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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. Keywords: GP96, oral cavity cancers, prognosis, radioresistance Background radiotherapy (Postop-RT) with/without concurrent che- Oral cavity cancers (ORC) are among the most common motherapy is added to eliminate microscopic tumor cancers in the world . Epidemiological studies have cells in high-risk patients. However, locoregional failure remains a major problem if the tumor is radioresistant shown strong associations between ORC and the use of tobacco, alcohol and betel quid . The standard treat- [4-7]. ment for ORC is radical surgery . Postoperative Heat shock protein (Hsp) is a highly conserved mole- cular chaperone protein that functions as biochemical * Correspondence: firstname.lastname@example.org; email@example.com regulators of cell growth, apoptosis, and homeostasis. It Department of Radiation Oncology, Chang Gung Memorial Hospital, is up-regulated under stress conditions, such as starva- Taoyuan 333, Taiwan tion,hypoxia,heat, virusinfectionand neoplasia[8,9]. Department of Medical Biotechnology, Chang Gung University, Taoyuan 333, Taiwan Hsp GP96, also known as glucose-regulated protein 94 Full list of author information is available at the end of the article © 2011 Lin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lin et al. Radiation Oncology 2011, 6:136 Page 2 of 8 http://www.ro-journal.com/content/6/1/136 (GRP94), is a member of the Hsp 90 family . It plays cord after 46 Gy. Doses of 1.8-2 Gy/fraction were given an important role in regulating mitogenesis, cell cycle in 5 fractions per week. Initial prophylactic doses of 46- and apoptosis [8,9,11]. In addition, GP96 has been 50 Gy were for all risk areas and a further boost of 60 foundtoinduceprotectivetumor-specific immunity Gy for the primary tumor bed and involved nodal areas. . Recently, aberrant GP96-expression has been Elevated doses of 66 Gy in combination with concurrent observed in several cancers [12,13], suggesting a link chemotherapy were used in patients with positive mar- between neoplasms and GP96-expression. Our previous gins, nodal extracapsular spreading (ECS) or pathologi- cal multiple nodal metastasis. Concurrent chemotherapy work has shown that GP96 contributed to radioresis- was administered with intravenous Cisplatin 50 mg/m2 tance in nasopharyngeal carcinoma (NPC) and ORC cell lines [14,15], indicating that this molecule may affect and oral 5-FU analogue 1400 mg/m2 combined with the efficacy of radiotherapy. In this study, we investi- leucovorin 60 mg on a biweekly schedule during radio- gated the clinical significance of GP96 and the impact therapy. Patients were closely followed for at least three on treatment outcome in ORC patients with Postop-RT. years or until death. Patient status as of the last follow- up was recorded at the last outpatient visit, telephone Materials and methods interview or date of death. Patients and specimens We obtained tissue bank specimens from ORC patients Tissue processing, protein extraction and western blot visiting the Chang Gung Memorial Hospital-Linko analysis between Oct 1999 and Dec 2004. Samples were from 79 For each tissue, cellular proteins were extracted and the patients with newly diagnosed non-metastatic ORC level of GP96 protein was determined by western blot receiving radical surgery followed by Postop-RT. A method, similarly as previously described. Briefly, total grossly normal sample of oral mucosal tissue as well as of 20 μg tissues protein were separated by 8% SDS-poly- a tumor specimen was collected. This study was acrylamide gel electrophoresis and transferred to a approved by the Institutional Review Broad of the nitrocellulose membrane. The membrane was hybridized Human Investigation Committee in our institution. with an anti-GP96 antibody (NeoMarkers, Fremont, CA, USA) and subsequently incubated with secondary anti- Staging and Treatments bodies conjugated to horseradish peroxidase. The blots The pre-treatment workup included a chest X-ray, liver were developed using Renaissance chemiluminescence ultrasound and bone scan to exclude distant metastases. reagent (NEN Life Science Products, MA, USA) follow- F18-FDG PET (18-fluoro, 2-fluoro-2-deoxy-D-glucose, ing autoradiography. To determine the relative expres- positron emission tomography) was incorporated after sion of GP96 in tumor tissue, the band density of each Oct. 2003. Computed tomography (CT) or magnetic tumor sample was compared with the normal oral resonance imaging (MRI) was used to determine tumor mucosa sample taken from the same patient after nor- burden. Radical surgery was defined as a wide excision malization to an internal control (actin). GP96-overex- with a 1-2 cm safety margin with/without immediate pression was defined as a 1.5-fold increase in lesion free-flap reconstruction. Mandibulectomy or maxillect- tissue as compared with the normal oral mucosa. The omy were performed as dictated by tumor extension or level of GP96-expression and its associations with clini- margin space. Ipsilateral elective neck dissection was copathological parameters and treatment outcomes were used for clinical N0 patients and radical neck dissection analyzed. for clinical N+ patients. Intraoperative frozen examina- tions were performed to ensure adequate margins. The Statistical analysis definition of an adequate margin was a tumor-free mar- Time intervals were calculated from the end of RT to gin of at least 5 mm according to final pathological the events of interest. Locoregional control (LRC) was report. All tumor stage evaluations were revised accord- defined as freedom from relapse at the primary site or ing to the 2002 AJCC pathological staging criteria. neck, distant relapse for distant metastasis-free survival Postop-RT was scheduled within 4-8 weeks of surgery (DMFS), and either one for disease-free survival (DFS). and was administered as 6 megavolt x-ray generated by Disease-specific survival (DSS) was defined as survival a linear accelerator. Conventional radiotherapy techni- until death from the disease or treatment-related toxici- ques, 2-dimensional planning or 3-dimensional confor- ties, and any other cause for overall survival (OS). mal radiotherapy were used in early patients, while Relapse events were defined by imaging findings, clinical intensity-modulated radiotherapy (IMRT) was incorpo- or pathological examination. Commercial statistical soft- rated after 2001. Conventional techniques consisted of ware (SPSS 13.0; SPSS, Chicago, IL) was used for data bilateral-opposing and lower-anterior neck portals. Neck analysis. Variables that might affect outcomes were eval- boosts by megavolt electron were used for sparing spinal uated using the chi-squared test, independent t-test or Lin et al. Radiation Oncology 2011, 6:136 Page 3 of 8 http://www.ro-journal.com/content/6/1/136 Fisher’s exact test as appropriate. Survival curves were Table 1 Association between GP96 overexpression and clinicopathological parameters calculated by the Kaplan-Meier method with a log-rank test for univariate analysis. A stepwise Cox-regression Total GP96 over- patients expression model for multivariate analysis was used for further ana- No Yes lysis of potentially significant variables. No. % No. % No. % P Results Gender 0.518* Patient characteristics and treatment outcome Male 77 97.5 23 30 54 70 Our study included 79 patients, and median age was 48 Female 2 2.5 1 50 1 50 years old (range 30-75). The patient characteristics were Age (years) 0.573 listed in Table 1. Pre-treatment imaging was performed ≤ 48 44 51 11 27.5 29 72.5 using MRI (n = 42, 53%), CT scan (n = 32, 41%) or >48 39 49 13332667 both (n = 5, 6%). Thirteen (16.5%) patients also had Smoking 0.573* F18-FDG PET scans to aid diagnosis. Primary tumor No 14 18 4 29 10 71 site were buccal (n = 57, 72%) and majority of patients Yes 65 82 20 31 45 69 were stage IV disease (67%). The detailed T-N distribu- Drinking 0.237 tion is shown in Table 2. No 19 24 4 21 15 79 Radical surgery followed by Postop-RT was performed Yes 60 76 20 33 40 67 in this cohort. The median nearest resection margin was Betel-quid chewing 0.427* 8 mm (range: 1-15), and no patients had positive mar- No 14 18 5 36 9 64 gins. Neck dissection was ipsilateral (n = 67, 85%), bilat- Yes 65 82 19 29 46 71 eral (n = 10, 13%), and none (n = 1). For Postop-RT, Stage 0.349* elective neck irradiation was ipsilateral (n = 58, 73%) I-II 13 16.5 5 38.5 8 61.5 and bilateral in remaining cases. The median time inter- III-IV 66 83.5 19 29 47 71 val between operation and radiotherapy was 5.5 weeks T stage 0.390 (range: 2.7-15),and amediandoseof 66Gy(range: 56- T1-2 36 46 12 33 24 67 68) in median of 7 weeks (rang: 5.8-16). Thirty-eight T3-4 43 54 12 28 31 72 (48%) patients received concurrent chemotherapy. Nodal stage 0.020 The median follow-up time was 4.3 years (range, 2.1- N0-1 44 56 18 41 26 59 8.0). At the end of the study, 39 patients remained alive N2 35 44 6 17 29 83 and 40 had died. Deaths were due to locoregional dis- Nodal ECS 0.183 ease (n = 14), distant metastasis (n = 14), second pri- No 45 57 16 33 29 67 mary malignancy (n = 3), intercurrent disease (n = 8) Yes 34 43 8 23.5 26 76.5 and traffic accident (n = 1). Thirty-two patients suffered Differentiation 0.654 from recurrent disease and the detailed failure pattern is Well 24 30 9 37.5 15 62.5 showninFigure1.Atotalof20patients(25%) had Moderate 47 60 13 28 34 72 locoregional recurrence and 15 patients (19%) had dis- Poor 8 10 2 25 6 75 tant metastasis. All locoregional failures were infield Depth (millimeters) 0.045 recurrences except for two outfield neck recurrences. ≤10 30 38 13 43 17 57 >10 49 62 11223878 GP96 is over-expressed in oral cavity cancers and predicts Skin invasion 0.641* poorer treatment outcome No 72 91 22 31 50 69 Using the criterion of a 1.5-fold differential expression Yes 7 9 2 29 5 71 in tumor tissue compared to the normal counterpart, Bone invasion 0.402 there were 9 out of 79 patients (11.4%) whose tumor No 56 71 18 32 38 68 had GP96 under-expression (≤ 1.5-fold), 11 patients Yes 23 29 6 26 17 74 (19.0%) equal expression (between 0.67- to 1.5-fold), Perineural invasion 0.424 and 55 patients (69.6%) over-expression (≥ 1.5-fold, Fig- No 53 67 15 28 38 72 ure 2). However, the treatment outcomes had no statis- Yes 24 30 8 33 16 67 tical difference between under- and equal-expressed Missing 2 3 patients. Therefore, we categorized GP96 under- and Blood Vessel invasion equal-expression into the same group for analysis. The No 72 91 22 31 50 69 0.528* associations between GP96 over-expression and clinico- Yes 5 6 1 20 4 80 pathological factors are summarized in Table 1. Lin et al. Radiation Oncology 2011, 6:136 Page 4 of 8 http://www.ro-journal.com/content/6/1/136 Table 1 Association between GP96 overexpression and clinicopathological parameters (Continued) Missing 2 3 Lymphatic vessel invasion 0.069* No 65 82 22 34 43 66 Yes 12 15 1 8 11 92 Missing 2 3 Margin status (millimeters) 0.605* ≥ 5 66 83.5 20 30 46 70 < 5 13 16.5 4 31 9 69 * Fisher’s exact test Abbreviations: ECS = extracapsular spreading Figure 2 GP96 is highly expressed in advanced oral cancer tissues. Four pairs of normal (N) and tumor (T) tissues from oral Table 2 Distribution of pathological T and N stage cancer patients were examined. Protein expression was determined by western blot analysis. Actin protein expression served as an Pathological N stage internal control. Pathological T stage N0 N1 N2 Total T1 0 2 2 4 (5) T2 13 6 13 32 (40.5) DMFS (p = 0.018), DFS (p = 0.001), DSS (p = 0.001) T3 3 2 8 13 (16.5) and OS (p = 0.003). In multivariate analysis, GP96-over- T4 12 6 12 30 (38) expression remained independent significance on LRC Total 28 (36) 16 (20) 35 (44) 79 (100) (p = 0.018),DFS (p = 0.006),DSS (p = 0.011),OS (p = Values in parentheses are percentages 0.012), and marginal effect on DMFS (p = 0.072). Significant correlations were found between GP96-over- Contribution of GP96-expression to LRC in N stage or expression and nodal stage (p = 0.020) or tumor depth ECS-stratified populations (p = 0.045). Other associations were not observed. According to well-known pathological risk factors, The three-year overall LRC, DMFS, DFS, DSS and OS patients displaying positive margins, nodal ECS or pN2 were 69%, 78.6%, 57.5%, 63.3% and 56.6%, respectively. stage disease are at high risk in terms of selection for The treatment prognosis evaluation by univariate analy- concurrent chemoradiotherapy [5-7,16]. Therefore, we sis and multivariate analysis were summarized in Table further examined the effect of GP96-expression in rela- 3 and Table 4. In univariate analysis, patients with the tion to these indicators. Because no case with positive status of GP96-overexpression in tumors predicts poorer margins was available in this study, only pN2 stage dis- treatment outcome on 3-year LRC (p = 0.008, Figure 3), ease and nodal ECS were used. In this study, 3-year LRC for nodal ECS or pN2 were 54% and 62%, respec- tively (Figure 4A-B). Further stratified by GP96-expres- sion status, distinguishable four groups were observed. In patients with nodal ECS, GP96-overexpression still predicts poorer 3-year LRC 39% (vs.100%) (Figure4C) and also noted in patients with pN2 stage (54% vs. 100%) (Figure 4D). These results suggest that GP96 overexpression in tumor cells may be a significant pre- dictor of poor prognosis for those patients receiving radiotherapy. Discussion In this study, the treatment outcomes of ORC were comparable to previously published data [5-7]. Our data indicate that nodal ECS is a predictor of treatment out- comes by univariate analysis (Table 3). This effect was lost in the multivariate analysis of LRC, but it remained significant for other outcome (Table 4). The impact on treatment outcome of pN2 has only marginal effect. Figure 1 Treatment failure pattern. This observation agrees with our retrospective data Lin et al. Radiation Oncology 2011, 6:136 Page 5 of 8 http://www.ro-journal.com/content/6/1/136 Table 3 Univariate analysis of 3-year survival LRC (%) p DMFS (%) p DFS (%) p DSS (%) p OS (%) p Stage I-II 81.8 0.245 84.6 0.548 69.2 0.282 76.9 0.208 76.9 0.033 III-IV 66.4 77.5 55.1 60.4 54.2 T stage T1-2 77.5 0.145 81.9 0.458 66.3 0.139 71.3 0.144 66.7 0.021 T3-4 61.6 75.6 49.6 55.9 50.4 N stage N0-1 74.1 0.196 87.5 0.023 66.7 0.024 75.8 0.007 72.3 0.002 N2-3 62.2 66.8 45.8 46.6 40.0 Depth (millimeters) ≤10 61.2 0.367 90.0 0.118 55.1 0.938 67.9 0.694 62.4 0.417 >10 74.8 71.7 58.8 60.3 55.1 Differentiation Well 72.0 0.818 86.6 0.003 66.0 0.264 70.2 0.203 66.7 0.580 Moderate 67.1 82.5 56.6 64.1 56.8 Poor 75.0 37.5 37.5 37.5 37.5 Nodal ECS No 78.1 0.049 87.9 0.019 70.7 0.005 79.5 0.001 75.6 0.001 Yes 53.8 63.7 38.3 39.4 34.3 Skin invasion No 71.6 0.153 81.3 0.076 60.5 0.071 67.0 0.033 60.8 0.204 Yes 41.7 51.4 28.6 28.6 28.6 Bone invasion No 71.6 0.407 74.5 0.226 57.7 0.871 64.2 0.940 58.9 0.251 Yes 62.7 90.7 56.9 60.2 54.8 Perineural invasion No 68.1 0.717 81.3 0.295 58.6 0.349 67.8 0.170 62.0 0.318 Yes 71.9 69.2 51.9 50.0 45.8 Blood vessel invasion No 67.5 0.729 78.0 0.999 56.0 0.891 62.4 0.909 56.6 0.741 Yes 80.0 75.0 60.0 60.0 60.0 Lymphatic vessel invasion No 67.6 0.845 81.9 0.014 58.1 0.218 65.1 0.106 59.6 0.117 Yes 75.8 55.6 46.3 45.8 41.7 Margin status (millimeters) ≥ 5 67.1 0.406 77.3 0.737 55.4 0.517 59.2 0.152 54.1 0.157 <5 80.8 84.6 68.4 83.3 65.9 Concurrent chemotherapy No 70.8 0.613 89.3 0.014 65.2 0.071 72.6 0.506 70.6 0.022 Yes 67.8 66.0 48.9 52.4 44.3 GP96 overexpression No 90.2 0.008 95.8 0.018 86.5 0.001 95.7 0.001 87.5 0.003 Yes 58.7 69.5 44.7 49.0 44.9 Abbreviation: LRC = locoregional control; DMFS = distant metastasis-free survival; DFS = disease-free survival; DSS = disease-specific survival; OS = overall-survival; ECS = extra-capsular spreading. Table 4 Multivariate analysis of significant risk factors for survival P Hazard % 95 CI LRC GP96 over-expression 0.018 5.808 1.345-25.093 DMFS GP96 over-expression 0.072 6.504 0.848-49.871 Skin invasion 0.020 4.973 1.289-19.190 Differentiation 0.015 3.975 1.309-12.065 Concurrent chemotherapy 0.052 3.276 0.992-10.821 DFS GP96 over-expression 0.006 5.326 1.614-17.580 Nodal ECS 0.019 2.337 1.148-4.758 DSS GP96 over-expression 0.011 6.532 1.530-27.890 Nodal ECS 0.014 2.698 1.225-5.942 Skin invasion 0.040 2.806 1.046-7.526 Figure 3 GP96-overexpression is a poorer prognostic factor on locoregional control (LRC), as shown by the survival curves OS calculated by the Kaplan-Meier method. GP96(+): GP96 GP96 over-expression 0.012 3.355 1.302-8.648 overexpression, as the protein level is 1.5-fold higher in the tumor Nodal ECS 0.005 2.533 1.332-4.819 tissue compared to the normal counterpart; GP96(-): GP96 non- Abbreviation: LRC = locoregional control; DMFS = distant metastasis-free overexpression, as the protein level is comparable or lower (≤ 1.5- survival; DFS = disease-free survival; DSS = disease-specific survival; OS = fold) compared to the normal counterpart. overall-survival; ECS = extra-capsular spreading. Lin et al. Radiation Oncology 2011, 6:136 Page 6 of 8 http://www.ro-journal.com/content/6/1/136 (A) (B) (C) (D) Figure 4 Contribution of GP96-expression on locoregional control (LRC) in nodal ECS (A) or pN2 (B) stage-stratified patients, and provides additional information when stratified by risk of ECS (C) or N stage (D). All the survival curves were calculated by the Kaplan- Meier method. ECS(+): positive for nodal ECS; ECS(-): negative for nodal ECS; N0-1: N0-1 stage; N2: N2 stage; GP96(+): GP96 overexpression, as the protein level is 1.5-fold higher in the tumor tissue compared to the normal counterpart; GP96(-): GP96 non-overexpression, as the protein level is comparable or lower (≤ 1.5-fold) 1.5-fold) compared to the normal counterpart. indicating that concurrent chemoradiotherapy can over- that GP96 is overexpressed in several human neoplasms come this negative effect, and considering of GP96- [12,13,17]. It indicates that GP96 plays an important expression is another important issue. role in cancer development and continuous expression 2+ GP96, a 94-100 kDa Ca -binding protein, is the most required for regulation and stabilizing tumor growth abundant protein in the endoplasmic reticulum (ER). It . We also found that GP96-expression was corre- functions as a chaperone in ER, regulates mitogenesis, lated with tumor depth and N stage (Table 1). It is con- apoptosis, and antigenic-presenting immune response sistent with reports suggesting associations between [8-11]. Up-regulation of GP96-expression has been elevated GP96-expression and tumor advanced stage or reported under stress conditions, including starvation, invasive ability. In addition, we found that GP96-overex- hypoxia, heat, viral infection and neoplasia [8,9]. In the pression was a strong independent prognostic factor for presence of stress, the final fate of cells may depend on LRC, DFS, DSS and OS, although a marginal effect on their ability to resist stress. GP96 regulates cell fate by DMFS (Table 3). It is consistent with a previous report 2+ maintaining the intracellular Ca balance between the indicating that GP96-expression serves as a poor prog- cytosol, ER and mitochondria. In this study, we exam- nostic factor in gastric carcinoma . ined GP96-expression in advanced ORC patients and As mentioned above, GP96-expression was a strong found that GP96 is overexpressed in 70% of patients, predictor of LRC (p=0.008, Table 3, Figure 3) and which is consistent with previous findings indicating was the only independent predictor in the multivariate Lin et al. Radiation Oncology 2011, 6:136 Page 7 of 8 http://www.ro-journal.com/content/6/1/136 processing. CYL and AJC did the laboratory interpretation. CYL did the data models (Table 4). We therefore hypothesize that GP96- analysis. HMW, SFH, KHF and JTC participated in the clinical data expression is strongly associated with tumor radioresis- interpretation. CYL, HMW, SFH, KHF, CTL and IHC treated the patients and tance. Based on these observations, we further analyzed did the data collection. All authors read and approved the final manuscript the effect of GP96-expression using stratification by Competing interests well-established pathological risk factors such as nodal The authors declare that they have no competing interests. ECS or pN2 stage; the adverse effect of GP96-expres- Received: 28 April 2011 Accepted: 12 October 2011 sion was still distinguishable (Figure 4C-D). We Published: 12 October 2011 observed GP96-overexpression makes it poorer on LRC in patients with nodal ECS or pN2 stage, suggest- References ing that GP96 may exhibit tumor radioresistance. 1. 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 Interestingly, in non-GP96-overexpression group, if advances in molecular carcinogenesis. Cancer Sci 2008, 99:1507-1514. patients with nodal ECS or pN2, which were high-risk 2. 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Wang XP, Qiu FR, Liu GZ, Chen RF: Correlation between clinicopathology Authors’ contributions and expression of heat shock protein 70 and glucose-regulated protein CYL, AJC and JTC prepared the study concept and design. CYL did the 94 in human colonic adenocarcinoma. World J Gastroenterol 2005, major manuscript writing. AJC and JTC did the major revision of the 11:1056-1059. manuscript. CYL, YLL and TYL made the major contribution for tissue Lin et al. Radiation Oncology 2011, 6:136 Page 8 of 8 http://www.ro-journal.com/content/6/1/136 18. 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. doi:10.1186/1748-717X-6-136 Cite this article as: Lin et al.: GP96 is over-expressed in oral cavity cancer and is a poor prognostic indicator for patients receiving radiotherapy. Radiation Oncology 2011 6:136. 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Radiation Oncology – Springer Journals
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