Excision repair cross‑complementing group 2 upregulation is a potential predictive biomarker for oral squamous cell carcinoma recurrence
- Authors:
- Published online on: April 7, 2021 https://doi.org/10.3892/ol.2021.12711
- Article Number: 450
-
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The oral cavity is the most prevalent area of malignancy in the head and neck region, with the GLOBOCAN 2020 data estimating the annual incidence and mortality as ~377,713 new cases and 177,757 deaths, respectively, for lip and oral cavity cancer, which is the fourth most common type of cancer among males in Taiwan (1–3). Squamous cell carcinoma constitutes the most commonly seen histological type in patients with oral cavity cancer (4). Radical surgery with or without adjuvant chemo-radiotherapy is part of the primary management for patients with oral squamous cell carcinoma (OSCC), and radical surgery has proven to be valuable in loco-regional disease control (5). Although 80–90% of early OSCC cases are cured, the prognosis for patients with advanced-stage OSCC remains poor (6,7). For patients who have undergone standard management, OSCC recurrence varies between 18 and 76%, and recurrence has been identified as the major cause of poor survival rates (8–11). Previous studies have indicated that the median time to recurrence is 7.5 months after therapy, with 86% of recurrences occurring among 24 months (12–14).
In Taiwan, cisplatin is the mainstay of chemotherapy for locally advanced oral cancer treatment. Its crucial cytotoxic activity is due to the formation of DNA adducts, which result in inter-strand and intra-strand cross-linking (15,16). These DNA cross-links are identified and eliminated by the nucleotide excision repair (NER) pathway protecting the integrity of the genome (17,18). Tumor resistance to this platinum complex seems to be multifactorial, with the NER pathway serving a crucial role (19). NER is a stepwise procedure of recognition, incision, excision, DNA synthesis and ligation, which is executed by a multienzyme complex (20,21). Previous studies have investigated the association between gene expression and the effects of various chemotherapeutic agents in cancer (22–24), such as excision repair cross-complementing group 1 (ERCC1) being identified as a marker for resistance to cisplatin in non-small-cell lung cancer. Platinum resistance has been attributed to enhanced repair of DNA damage via the NER pathway, which consists of X-ray cross-complementing 1 (XRCC1), ERCC1 and ERCC2 (25–28).
Concurrent chemo-radiotherapy is regularly used for locally advanced oral cancer treatment. DNA single-strand breaks may take place directly from the damage to deoxyribose, or indirectly as the ordinary intermediates of DNA base excision repair (29). Since single-strand breaks are provoked by endogenous reactive molecules, such as reactive oxygen species, these injuries create a sustained threat to genetic integrity (29). In mammalian cells, the XRCC1 protein plays a leading part in the repair of single-strand breaks via its capability to interact with multiple enzymatic complexes of restoration (29). Hypersensitivity to oxidative stress, ionizing radiation and alkylating agents has been observed in cells lacking XRCC1 (29). A previous study has indicated that high expression of both XRCC1 and ERCC1 is significantly associated with radioresistant laryngeal carcinoma (30).
XRCC1, ERCC1 and ERCC2 are well-reported DNA repair proteins, implying their involvement in resistance to chemo-radiotherapy; however, to the best of our knowledge, no studies have explored the association of these NER pathway-associated proteins with recurrence and prognosis in patients with OSCC. Therefore, the current study hypothesized that high protein expression levels of XRCC1, ERCC1 and ERCC2 may lead to treatment resistance and recurrence or poor clinical outcomes in patients with OSCC.
Materials and methods
Cell culture
Human oral keratinocytes (HOK; ScienCell Research Laboratories, Inc.) were incubated with Oral Keratinocyte Medium (ScienCell Research Laboratories, Inc.) in plates pre-coated with 2 µg/cm2 poly-L-lysine. DOK oral precancerous cells were grown in DMEM supplemented with 10% FBS (both Thermo Fisher Scientific, Inc.), penicillin (100 U/ml), streptomycin (100 µg/ml), glutamine (2 mM) and hydrocortisone (5 µg/ml). Oral cancer SAS, OECM1, HSC-3 and Cal-27 cells were grown in Eagle's Minimum Essential Medium (Thermo Fisher Scientific, Inc.) with glutamine (2 mM) and FBS (10%), while human malignant glioma U87MG cells (American Type Culture Collection; glioblastoma of unknown origin) were grown in DMEM supplemented with 10% FBS. All cells were incubated in 5% CO2 at 37°C.
Western blotting
Total cell lysates were extracted using RIPA buffer (Thermo Fisher Scientific, Inc.) and protein concentrations were detected using the BCA protein assay (Bio-Rad Laboratories, Inc.). Protein lysates (20 µg/lane) were separated via 10% SDS-PAGE and transferred to a PVDF membrane, which was then blocked for 1 h at room temperature with 5% non-fat milk in TBS-0.1% Tween-20 (TBST). Subsequently, the membrane was incubated overnight at 4°C with primary antibodies including XRCC1 monoclonal antibody (1:1,000; cat. no. GTX83411; GeneTex, Inc.), ERCC1 monoclonal antibody (1:1,000; cat. no. GTX22356; GeneTex, Inc.), ERCC2 polyclonal antibody (1:1,000; cat. no. GTX105357; GeneTex, Inc.) and β-actin antibody (1:10,000; cat. no. GTX629630; GeneTex, Inc.). After washing three times with TBST for 10 min, the membrane was incubated with HRP-conjugated secondary antibody (1:5,000; cat. no. GTX213110-01; GeneTex, Inc.) for 2 h at room temperature. The immunoblots were visualized using Chemiluminescence Reagent Plus (PerkinElmer, Inc.) and quantified using Image Lab™ software version 5.1 (Bio-Rad Laboratories, Inc.).
Oncomine™ platform
To study the mRNA expression levels of XRCC1, ERCC1 and ERCC2 in oral cancer and normal oral tissues, Oncomine™ [Estilo Head-Neck: XRCC1160033_s_at (31), Peng Head-Neck: XRCC13864445 (32), Cromer Head-Neck: ERCC11902_at (33), Ginos Head-Neck: ERCC1203720_s_at (34), Peng Head-Neck: ERCC13865378 (32), Peng Head-Neck: ERCC23865301 (32), Ginos Head-Neck: ERCC2213468_at (34), Cromer Head-Neck: ERCC241095_at (33)], an integrated cancer microarray database and web-based data-mining platform (35), was used.
Patients
Between September 2002 and December 2011, a total of 98 patients with OSCC (92 men and 6 women) were enrolled from the Department of Oral and Maxillofacial Surgery of Kaohsiung Medical University Hospital (Kaohsiung, Taiwan), with a median follow-up time of 40 months (range, 2.4–137.4 months). G*Power (version 3.1.9.4; http://ps-power-and-sample-size-calculation.software.informer.com/3.1/), a freely available windows application software, was used for sample size and power estimation, with α=0.05 and estimated effect size w=0.46. A total of 98 patients were recruited in the present study to achieve sufficient power of ≥90%. The current study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (approval no. 20140158) and patient informed consent was waived by the Institutional Review Board due to the retrospective nature of the study. OSCC pathology was determined by two pathologists independently, and the final diagnoses were made using clinical and histological data. Patients without previous history of any treatment for oral cancer were included. Patients who were <18 or >80 years old were excluded. Baseline characteristic data included patient age, sex, tumor location, grade, tumor size, lymph node metastases and tumor stage; additionally, substance use, such as alcohol consumption, betel nut chewing or cigarette smoking, and adjunct treatment details were recorded (Table I). The mean age of the study group was 51.4 years and the median age was 51 years (age range, 31–76 years). Clinical staging of the patients was determined using the TNM staging system according to the 1992 criteria of the American Joint Committee on Cancer/Union for International Cancer Control (36). The primary tumor locations were buccal mucosa (77.6%) and tongue (22.4%). All of the patients received surgery as primary treatment, and some patients received adjuvant treatment, such as radiotherapy and chemotherapy. A total of 62 patients received adjuvant chemotherapy, with the chemotherapy regimen consisting of cisplatin or carboplatin with or without the addition of 5-fluorouracil or paclitaxel. A total of 45 patients received adjuvant intensity-modulated radiotherapy, and the scheduled doses were given once per day, 5 days per week. Postoperative patients received the planned course of adjuvant radiotherapy of 60–66 Gy in 2-Gy fractions to the post-operative high-risk region.
Survival endpoints and recurrence
Follow-up data was retrieved and updated from case records obtained from the medical records department until October 2014. Any patient not followed up within the last six months was contacted by phone to determine their current health status. Primary endpoints were disease-free survival (DFS) and overall survival (OS), with DFS being measured from the date of surgery to the date of locoregional recurrence, distant metastases or death from any cause, while OS was measured from the date of surgery to the date of death from any cause. Postoperative recurrence was defined as a lesion that exhibited postoperative regrowth at the same site after confirmation of healing of the surgical wounds.
Immunohistochemical (IHC) analysis
To determine the expression levels of XRCC1, ERCC1 and ERCC2 in OSCC tissues by IHC staining, the tissues were fixed in 10% neutral buffered formalin for 48 h at room temperature to prepare paraffin-embedded tumor tissue blocks for IHC sections (4-mm-thick). For the normal control, the oral mucosa tissue from a delinked patient with fibroma was used after Institutional Review Board approval (approval no. KMUH-IRB-20140158). Sections were deparaffinized and rehydrated following standard methods. Briefly, the sections were deparaffinized with xylene for 5 min for three times and rehydrated in graded ethanol (80–100%) for 5 min. A microwave antigen retrieval procedure was performed for 20 min in citrate buffer (pH 6.0), and 3% hydrogen peroxide was used to block non-specific peroxidase reactions at room temperature for 10 min. After washing twice with TBS, non-specific blocking was performed with Protein Block (Novolink Polymer Detection System; Leica Microsystems, Inc.) for 5 min at room temperature and washed twice with TBS. Following washing with TBS, sections were incubated with the aforementioned XRCC1 monoclonal antibody (1:100), ERCC1 monoclonal antibody (1:200) and ERCC2 polyclonal antibody (1:100) at 4°C overnight. The sections were subsequently incubated with the Post Primary rabbit anti-mouse IgG antibody (Novolink Polymer Detection System; Leica Microsystems, Inc.) for 30 min at room temperature as secondary antibody application. The staining intensity of tumor tissues was determined as score 0 (negative), score 1 (weak), score 2 (moderate) and score 3 (strong) for antigens present in the cytoplasm and nucleus of cells using a light microscope (magnification, ×200), determined separately by two independent pathologists.
Statistical analysis
Statistical analyses were performed using SPSS 19.0 (IBM Corp.). Descriptive statistics were used and compared using independent t-test, χ2 test or Fisher's exact test. Survival analyses were evaluated using the Kaplan-Meier method with the log-rank test, while the Cox proportional-hazards model was used for multivariate analysis. Furthermore, hazard ratios (HRs) and 95% CIs were calculated by multivariable Cox regression models and used to investigate the association between clinicopathological characteristics and survival. DFS was defined as the time after surgery during which the patient survived with no sign of recurrence. OS was defined as the time elapsed between surgery and death. All P-values were two-sided, with P<0.05 considered to indicate a statistically significant difference.
Results
Expression profiles of XRCC1, ERCC1 and ERCC2 in oral cancer cell lines
Since DNA repair proteins are essential for oral cancer cells in response to chemo-radiotherapy, the expression levels of XRCC1, ERCC1 and ERCC2 in HOK normal oral epithelial cells, DOK oral pre-cancer cells and oral cancer SAS, OECM1, HSC-3 and Cal-27 cell lines were first examined using western blotting (Fig. 1), with U87MG glioblastoma cells being included as a positive control for XRCC1, ERCC1 and ERCC2 proteins (37). The results revealed that the expression levels of XRCC1 and ERCC1 were weakly detected in all oral cancer cells, while ERCC2 expression was detected in all cell lines (Fig. 1). Notably, HOK cells had lower ERCC2 protein expression compared with DOK cells and the oral cancer cell lines.
Association of XRCC1, ERCC1 and ERCC2 expression in OSCC tissues with clinicopathological characteristics
In the present study, 98 patients with OSCC (92 men and 6 women) were included. The clinicopathological characteristics of these patients, including age, sex, tumor location, grade, tumor size, lymph node metastases, tumor stage, radiotherapy, chemotherapy, smoking habit and recurrence, are shown in Table I. XRCC1, ERCC1 and ERCC2 expression in oral cancer tissues, as well as in normal oral mucosa tissue of a patient with fibroma, was analyzed using an online database and IHC analysis. The Oncomine database revealed that the mRNA expression levels of XRCC1, ERCC1 and ERCC2 were significantly increased in oral cancer tissues compared with in normal epithelial tissues (Fig. S1), except in the Peng Head-Neck XRCC1-3864445 dataset, where there was no significant difference, but there was still a trend toward XRCC1 elevation in oral cancer tissues (P=0.061; Fig. S1A). Notably, IHC staining without addition of the primary antibody was used as a negative control for XRCC1, ERCC1 and ERCC2 staining (Fig. S2). According to the staining intensity in tumor tissues, the expression levels of the three proteins were categorized into four scores (0–3). XRCC1 and ERCC1 proteins were predominantly stained in the nuclei, while ERCC2 protein was predominantly stained in the cytoplasm of oral cancer tissues (Fig. 2). To analyze the association between the protein expression levels of the three proteins in OSCC tissues and clinicopathological characteristics, the expression levels of the three proteins were further divided into high expression (score 3) and low expression (score 0–2) groups. High expression groups of XRCC1 (P=0.020), ERCC1 (P=0.006) or ERCC2 (P<0.001) were significantly associated with OSCC recurrence (Tables II–IV). Furthermore, univariate and multivariate analyses were used to explore OSCC recurrence predictors in patients with OSCC. In univariate analysis, lymph node metastases (N1+N2), high XRCC1 expression, high ERCC1 expression and high ERCC2 expression were significantly associated with OSCC recurrence (P=0.006, P=0.020, P=0.006 and P<0.001, respectively; Table V). In multivariate analysis, lymph node metastases (N1+N2) (2.38-fold; 95% CI, 1.02–5.58; P=0.045) and high ERCC2 expression (4.84-fold; 95% CI, 2.56–9.16; P<0.001) were significantly associated with increased risk of OSCC recurrence (Table V).
 | Table II.Association between clinical characteristics of patients with oral squamous cell carcinoma and XRCC1 expression. |
| Table IV.Association between clinical characteristics of patients with oral squamous cell carcinoma and ERCC2 expression. |
| Table V.Univariate and multivariate analyses of recurrence predictors in 98 patients with oral squamous cell carcinoma. |
Univariate and multivariate analyses were also used to explore OSCC survival predictors in patients with OSCC. In univariate analysis, tumor size, lymph node metastases (N1+N2), tumor stage, high XRCC1 expression, high ERCC1 expression and high ERCC2 expression were significantly associated with a worse survival in patients with OSCC (P=0.001, P=0.005, P=0.001, P=0.002, P=0.014 and P<0.001, respectively; Table VI). In multivariate analysis, tumor location (4.11-fold; 95% CI, 1.392–12.14; P=0.01) and high ERCC2 expression (15.55-fold; 95% CI, 4.34–55.67; P<0.001) were significantly associated with increased risk of death (Table VI).
| Table VI.Univariate and multivariate analysis of survival predictors in 98 patients with oral squamous cell carcinoma. |
The association between the expression levels of the three proteins and DFS or OS rates in patients with OSCC was analyzed using the Kaplan-Meier method. Significantly decreased DFS rates were observed in patients with high expression levels of XRCC1, ERCC1 and ERCC2 (P=0.020, P=0.040 and P<0.001, respectively), as well as significantly decreased OS rates in patients with high expression levels of XRCC1, ERCC1 and ERCC2 (P=0.002, P=0.014 and P<0.001, respectively), as determined using the log-rank test (Fig. 3). The findings of the survival analysis indicating that high ERCC2 expression indicated a poor prognosis were consistent with the results of the multivariate analysis.
Discussion
In the present study, the association between the expression levels of NER pathway-associated genes and the recurrence and survival outcome in patients with OSCC was explored by examining the expression levels of XRCC1, ERCC1 and ERCC2 in a series of oral cavity epithelial cells, revealing that ERCC2, but not ERCC1 or XRCC1, exhibited a trend of positive association with the neoplastic development from normal epithelium to dysplasia and OSCC. However, some cancer cells expressed lower expression levels of XRCC1, ERCC1 and ERCC2 than HOK normal oral keratinocytes and DOK oral precancerous cells, and this requires further investigation. In addition, high expression levels of the three proteins in OSCC tissues were significantly associated with worse OS and DFS rates compared with low expression levels. Notably, the multivariate analysis revealed that high ERCC2 expression was an independent prognostic marker for OSCC recurrence.
High ERCC1 expression in head and neck squamous cell carcinoma (HNSCC) has been extensively studied as a potential prognostic biomarker for the chemoradiotherapy response and survival prognosis of patients with HNSCC (38–42). Although the genetic variations of ERCC2 and XRCC1 have been reported to be associated with increased risk and worse clinical outcome of oral cancer (43–47), there is very little data on ERCC2 and XRCC1 expression in oral cancer. A systematic review and case-control study has revealed that ERCC2 expression is significantly increased in HNSCC tissues compared with in adjacent normal tissues, and that it is positively associated with tumor stage and grade (48). The present study indicated that ERCC1, ERCC2 and XRCC1 expression was associated with the survival rate of patients with OSCC. To the best of our knowledge, the current study is the first to suggest ERCC2 as a prognostic marker for OSCC recurrence.
The association between the synthesis of DNA repair proteins in tumor cells and the patient response to chemo-radiotherapy has been reported in different types of cancer. In patients with non-small cell lung cancer, low ERCC1 expression indicates an improved prognosis after treatment with multidrug chemotherapy (22). High XRCC1 and ERCC1 expression is associated with a poor prognosis in patients with HER2+ breast cancer (47), while high ERCC1 expression has been associated with resistance to platinum-based chemotherapy in patients with ovarian cancer (49). In addition, ectopic ERCC1 expression in ovarian cancer cells increases the resistance to cisplatin-mediated growth inhibition (50). NER capacity serves a major role in normal tissue tolerance and drug resistance; moreover, ERCC2 and ERCC1 act as rate-limiting enzymes in NER (51). During NER, ERCC2 participates in DNA unwinding, and this function may alter the platinum-based chemotherapy effect (52). In a previous study, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes were significantly associated with oral cancer in Taiwan (44). Several studies have suggested that cancer cells with upregulation of DNA repair proteins are more resistant to chemoradiotherapy (53–55). Therefore, according to the present study, further investigation on the mechanism of the biological process of ERCC2 may provide potential targets for pharmacological modulation that helps improve the efficiency of chemo-radiotherapy.
Cigarette smoking, alcohol consumption and betel quid chewing are well-known risk factors for oral cancer. Most oral cancer cases (~90%) in South-East Asia are associated with smoking (56), while the proportions of cases associated with alcohol drinking and betel quid chewing are 80 and 75%, respectively. These agents may act synergistically. A working group of the International Agency for Research on Cancer concluded that there was adequate evidence of an association between chewing betel quid together with tobacco use (chewing or smoking) as a combined risk factor (57). In areas where the habit of betel quid chewing is widespread, these risk factors should be taken into consideration and require further investigation. However, the influence of smoking on clinical outcome of patients with oral cancer is in debate, since while smoking has a negative impact on survival, its effect is influenced by other confounding factors, such as treatment method, age, tumor size, smoking status or dose-response relationship (58–62). When patients stop smoking, survival benefits have been observed in several types of cancer, including head and neck cancer (59,63). In the current study, cigarette smoking, alcohol consumption and betel quid chewing were not associated with recurrence in univariate or multivariate analysis, which may be due to fewer non-users. Further larger scale studies are required to solve this contradiction.
According to GLOBOCAN 2020, the ratio of oral cancer incidence in male and female is 2:1 in Asia and 2.5:1 worldwide; however, male is the predominant sex for oral cancer in Taiwan (2). According to the Taiwan cancer registry annual report 2017, the proportion of female patients with oral cancer was 10.7%, and females represented 6% of the total sample size in the present study, which is similar to the general oral cancer population in Taiwan (3).
The current study has some limitations. First, data regarding socioeconomic factors were not collected and analyzed, and second, data were from a single tertiary cancer care center; therefore, more extensive multi-center studies are required to reinforce the present findings. Third, the median follow-up time was 40 months, and a longer follow-up time is required for full surveillance of cancer recurrence. Lastly, reverse transcription-quantitative PCR may also be a useful approach to analyze mRNA expression.
In future studies, the mechanisms of ERCC1, ERCC2 and XRCC1 participating in OSCC carcinogenesis through the NER pathway should be analyzed both in vitro and in vivo, and larger prospective studies to validate the possible role of ERCC2 in OSCC outcome prediction should be performed.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was financially supported by grants from the Ministry of Health and Welfare of Taiwan (grant no. MOHW109-TDU-B-212-134016, Health and Welfare Surcharge of Tobacco Products) and from the ‘Center For Intelligent Drug Systems and Smart Bio-devices’ from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (grant no. IDS2B). Additionally, it was supported by grants from the Kaohsiung Medical University Hospital (grant nos. KMUH105-5R32, KMUH106-6R41, KMUH106-6R83, KMUH107-7R36, KMUH108-8R42, KMUH108-8R66, KMUH-DK109001-3 and KMUH109-9R78), Kaohsiung Medical University (Research Center Grant; grant nos. KMU-DK108005 and KMU-DK109001), Kaohsiung Medical University Research Center Grant (Center for Cancer Research; grant nos. KMU-TC108A04-0 and KMU-TC108A04-1) and the Ministry of Science and Technology of Taiwan (grant nos. MOST 107-2314-B-037-097-MY2, MOST 108-2314-B-037-021-MY3 and MOST 108-2314-B-037-014).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on request.
Authors' contributions
YYW, PTF, CWS, YKC, JJH, MYH and SSFY conceived and designed the experiments. YYW, YKC, MYH and SSFY performed the experiments. YYW, PTF, JYH, MYH and SSFY analyzed and discussed the data. YYW, PTF, MYH and SSFY contributed to reagents/materials/analysis tools. YYW, PTF, JYH, YKC, JJH, MYH and SSFY wrote the manuscript. MYH and SSFY are responsible for confirming the authenticity of the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethics approval was obtained from the Institutional Review Board of Kaohsiung Medical University Hospital (approval no. 20140158) and informed consent was waived due to the retrospective nature of the study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Hsieh TY, Chang KP, Lee SS, Chang CH, Lai CH, Wu YC, Huang SH, Lai CS and Lin SD: Free flap reconstruction in patients with advanced oral squamous cell carcinoma: Analysis of patient survival and cancer recurrence. Microsurgery. 32:598–604. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Feb 4–2021.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI | |
|
Ministry of Health Welfare, . The cause of death in Taiwan in 2018. https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=269&pid=13498 | |
|
Rivera C and Venegas B: Histological and molecular aspects of oral squamous cell carcinoma (Review). Oncol Lett. 8:7–11. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Liao CT, Wang HM, Ng SH, Yen TC, Lee LY, Hsueh C, Wei FC, Chen IH, Kang CJ, Huang SF and Chang JT: Good tumor control and survivals of squamous cell carcinoma of buccal mucosa treated with radical surgery with or without neck dissection in Taiwan. Oral Oncol. 42:800–809. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Eich HT, Löschcke M, Scheer M, Kocher M, Bongartz R, Wacker S, Zöller JE and Müller RP: Neoadjuvant radiochemotherapy and radical resection for advanced squamous cell carcinoma of the oral cavity. Outcome of 134 patients. Strahlenther Onkol. 184:23–29. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Kreppel M, Drebber U, Eich HT, Dreiseidler T, Zöller JE, Müller RP and Scheer M: Combined-modality treatment in advanced oral squamous cell carcinoma: Primary surgery followed by adjuvant concomitant radiochemotherapy. Strahlenther Onkol. 187:555–560. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Fan KH, Wang HM, Kang CJ, Lee LY, Huang SF, Lin CY, Chen EY, Chen IH, Liao CT and Chang JT: Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: Coexistence of multiple minor risk factors results in higher recurrence rates. Int J Radiat Oncol Biol Phys. 77:1024–1029. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Woolgar JA, Rogers S, West CR, Errington RD, Brown JS and Vaughan ED: Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol. 35:257–265. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Liu CH, Chen HJ, Wang PC, Chen HS and Chang YL: Patterns of recurrence and second primary tumors in oral squamous cell carcinoma treated with surgery alone. Kaohsiung J Med Sci. 29:554–559. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Wang B, Zhang S, Yue K and Wang XD: The recurrence and survival of oral squamous cell carcinoma: A report of 275 cases. Chin J Cancer. 32:614–618. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 350:1945–1952. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 350:1937–1944. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Fan S, Tang QL, Lin YJ, Chen WL, Li JS, Huang ZQ, Yang ZH, Wang YY, Zhang DM, Wang HJ, et al: A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma. Int J Oral Sci. 3:180–191. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Pignon JP, le Maître A, Maillard E and Bourhis J; MACH-NC Collaborative Group, : Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol. 92:4–14. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Winquist E, Agbassi C, Meyers BM, Yoo J and Chan KKW; Head and Neck Disease Site Group, : Systemic therapy in the curative treatment of head and neck squamous cell cancer: A systematic review. J Otolaryngol Head Neck Surg. 46:292017. View Article : Google Scholar : PubMed/NCBI | |
|
Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ and Reed E: Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest. 94:703–708. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Murray D and Rosenberg E: The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. Mutat Res. 364:217–226. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Manic S, Gatti L, Carenini N, Fumagalli G, Zunino F and Perego P: Mechanisms controlling sensitivity to platinum complexes: Role of p53 and DNA mismatch repair. Curr Cancer Drug Targets. 3:21–29. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Sancar A: DNA excision repair. Annu Rev Biochem. 65:43–81. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Petit C and Sancar A: Nucleotide excision repair: From E. coli to man. Biochimie. 81:15–25. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 355:983–991. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Felip E and Rosell R: Testing for excision repair cross-complementing 1 in patients with non-small-cell lung cancer for chemotherapy response. Expert Rev Mol Diagn. 7:261–268. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Olaussen KA, Mountzios G and Soria JC: ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer. Curr Opin Pulm Med. 13:284–289. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Altaha R, Liang X, Yu JJ and Reed E: Excision repair cross complementing-group 1: Gene expression and platinum resistance. Int J Mol Med. 14:959–970. 2004.PubMed/NCBI | |
|
Weaver DA, Crawford EL, Warner KA, Elkhairi F, Khuder SA and Willey JC: ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer. 4:182005. View Article : Google Scholar : PubMed/NCBI | |
|
Huang MY, Tsai HL, Lin CH, Huang CW, Ma CJ, Huang CM, Chai CY and Wang JY: Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy. J Surg Oncol. 108:457–464. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Chiu TJ, Chen CH, Chien CY, Li SH, Tsai HT and Chen YJ: High ERCC1 expression predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous cell carcinoma of head and neck in a betel-chewing area. J Transl Med. 9:312011. View Article : Google Scholar : PubMed/NCBI | |
|
Caldecott KW: XRCC1 and DNA strand break repair. DNA Repair (Amst). 2:955–969. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Nix P, Greenman J, Stafford N and Cawkwell L: Expression of XRCC 1 and ERCC 1 proteins in radioresistant and radiosensitive laryngeal cancer. Cancer Ther. 2:47–53. 2004. | |
|
Estilo CL, O-charoenrat P, Talbot S, Socci ND, Carlson DL, Ghossein R, Williams T, Yonekawa Y, Ramanathan Y, Boyle JO, et al: Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis. BMC Cancer. 9:112009. View Article : Google Scholar : PubMed/NCBI | |
|
Peng CH, Liao CT, Peng SC, Chen YJ, Cheng AJ, Juang JL, Tsai CY, Chen TC, Chuang YJ, Tang CY, et al: A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One. 6:e234522011. View Article : Google Scholar : PubMed/NCBI | |
|
Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, Lemaire F, Young J, Dembélé D, Thibault C, Muller D, et al: Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene. 23:2484–2498. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, Ondrey FG, Adams GL and Gaffney PM: Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res. 64:55–63. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Verschuur HP, Irish JC, O'Sullivan B, Goh C, Gullane PJ and Pintilie M: A matched control study of treatment outcome in young patients with squamous cell carcinoma of the head and neck. Laryngoscope. 109:249–258. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Boccard SG, Marand SV, Geraci S, Pycroft L, Berger FR and Pelletier LA: Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: A pre-clinical study. Oncotarget. 6:29456–29468. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Huang PY, Li Y, Mai HQ, Luo RZ, Cai YC and Zhang L: Expression of ERCC1 predicts clinical outcome in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy. Oral Oncol. 48:964–968. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Gao Y and Liu D: The roles of excision repair cross-complementation group1 in objective response after cisplatin-based concurrent chemoradiotherapy and survival in head and neck cancers: A systematic review and meta-analysis. Oral Oncol. 51:570–577. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Bauman JE, Austin MC, Schmidt R, Kurland BF, Vaezi A, Hayes DN, Mendez E, Parvathaneni U, Chai X, Sampath S and Martins RG: ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: Results from a randomised, phase II trial. Br J Cancer. 109:2096–2105. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
An HJ, Jo H, Jung CK, Kang JH, Kim MS, Sun DI, Cho KJ, Cho JH, Won HS, Sun S and Ko YH: Prognostic implication of ERCC1 protein expression in resected oropharynx and oral cavity cancer. Pathol Res Pract. 213:949–955. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Yang L, Wei W, Zhou L, Wang J and Hu G: High/positive expression of ERCC1 predicts poor treatment response and survival prognosis in nasopharyngeal carcinoma: A systematic meta-analysis from 21 studies. Medicine (Baltimore). 98:e156412019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Wang Y, Wu J and Li LJ: XRCC1 Arg194Trp polymorphism is associated with oral cancer risk: Evidence from a meta-analysis. Tumour Biol. 34:2321–2327. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Yang CH, Lin YD, Yen CY, Chuang LY and Chang HW: A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk. Omics. 19:238–247. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Avci H, Ergen A, Bireller ES, Ertugrul B and Cakmakoglu B: A strong relationship between oral squamous cell carcinoma and DNA repair genes. Biochem Genet. 55:378–386. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang E, Cui Z, Xu Z, Duan W, Huang S, Tan X, Yin Z, Sun C and Lu L: Association between polymorphisms in ERCC2 gene and oral cancer risk: Evidence from a meta-analysis. BMC Cancer. 13:5942013. View Article : Google Scholar : PubMed/NCBI | |
|
Vaezi A, Feldman CH and Niedernhofer LJ: ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer. Pharmgenomics Pers Med. 4:47–63. 2011.PubMed/NCBI | |
|
Zafeer M, Mahjabeen I and Kayani MA: Increased expression of ERCC2 gene in head and neck cancer is associated with aggressive tumors: A systematic review and case-control study. Int J Biol Markers. 31:e17–e25. 2016. View Article : Google Scholar | |
|
Du P, Wang Y, Chen L, Gan Y and Wu Q: High ERCC1 expression is associated with platinum-resistance, but not survival in patients with epithelial ovarian cancer. Oncol Lett. 12:857–862. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Liu J, Zhang L, Mao P, Jiang G, Liu L, Wang J, Yang W, Owusu L and Li W: Functional characterization of a novel transcript of ERCC1 in chemotherapy resistance of ovarian cancer. Oncotarget. 8:85759–85771. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Gossage L and Madhusudan S: Current status of excision repair cross complementing-group 1 (ERCC1) in cancer. Cancer Treat Rev. 33:565–577. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Lai JI, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS and Wang WS: Very low prevalence of XPD K751Q polymorphism and its association with XPD expression and outcomes of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci. 100:1261–1266. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Curtin NJ: DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 12:801–817. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Schulz A, Meyer F, Dubrovska A and Borgmann K: Cancer stem cells and radioresistance: DNA repair and beyond. Cancers (Basel). 11:8622019. View Article : Google Scholar : PubMed/NCBI | |
|
Huang RX and Zhou PK: DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther. 5:602020. View Article : Google Scholar : PubMed/NCBI | |
|
Johnson N: Tobacco use and oral cancer: A global perspective. J Dent Educ. 65:328–339. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM and Tsai CC: Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 24:450–453. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Abrahão R, Anantharaman D, Gaborieau V, Abedi-Ardekani B, Lagiou P, Lagiou A, Ahrens W, Holcatova I, Betka J, Merletti F, et al: The influence of smoking, age and stage at diagnosis on the survival after larynx, hypopharynx and oral cavity cancers in Europe: The ARCAGE study. Int J Cancer. 143:32–44. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Cao W, Liu Z, Gokavarapu S, Chen Y, Yang R and Ji T: Reformed smokers have survival benefits after head and neck cancer. Br J Oral Maxillofac Surg. 54:818–825. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Colares N, Souza Rodrigues DF, Freitas MO, Dantas TS, Cunha MDPSS, Sousa FB and Barros Silva PG: Smoking history decreases survival in patients with squamous cell carcinoma of the mouth: A retrospective study with 15 years of follow-up. Asian Pac J Cancer Prev. 20:1781–1787. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Kawakita D, Hosono S, Ito H, Oze I, Watanabe M, Hanai N, Hasegawa Y, Tajima K, Murakami S, Tanaka H and Matsuo K: Impact of smoking status on clinical outcome in oral cavity cancer patients. Oral Oncol. 48:186–191. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Lee SU, Moon SH, Choi SW, Cho KH, Park JY, Jung YS, Ryu J, Ryu CH, Yun T, Kim TH, et al: Prognostic significance of smoking and alcohol history in young age oral cavity cancer. Oral Dis. 26:1440–1448. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Koshiaris C, Aveyard P, Oke J, Ryan R, Szatkowski L, Stevens R and Farley A: Smoking cessation and survival in lung, upper aero-digestive tract and bladder cancer: Cohort study. Br J Cancer. 117:1224–1232. 2017. View Article : Google Scholar : PubMed/NCBI |
