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High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy

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High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy RESEARCH ARTICLE High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy Guang Yang☯, Xue-Jiao Wang☯, Li-Jun Huang☯, Yong-An Zhou, Feng Tian, Jin-Bo Zhao, Peng Chen, Bo-Ya Liu, Miao-Miao Wen, Xiao-Fei Li*, Zhi-Pei Zhang* Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, 710038, China ☯ These authors contributed equally to this work. * [email protected] (XFL); [email protected] (ZPZ) Abstract ATP-binding cassette (ABC) transporters are associated with poor response to chemother- OPEN ACCESS apy, and confer a poor prognosis in various malignancies. However, the association Citation: Yang G, Wang X-J, Huang L-J, Zhou Y-A, between the expression of the ABC sub-family G member 4 (ABCG4) and prognosis in Tian F, Zhao J-B, et al. (2015) High ABCG4 patients with non-small-cell lung cancer (NSCLC) remains unclear. NSCLC tissue samples Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with (n = 140) and normal lung tissue samples (n = 90) were resected from patients with stage II Cisplatin-Based Chemotherapy. PLoS ONE 10(8): to IV NSCLC between May 2004 and May 2009. ABCG4 mRNA and protein expressions e0135576. doi:10.1371/journal.pone.0135576 were detected by RT-PCR, western blot, and immunohistochemistry. Patients received four st Editor: Gergely Szakacs, Hungarian Academy of cycles of cisplatin-based post-surgery chemotherapy and were followed up until May 31 , Sciences, HUNGARY 2014. ABCG4 positivity rate was higher in NSCLC than in normal lung tissues (48.6% vs. Received: October 29, 2014 0%, P<0.001) and ABCG4 expression was significantly associated with poor differentiation, Accepted: July 23, 2015 higher tumor node metastasis (TNM) stage, and adenocarcinoma histological type (all P<0.001). Univariate (HR = 2.284, 95%CI: 1.570–3.324, P<0.001) and multivariate (HR = Published: August 13, 2015 2.236, 95%CI: 1.505–3.321, P<0.001) analyses showed that ABCG4 expression was an Copyright: © 2015 Yang et al. This is an open independent factor associated with a poor prognosis in NSCLC. Patients with ABCG4-posi- access article distributed under the terms of the vs Creative Commons Attribution License, which permits tive NSCLC had shorter median survival than ABCG4-negative NSCLC (20.1 . 43.2 unrestricted use, distribution, and reproduction in any months, P<0.001). The prognostic significance of ABCG4 expression was apparent in medium, provided the original author and source are stages III and IV NSCLC. In conclusion, high ABCG4 expression was associated with a credited. poor prognosis in patients with NSCLC treated with cisplatin-based chemotherapy. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the National Natural Science Foundation of China (grant No. 81172224). The funders had no role in study design, data collection and analysis, decision to publish, or Introduction preparation of the manuscript. About 1.5 million new cases of lung cancer are diagnosed annually worldwide, and about 85% Competing Interests: The authors have declared of them are non-small-cell lung cancers (NSCLCs) [1]. In 2012, about 58% of cases of NSCLCs that no competing interests exist. occurred in the less developed countries [2]. Surgery is considered to be the best treatment PLOS ONE | DOI:10.1371/journal.pone.0135576 August 13, 2015 1/14 ABCG4 Is Associated with NSCLC Prognosis option, but resection is only potentially curative for 20–25% of tumors [1]. Most patients will present with an incurable disease and face a 5-year relative survival rate of <17% with current standard therapies [3]. Postoperative chemotherapy, with or without radiotherapy, improves survival by 4% in terms of absolute 5-year survival, as demonstrated by a meta-analysis [4]. Currently, cisplatin-based combination chemotherapy regimens are the most effective first- line therapies for the treatment of NSCLC, according to The National Comprehensive Cancer Network (NCCN) guidelines (version 4.2014) [5]. However, the efficacy of chemotherapy is limited, with response rates (RRs) of 20–35%, progression-free survival (PFS) of 3.1–5.5 months, and overall survival (OS) 7.4–11.3 months [6,7]. Accordingly, improving outcomes after chemotherapy has been one of the most challenging issues in the successful treatment of lung cancer [8]. This is primarily attributed to drug resistance, which occurs in virtually all can- cers and is a serious impediment to the success of chemotherapy [6,7]. It is increasingly recog- nized that primary and secondary drug resistances developing in cancer cells are the most fundamental reason underlying chemotherapy failure [6,7]. Drug resistance is usually the result of the over-expression of ATP-binding cassette (ABC) transporters [9,10]. ABC transporter proteins are optimal candidates as biomarkers for the pre- diction of chemotherapy resistance and prognosis after chemotherapy [11,12]. ABC transport- ers are transmembrane proteins that facilitate translocation of heterogeneous substances across cellular membranes by utilizing the energy of ATP hydrolysis [13]. To date, at least 48 human ABC transporter genes have been identified, and they have been divided into seven subfamilies (ABCA through ABCG) [14]. Among these, ABCA2, ABCB1 (also known as P-glycoprotein or multidrug resistance 1 (MDR1)), ABCB4, ABCB11, ABCC1-6, ABCC10, ABCC11, and ABCG2 (also known as BCRP or MXR) have all been shown to be associated with the efflux and transportation of cytotoxic drugs (structurally diverse chemotherapeutic agents and their metabolites) from lung cancer cells, thus reducing intracellular drug concentrations [15]. ABCA1 has also been identified as mediating drug resistance in lung cancer and drug-resistant lung cancer cell lines [16]. Currently, P-gp (ABCB1), MRP1 (ABCC1), and ABCG2 are consid- ered to be the main drug transporters for their roles in multi-drug resistance observed in many tumors and cell lines [17]. Although discovery and use of inhibitors for ABC transporters have been studied over the past years, these inhibitors were not completely successful in overcoming drug resistance [18]. As a result, identification of new ABC drug transporter proteins and investigation of their mechanisms and inhibitors are highly warranted and extremely impor- tant to evaluate new targets for overcoming drug resistance. Several studies have demonstrated that the members of the ABCG (or White) subfamily are associated with cellular lipid transport and drug resistance [19–21]. ABCG5 and ABCG8 are highly expressed in epithelial cells of the intestine and likely act as a heterodimer; they have been associated with the efflux of plant sterols and cholesterol into bile [22,23]. Over-expres- sion of ABCG2 leads to resistance of various cancer cell lines to anti-tumor drugs [24]. ABCG4 is the fourth member of the "G" family, and is located on chromosome 11q23.3. This gene encodes a 3874-bp transcript, and its expression is predominantly intracellular [25], but the exact intracellular localization is yet to be shown [26]. Indeed, the different ABC transporters may be localized in the cell membrane, on mitochondria, on the Golgi apparatus, on the endo- plasmic reticulum, or in the nuclear membrane, where they participate in different cellular pro- cesses [26]. Moreover, according to previous studies [27–30], ABCG4 expression in NSCLC remains unclear. Previous studies have revealed that ABCG1 and ABCG4 are responsible for the transportation of cholesterol onto high density lipoprotein (HDL) particles [31,32], and over-expression of ABCG4 also confers resistance to alkyl-phospholipid analogues (miltefo- sine, edelfosine, and perifosine) in Leishmania [33]. However, whether ABCG4 plays a signifi- cant role in prognosis after chemotherapy, and whether it has potential function of mediating PLOS ONE | DOI:10.1371/journal.pone.0135576 August 13, 2015 2/14 ABCG4 Is Associated with NSCLC Prognosis drug resistance in lung cancer also remain unclear. Therefore, the present study focused on understanding the expression and post-chemotherapy prognostic value of ABCG4 in NSCLC. In this retrospective study, we investigated the expression of ABCG4 in NSCLC. We also evaluated the value of ABCG4 protein for predicting survival in NSCLC patients treated with cisplatin-based combination chemotherapy. Materials and Methods Patients and samples A total of 140 NSCLC tissue samples (74 cases of lung squamous cell carcinoma and 66 cases of lung adenocarcinoma) and 90 normal lung tissue samples (located >5 cm from the primary tumors) obtained by surgical resection at the Department of Thoracic Surgery, Tang Du Hospi- tal Affiliated to the Fourth Military Medical University (Xi'an, China) between May 2004 and May 2009, were investigated in the present study. Tumor and normal lung tissues were har- vested using sterile surgical instruments. Patients were aged 45–76 years (mean ± SD: 60.76 ± 6.88 years). All samples were reviewed by pathologists, and histological classification of tumors was performed according to the World Health Organization criteria. Tumors were classified as stage II (n = 42), III (n = 56), or IV (n = 42) according to the NCCN guidelines (Version 4.2014) [5]. Clinicopathological char- acteristics of all patients were recorded. No patient had received chemotherapy, radiotherapy, biotherapy, or any other operation before lung cancer surgery. All patients were treated with cisplatin-based combination chemotherapeutic regimens considered as standard postoperative regimens for NSCLC [5]. All patients received four cycles of cisplatin-based combination che- motherapeutic regimens (cisplatin 75 mg/m2 day 1+gemcitabine 1250 mg/m2 days 1, 8, every 21 days/pemetrexed 500 mg/m2 day 1 every 21 days/docetaxel 75 mg/m2 day 1 every 21 days). Follow-up was censored on May 31st, 2014, with a total follow-up period of 60 months. The day when chemotherapy started was considered as the starting point for estimating postopera- tive survival.
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