Skip to main content
Top
Published in: Radiation Oncology 1/2011

Open Access 01-12-2011 | Research

GP96 is over-expressed in oral cavity cancer and is a poor prognostic indicator for patients receiving radiotherapy

Authors: Chien-Yu Lin, Ting-Yang Lin, Hung-Ming Wang, Shiang-Fu Huang, Kang-Hsing Fan, Chun-Ta Liao, I-How Chen, Li-Yu Lee, Yen-Liang Li, Yin-Ju Chen, Ann-Joy Cheng, Joseph T Chang

Published in: Radiation Oncology | Issue 1/2011

Login to get access

Abstract

Background

Oral cavity cancers (ORC) are the most common cancers, and standard treatment is radical surgery with postoperative radiotherapy. However, locoregional failure remains a major problem, indicating radioresistance an important issue. Our previous work has shown that GP96 contributed to radioresistance in nasopharyngeal and oral cancer cell lines. In this study, we determined clinical significance of GP96 in ORC by evaluation of GP96 expression and its association with disease prognosis in patients receiving radiotherapy

Methods

Total of 79 ORC patients (77 males, median age: 48 years old) receiving radical surgery and postoperative radiotherapy between Oct 1999 and Dec 2004 were enrolled. Patients in pathological stages II, III and IV were 16.5%, 16.5% and 67%, respectively. For each patient, a pair of carcinoma tissue and grossly adjacent normal mucosa was obtained. GP96-expression was examined by western blot analysis, and the association with clinicopathological status was determined.

Results

Three-year locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) rates were 69%, 79%, 63% and 57%, respectively. We found that 55 patients (70%) displayed GP96-overexpression in the tumor tissue, which correlated with a higher pN stage (p = 0.020) and tumor depth (> 10 mm) (p = 0.045). Nodal extracapsular spreading (ECS) and GP96-overexpression predicted adverse LRC (p = 0.049 and p = 0.008). When stratified by nodal ECS, the adverse impact of GP96 remained significant in three-year LRC (p = 0.004). In multivariate analysis, GP96-overexpression was also an independent predictor of LRC, DSS and OS (p = 0.018, p = 0.011 and p = 0.012).

Conclusion

GP96 may play roles in radioresistance which attributes to tumor invasiveness in oral cancer patients receiving radiotherapy. GP96 may serve as a novel prognostic marker of radiotherapy. However, further independent studies are required to validate our findings in a larger series.
Appendix
Available only for authorised users
Literature
1.
go back to reference Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF, Cheng AJ: Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 2008, 99: 1507-1514. 10.1111/j.1349-7006.2008.00863.xCrossRefPubMed Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF, Cheng AJ: Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 2008, 99: 1507-1514. 10.1111/j.1349-7006.2008.00863.xCrossRefPubMed
2.
go back to reference Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC: Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med 1995, 24: 450-453. 10.1111/j.1600-0714.1995.tb01132.xCrossRefPubMed Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC: Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med 1995, 24: 450-453. 10.1111/j.1600-0714.1995.tb01132.xCrossRefPubMed
4.
go back to reference Gonzalez-Garcia R, Naval-Gias L, Roman-Romero L, Sastre-Perez J, Rodriguez-Campo FJ: Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity: a retrospective analytic study of 500 patients. Head Neck 2009, 31: 1168-1180. 10.1002/hed.21088CrossRefPubMed Gonzalez-Garcia R, Naval-Gias L, Roman-Romero L, Sastre-Perez J, Rodriguez-Campo FJ: Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity: a retrospective analytic study of 500 patients. Head Neck 2009, 31: 1168-1180. 10.1002/hed.21088CrossRefPubMed
5.
go back to reference Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, Lin CH, Chen IH, Huang SF, Cheng AJ, et al.: Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 2008, 15: 915-922. 10.1245/s10434-007-9761-5CrossRefPubMed Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, Lin CH, Chen IH, Huang SF, Cheng AJ, et al.: Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 2008, 15: 915-922. 10.1245/s10434-007-9761-5CrossRefPubMed
6.
go back to reference Lin CY, Lee LY, Huang SF, Kang CJ, Fan KH, Wang HM, Chen EY, Chen IH, Liao CT, Cheng AJ, et al.: Treatment outcome of combined modalities for buccal cancers: unilateral or bilateral neck radiation? Int J Radiat Oncol Biol Phys 2008, 70: 1373-1381. 10.1016/j.ijrobp.2007.08.022CrossRefPubMed Lin CY, Lee LY, Huang SF, Kang CJ, Fan KH, Wang HM, Chen EY, Chen IH, Liao CT, Cheng AJ, et al.: Treatment outcome of combined modalities for buccal cancers: unilateral or bilateral neck radiation? Int J Radiat Oncol Biol Phys 2008, 70: 1373-1381. 10.1016/j.ijrobp.2007.08.022CrossRefPubMed
7.
go back to reference Fan KH, Lin CY, Kang CJ, Huang SF, Wang HM, Chen EY, Chen IH, Liao CT, Cheng AJ, Chang JT: Combined-modality treatment for advanced oral tongue squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2007, 67: 453-461. 10.1016/j.ijrobp.2006.06.026CrossRefPubMed Fan KH, Lin CY, Kang CJ, Huang SF, Wang HM, Chen EY, Chen IH, Liao CT, Cheng AJ, Chang JT: Combined-modality treatment for advanced oral tongue squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2007, 67: 453-461. 10.1016/j.ijrobp.2006.06.026CrossRefPubMed
9.
go back to reference Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR: Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 2006, 31: 164-172. 10.1016/j.tibs.2006.01.006CrossRefPubMed Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR: Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 2006, 31: 164-172. 10.1016/j.tibs.2006.01.006CrossRefPubMed
10.
go back to reference Nicchitta CV: Biochemical, cell biological and immunological issues surrounding the endoplasmic reticulum chaperone GRP94/gp96. Curr Opin Immunol 1998, 10: 103-109. 10.1016/S0952-7915(98)80039-3CrossRefPubMed Nicchitta CV: Biochemical, cell biological and immunological issues surrounding the endoplasmic reticulum chaperone GRP94/gp96. Curr Opin Immunol 1998, 10: 103-109. 10.1016/S0952-7915(98)80039-3CrossRefPubMed
11.
go back to reference Fu Y, Lee AS: Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther 2006, 5: 741-744. 10.4161/cbt.5.7.2970CrossRefPubMed Fu Y, Lee AS: Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther 2006, 5: 741-744. 10.4161/cbt.5.7.2970CrossRefPubMed
12.
go back to reference Wang XP, Liu GZ, Song AL, Chen RF, Li HY, Liu Y: Expression and significance of heat shock protein 70 and glucose-regulated protein 94 in human esophageal carcinoma. World J Gastroenterol 2005, 11: 429-432.PubMedCentralCrossRefPubMed Wang XP, Liu GZ, Song AL, Chen RF, Li HY, Liu Y: Expression and significance of heat shock protein 70 and glucose-regulated protein 94 in human esophageal carcinoma. World J Gastroenterol 2005, 11: 429-432.PubMedCentralCrossRefPubMed
13.
go back to reference Zheng HC, Takahashi H, Li XH, Hara T, Masuda S, Guan YF, Takano Y: Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum Pathol 2008, 39: 1042-1049. 10.1016/j.humpath.2007.11.009CrossRefPubMed Zheng HC, Takahashi H, Li XH, Hara T, Masuda S, Guan YF, Takano Y: Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum Pathol 2008, 39: 1042-1049. 10.1016/j.humpath.2007.11.009CrossRefPubMed
14.
go back to reference Chang JT, Chan SH, Lin CY, Lin TY, Wang HM, Liao CT, Wang TH, Lee LY, Cheng AJ: Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15. Mol Cancer Ther 2007, 6: 2271-2279. 10.1158/1535-7163.MCT-06-0801CrossRefPubMed Chang JT, Chan SH, Lin CY, Lin TY, Wang HM, Liao CT, Wang TH, Lee LY, Cheng AJ: Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15. Mol Cancer Ther 2007, 6: 2271-2279. 10.1158/1535-7163.MCT-06-0801CrossRefPubMed
15.
go back to reference Lin TY, Chang JT, Wang HM, Chan SH, Chiu CC, Lin CY, Fan KH, Liao CT, Chen IH, Liu TZ, et al.: Proteomics of the radioresistant phenotype in head-and-neck cancer: Gp96 as a novel prediction marker and sensitizing target for radiotherapy. Int J Radiat Oncol Biol Phys 2010, 78: 246-256. 10.1016/j.ijrobp.2010.03.002CrossRefPubMed Lin TY, Chang JT, Wang HM, Chan SH, Chiu CC, Lin CY, Fan KH, Liao CT, Chen IH, Liu TZ, et al.: Proteomics of the radioresistant phenotype in head-and-neck cancer: Gp96 as a novel prediction marker and sensitizing target for radiotherapy. Int J Radiat Oncol Biol Phys 2010, 78: 246-256. 10.1016/j.ijrobp.2010.03.002CrossRefPubMed
16.
go back to reference Bernier J, Cooper JS, Pajak TF, van GM, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005, 27: 843-850. 10.1002/hed.20279CrossRefPubMed Bernier J, Cooper JS, Pajak TF, van GM, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005, 27: 843-850. 10.1002/hed.20279CrossRefPubMed
17.
go back to reference Wang XP, Qiu FR, Liu GZ, Chen RF: Correlation between clinicopathology and expression of heat shock protein 70 and glucose-regulated protein 94 in human colonic adenocarcinoma. World J Gastroenterol 2005, 11: 1056-1059.PubMedCentralCrossRefPubMed Wang XP, Qiu FR, Liu GZ, Chen RF: Correlation between clinicopathology and expression of heat shock protein 70 and glucose-regulated protein 94 in human colonic adenocarcinoma. World J Gastroenterol 2005, 11: 1056-1059.PubMedCentralCrossRefPubMed
18.
go back to reference Kubota H, Suzuki T, Lu J, Takahashi S, Sugita K, Sekiya S, Suzuki N: Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines. Int J Radiat Biol 2005, 81: 701-709. 10.1080/09553000500434727CrossRefPubMed Kubota H, Suzuki T, Lu J, Takahashi S, Sugita K, Sekiya S, Suzuki N: Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines. Int J Radiat Biol 2005, 81: 701-709. 10.1080/09553000500434727CrossRefPubMed
Metadata
Title
GP96 is over-expressed in oral cavity cancer and is a poor prognostic indicator for patients receiving radiotherapy
Authors
Chien-Yu Lin
Ting-Yang Lin
Hung-Ming Wang
Shiang-Fu Huang
Kang-Hsing Fan
Chun-Ta Liao
I-How Chen
Li-Yu Lee
Yen-Liang Li
Yin-Ju Chen
Ann-Joy Cheng
Joseph T Chang
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2011
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/1748-717X-6-136

Other articles of this Issue 1/2011

Radiation Oncology 1/2011 Go to the issue