Expression and Clinical Significance of Epidermal Growth Factor Receptor and Type 1 Insulin-Like Growth Factor Receptor in Nasopharyngeal Carcinoma

Yuan, Yuexing; Zhou, Xuhong; Jiang, Song; Qiu, Xiaoping; Li, Jun; Ye, Linfeng; Meng, Xiaoping; Xia, Dong

doi:10.1177/000348940811700306

Cited by 31 publications

(31 citation statements)

References 20 publications

(1 reference statement)

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“…It has been shown that NPC tumors express both EGFR and IGF1R, although it is not clear whether IGF1R expression is specifically upregulated in EBV-infected tumors (53)(54)(55). High expression of IGF1R has been correlated with poor NPC patient survival, and targeting NPC xenografts with PPP reduces tumor growth (53,56).…”

Section: Discussionmentioning

confidence: 99%

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LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

Tworkoski

Raab‐Traub

2015

J Virol

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Epstein-Barr Virus (EBV) is a gammaherpesvirus that infects the majority of the human population and is linked to the development of multiple cancers, including nasopharyngeal carcinoma. Latent membrane protein 1 (LMP1) is considered the primary oncoprotein of EBV, and in epithelial cells it induces the expression and activation, or phosphorylation, of the epidermal growth factor receptor kinase. To identify effects on additional kinases, an unbiased screen of receptor tyrosine kinases potentially activated by LMP1 was performed. Using a protein array, it was determined that LMP1 selectively activates insulin-like growth factor 1 receptor (IGF1R). This activation takes place in fibroblast, epithelial, and nasopharyngeal cell lines that express LMP1 stably and transiently. Of note, LMP1 altered the phosphorylation, but not the expression, of IGF1R. The use of LMP1 mutants with defective signaling domains revealed that the C-terminal activating region 2 domain of LMP1 increased the mRNA expression and the secretion of the ligand IGF1, which promoted phosphorylation of IGF1R. IGF1R phosphorylation was dependent upon activation of canonical NF-B signaling and was suppressed by IB␣ and a dominant negative form of TRAF6. Inhibition of IGF1R activation with two small-molecule inhibitors, AG1024 and picropodophyllin (PPP), or with short hairpin RNA (shRNA) directed against IGF1R selectively reduced proliferation, focus formation, and Akt activation in LMP1-positive cells but did not impair LMP1-induced cell migration. Expression of constitutively active Akt rescued cell proliferation in the presence of IGF1R inhibitors. These findings suggest that LMP1-mediated activation of IGF1R contributes to the ability of LMP1 to transform epithelial cells. IMPORTANCEEBV is linked to the development of multiple cancers in both lymphoid and epithelial cells, including nasopharyngeal carcinoma. Nasopharyngeal carcinoma is a major cancer that develops in specific populations, with nearly 80,000 new cases reported annually. LMP1 is consistently expressed in early lesions and continues to be detected within 50 to 80% of these cancers at later stages. It is therefore of paramount importance to understand the mechanisms through which LMP1 alters cell growth and contributes to tumorigenesis. This study is the first to determine that LMP1 activates the IGF1R tyrosine kinase by regulating expression of the ligand IGF1. Additionally, the data in this paper reveal that specific targeting of IGF1R selectively impacts LMP1-positive cells. These findings suggest that therapies directed against IGF1R may specifically impair the growth of EBV-infected cells. E pstein-Barr Virus (EBV) is a gammaherpesvirus transmitted through bodily fluids that infects both lymphocytes and oropharyngeal epithelial cells. It is estimated that greater than 90% of the human population are EBV carriers, and EBV infection is an etiological factor in the development of multiple cancers such as Burkitt lymphoma, Hodgkin lymphoma, gastric carcinoma, and nasopharynge...

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Section: Discussionmentioning

confidence: 99%

“…High expression of IGF1R has been correlated with poor NPC patient survival, and targeting NPC xenografts with PPP reduces tumor growth (53,56). Additionally, preliminary data suggest that targeting both EGFR and IGF1R in NPC may be more beneficial than targeting either RTK individually (15,57).…”

Section: Discussionmentioning

confidence: 99%

LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

Tworkoski

Raab‐Traub

2015

J Virol

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“…Finally, we enrolled 15 eligible articles containing survival outcomes [11,[15][16][17][18]22,[24][25][26][27][28][29][30][31][32][33][34][35], among which two studies were written in Chinese [22,33], whereas the others were English articles. These eligible studies were published from 2002 to 2012.…”

Section: Eligible Studiesmentioning

confidence: 99%

“…Studies [17,24,25,31] dealing with differentiated tumor samples yielded HRs [95% CI] for both OS and DFS/RFS/PFS. In this subgroup, EGFR showed no significant prognosis relevance to OS: 2.60 [0.85, 7.90], (I2 = 76%, P = 0.09); while DFS/ RFS/PFS was observably greatly related to EGFR: 2.38 [1.36, 3.55], (I2 = 40%, P < 0.00001), (Fig.…”

Section: Subgroup Analysismentioning

confidence: 99%

Epidermal growth factor receptor could play a prognostic role to predict the outcome of nasopharyngeal carcinoma: A meta-analysis

Huang

et al. 2014

CBM

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“…This lymphangiogenic activity may promote lymphatic spread, metastasis, and recurrence of malignant tumors. Increased expression of IGF-1R has been detected immunohistochemically in primary undifferentiated oropharyngeal and nasopharyngeal tumors as well as metastatic lymph nodes [68], and has been associated with poor prognosis, increased metastatic potential, and high recurrence rates (Table 1) [69]. On the other hand, down-regulation of IGFBP-3 has been found in patients with tongue carcinoma and significantly associated with shorter disease-specific survival [70].…”

Section: Other Factors Implicated In Lymphangiogenesismentioning

confidence: 99%

Molecular pathways of lymphangiogenesis and lymph node metastasis in head and neck cancer

Karatzanis

Koudounarakis

Papadakis

et al. 2011

Eur Arch Otorhinolaryngol

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Metastasis to regional lymph nodes constitutes the main route toward progression and dissemination of head and neck carcinoma; at the same time it is the most significant adverse prognostic indicator for this disease. In recent years, significant focus has been given on the molecular mechanisms behind lymph node metastasis of head and neck cancer. The aim of this study is to assess the role of growth factor expression and function in association with lymph node metastasis and overall prognosis of head and neck cancer. Current literature, searching for experimental data regarding the molecular pathways of lymph node dissemination of head and neck cancer, is reviewed giving special emphasis on the expression and prognostic significance of specific growth factors. Members of the vascular endothelial growth factor (VEGF), mostly VEGF-C and VEGF-D, with their action through the receptors VEGFR-3 and VEGFR-2, constitute the most extensively studied growth factors associated with lymphangiogenesis so far. High expression of these as well as other molecules, including angiopoietins, insulin-like growth factor, and fibroblast growth factor, has been associated with lymph node metastasis and poor prognosis in head and neck squamous cell carcinoma. Numerous growth factors seem to play an important role regarding the lymph node metastatic potential of head and neck cancer. Further research is necessary in order to further clarify the molecular pathways and introduce novel therapeutic options.

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Expression and Clinical Significance of Epidermal Growth Factor Receptor and Type 1 Insulin-Like Growth Factor Receptor in Nasopharyngeal Carcinoma

Cited by 31 publications

References 20 publications

LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

Epidermal growth factor receptor could play a prognostic role to predict the outcome of nasopharyngeal carcinoma: A meta-analysis

Molecular pathways of lymphangiogenesis and lymph node metastasis in head and neck cancer

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