such “molecular EGFR-ligand staging” predicted patient outcome much better than the TNM staging system (Fig. 2b). The same result was observed with patients with TNM stage IV disease. Whereas only 26 % (14/54) of stage IV patients died within five years when the HNSCCs expressed increased mRNA for none or one EGFR-ligand, the number increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two or more than three EGFR-ligands, respectively (Fig. 2c). Further analysis in patients with only “one-ligand” tumors revealed that patients with over-median AREG-mRNA expression levels had significantly increased mortality compared to patients with any of the other three “single ligand” expressing tumors (Fig. 2d).Fig. 2


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
EGFR-ligands-based molecular staging outperforms the TNM system in predicting patient prognosis. a The TNM staging was unable to predict patients five-year survival (Kaplan-Meier curve, Log rank test, p = 0.08). b Expressing more than median mRNA levels of either none, one, two, three or four of the EGFR ligands (i.e. AREG, EGF, HBEGF and BCT) was significantly linked to reduced five-year survival (Kaplan-Meier curve, Log rank test, p < 0.001). Whereas only 14 % of the patients (4/29) with tumors that expressed less than median mRNA levels of the four EGFR ligands died within five years, the number of death increased as the number of higher-than-median expressing ligands increased to one (25 %, 25/100), two (31 %, 44/142), three (35 %, 34/97) or four (45 %, 14/31). c EGFR-ligand mRNA expression predicted patient survival with TNM stage IV disease (Kaplan-Meier curve, Log rank test, p = 0.004). Whereas only 26 % (14/54) of patients died within five years if the OSCCs expressed increased mRNA for none or one of the EGFR-ligands, it increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two, or three to four EGFR-ligands, respectively. d Patients with over-median-AREG-expressing tumors had worse prognosis than patients expressing any of the other three ligands in the single-ligand-expressing group (Kaplan-Meier curve, Log rank test, p = 0.04)
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Related In: Results  -  Collection

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Fig2: EGFR-ligands-based molecular staging outperforms the TNM system in predicting patient prognosis. a The TNM staging was unable to predict patients five-year survival (Kaplan-Meier curve, Log rank test, p = 0.08). b Expressing more than median mRNA levels of either none, one, two, three or four of the EGFR ligands (i.e. AREG, EGF, HBEGF and BCT) was significantly linked to reduced five-year survival (Kaplan-Meier curve, Log rank test, p < 0.001). Whereas only 14 % of the patients (4/29) with tumors that expressed less than median mRNA levels of the four EGFR ligands died within five years, the number of death increased as the number of higher-than-median expressing ligands increased to one (25 %, 25/100), two (31 %, 44/142), three (35 %, 34/97) or four (45 %, 14/31). c EGFR-ligand mRNA expression predicted patient survival with TNM stage IV disease (Kaplan-Meier curve, Log rank test, p = 0.004). Whereas only 26 % (14/54) of patients died within five years if the OSCCs expressed increased mRNA for none or one of the EGFR-ligands, it increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two, or three to four EGFR-ligands, respectively. d Patients with over-median-AREG-expressing tumors had worse prognosis than patients expressing any of the other three ligands in the single-ligand-expressing group (Kaplan-Meier curve, Log rank test, p = 0.04)
Mentions: Standard algorithms for TNM staging in HNSCC patients did not predict prognosis, and patients in stage II and III had similar five-year survival (Fig. 2a). Since the mRNA expression levels of these four EGFR-ligands predicted patients outcome separately, we examined if the number of EGFR ligands with above-median mRNA expression level predicted the prognosis even better. Patients were divided into five groups according to number of ligands with increased tumorous mRNA expression levels. This revealed a dose-effect pattern with decreased survival as a function of the number of ligands that were expressed above median level. Thus, such “molecular EGFR-ligand staging” predicted patient outcome much better than the TNM staging system (Fig. 2b). The same result was observed with patients with TNM stage IV disease. Whereas only 26 % (14/54) of stage IV patients died within five years when the HNSCCs expressed increased mRNA for none or one EGFR-ligand, the number increased to 32 % (23/71) and 45 % (30/67) if the tumors expressed increased mRNA for two or more than three EGFR-ligands, respectively (Fig. 2c). Further analysis in patients with only “one-ligand” tumors revealed that patients with over-median AREG-mRNA expression levels had significantly increased mortality compared to patients with any of the other three “single ligand” expressing tumors (Fig. 2d).Fig. 2

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&nbsp;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&nbsp;% if tumor expressed none to one EGFR-ligand, to 45&nbsp;% 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