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Dissecting the EGFR-PI3K-AKT pathway in oral cancer highlights the role of the EGFR variant III and its clinical relevance

Kwang-Yu Chang124, Shan-Yin Tsai5, Shang-Hung Chen26, Hsiao-Hui Tsou3, Chia-Jui Yen4, Ko-Jiunn Liu2, Hsun-Lang Fang7, Hung-Chang Wu8, Bin-Fay Chuang2, Shao-Wen Chou2, Careen K Tang10, Shyun-Yeu Liu119, Pei-Jung Lu1, Ching-Yu Yen129* and Jang-Yang Chang24*

Author Affiliations

1 Institute of Clinical Medicine College of Medicine, National Cheng Kung University, 7th Floor, No.35 Xiaodong Rd., Tainan City 701, Taiwan

2 National Institute of Cancer Research National Health Research Institutes, 2nd Floor No.367, Shengli Rd., Tainan City 70456, Taiwan

3 Institute of Population Health Sciences National Health Research Institutes, No.35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan

4 Division of Hematology/Oncology Department of Internal Medicine, National Cheng Kung University Hospital, No.138 Shengli Rd., Tainan 704, Taiwan

5 Department of Pathology, Kaohsiung Medical University Hospital, No.100 , Tzyou 1st Rd., Kaohsiung 807, Taiwan

6 Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, No. 201, Taikang Village, Liuying Dist, Tainan City 73657, Taiwan

7 Department of Cosmetology and Health Care, Min-Hwei College of Health Care Management, No.1116, Sec. 2, Zhongshan E. Rd., Liuying Dist., Tainan 73658, Taiwan

8 Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, No.901, Zhonghua Rd., Tainan City, Yongkang Dist. 710, Taiwan

9 Oral and Maxillofacial Surgery Section, Chi-Mei Medical Center, No.901, Zhonghua Rd., Tainan City, Yongkang Dist. 710, Taiwan

10 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd., Washington, DC 20057, USA

11 Department of Dentistry, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Taipei City, Neihu District 114, Taiwan

12 Department of Dentistry, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei City 110, Taiwan

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Journal of Biomedical Science 2013, 20:43  doi:10.1186/1423-0127-20-43

Published: 27 June 2013



Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide-3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting.


A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants.


Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome.

AKT; EGFR; EGFRvIII; Oral cancer; PI3K; PTEN