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Int J Clin Exp Pathol 2017;10(2):1122-1130www.ijcep.com /ISSN:1936-2625/IJCEP0044294

Original ArticleMTAP deficiency is associated with an unfavourable prognosis and platinum resistance in ovarian cancer

Nan Ding1*, Fuqiang Yin2*, Xihan Deng1, Liyuan Feng1, Luwei Wei1, Yongzhi Huang2, Zhenxin Liang2, Wei Zhang1, Li Li1

1Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, P. R. China; 2Medical Scientific Research Centre, Guangxi Medical University, Nanning, Guangxi Prov-ince, P. R. China. *Equal contributors.

Received November 14, 2016; Accepted November 25, 2016; Epub February 1, 2017; Published February 15, 2017

Abstract: Methylthioadenosine phosphorylase (MTAP), a key enzyme of adenosine salvage pathway, has been re-ported to be high frequency absence or reduced in various human tumors. This study was to investigate the ex-pression of MTAP in ovarian cancer (OC) and the association with platinum based chemotherapy response and prognosis. We first examined the expression of MTAP in OC cell lines and 20 OC tissues. Then we retrieved the expression of MTAP in 90 platinum-resistant and 197 platinum-sensitive ovarian cancers, according to The Cancer Genome Atlas (TCGA) Ovarian Statistics data. Further, the association between MTAP and drug resistance in OC was analyzed by bioinformatic analysis. Last, Kaplan-Meier plotter (KM plotter), was invited to validate the MTAP’s prog-nostic value in OC, Kaplan-Meier survival plot and P value were calculated. Compared with the parental OC cell lines, low expression of MTAP was found in platinum-resistant cell lines: A2780/DDP (P=0.021), A2780/CBP (P=0.002) and SKOV3/DDP (P=0.008). Similarly, MTAP’s down-expression was also found between 10 platinum-resistant and 10 platinum-sensitive tissues (P=0.003). Running data from TCGA, MTAP in platinum-resistant group was down expressed compared with platinum-sensitive group (P=0.024). Bioinformatic process showed close relationship between MTAP and drug resistance. Computed by KM plotter, low expression of MTAP was associated with OC patients’ poor progression-free survival (P=0.027) and overall survival (P=0.0033). These data demonstrate that low expression of MTAP is associated with platinum based chemotherapy resistance and worse prognosis in OC. Taken together these findings suggest that MTAP could serve as a potential biomarker for prognosis and predictor for platinum based chemotherapy response in OC.

Keywords: Ovarian cancer, methylthioadenosine phosphorylase, prognosis, platinum resistance, biomarker

Introduction

Ovarian cancer (OC) is often referred to as the “The Silent Killer”, the patients were always first diagnosed at an advanced stage [International Federation of Gynecology and Obstetrics (FIGO) stage III/IV], and often progressed rapidly, which results in OC mortality among the top of the gynecology malignant tumors. Standardized surgery supplemented by platinum based che-motherapy is the main way of treatment, about 75% of the early cured people can get the com-plete response, however, months later, the majority of patients appear tumor recurrence or metastasis, and due to the existence of multi-ple drug resistance (MDR) of chemotherapy, the 5-year survival rate is only 30-45% of patients with OC [1, 2]. Predictive markers used to guide treatment decisions and prognostic

markers to estimate patient outcomes are des-perately needed.

Methylthioadenosine phosphorylase (MTAP) is a key enzyme of adenosine salvage pathway, catalyzes 5’-deoxy-5’-methylthioadenosine (MTA) to generate ATP, dAMP and methionine for participating in the energy generation and protein synthesis in the cell. The MTAP is locat-ed on chromosome 9p21-22, which is a herita-ble fragile site. Loss of heterozygosity and dele-tion of this region usually causes co-deletion of MTAP and some tumor suppressor genes such as p16 in various kinds of tumors. In normal cells and tissues, MTAP, is abundant and acted as a housekeeping gene, but in a variety of malignant tumor cell lines and cancer tissues, it appears high frequency absent or reduced. MTAP deficiency is found in hematologic malig-

MTAP deficiency in ovarian cancer

1123 Int J Clin Exp Pathol 2017;10(2):1122-1130

nancies [3-6] and solid tumors, such as blad-der cancer [7], breast cancer [8], nasopharyn-geal carcinoma [9], myxofibrosarcomas [10], non-small cell lung cancer (NSCLC) [11], laryn-geal carcinoma [12], etc. In addition, He etc [9] found down regulation of MTAP had been shown to correlate with advanced tumor stage and poor prognosis in nasopharyngeal carcino-ma. In myxofibrosarcomas, MTAP deficiency was associated with an unfavorable prognosis and when MTAP re-expressed in MTAP-deficient cells, the cells’ ability of migration and invasion, proliferation, and anchorage-indepen-dent colony formation was inhibited [10].

MTAP mainly functioned as a tumor suppressor in most carcinomas, but in some other malig-nancies, such as prostate cancer [13] and pilo-cytic astrocytomas [14], it was up regulated. Information on MTAP-expression in OC is lack-ing, and its association with chemoresistance and survival has never been systematically studied. In this study, we detected the expres-sion of MTAP and its relationship with OC clini-copathological parameters, trying to clarify its prognostic significance and correlation to plati-num resistance.

Materials and methods

Cell culture and tissue samples

The human ovarian cancer cell lines SKOV3 and A2780 were maintained in our lab, and the resistant cell lines A2780/DDP and A2780/CBP cell lines were established from A2780 by

exposed to increasing concentrations of cispla-tin and carboplatin, respectively. A stable cispl-atin-resistant cell line, SKOV3/DDP, was estab-lished from SKOV3 by exposure to increasing concentrations of cisplatin continuously [15]. The SKOV3 and A2780 cell lines and their derivative cell lines were routinely maintained in DMEM or RPMI-1640 (CORNING, USA) sup-plemented with 10% fetal bovine serum (FBS, CORNING, USA), 100 U/ml penicillin, and 100 μg/ml streptomycin (Gibco BRL, Grand Island, NY) at 37°C in a humidified atmosphere con-taining 5% CO2.

Ovarian cancer tissues were collected from patients who underwent optimal cytoreductive surgery for primary epithelial ovarian cancer at the department of gynecologic oncology, the Affiliated Tumor Hospital of Guangxi Medical University. All cancer tissues of FIGO stage IB-IV were proved as epithelial ovarian carcinoma by pathology. All patients treated with 6-8 cycles of postoperative platinum based chemothera-py: paclitaxel plus cisplatin (TP) or paclitaxel plus carboplatin (TC). The follow-up of the patients was at least 1 year after completing the chemotherapy. In addition, the patients were assigned into two groups: platinum resistant group (n=10) and the platinum sensitive group (n=10) according to the 2013 guidelines Na- tional Comprehensive Cancer Network (NCCN). The median age of the patients was 47 years (range, 28-60 years). The study was endorsed by the Ethics Committee of Affiliated Tumor Hospital of Guangxi Medical University. All patients received an explanation concerning the aims of the study and provided signed inform- ed consent. After surgical removal from the pri-mary lesions, the tissues were frozen in liquid nitrogen tank until they were used for mRNA isolation.

qRT-PCR analysis

Total RNA of ovarian cancer cells/tissues was isolated by TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s pro-tocols and then 1 µg RNA was reverse tran-scribed using the RevertAid First Strand cDNA Synthesis Kit (Thermo, Austin, TX, USA) to gen-erate cDNA. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed using a standard SYBR® Premix Ex Taq™ II (Takara, Japan). The primers were synthesized by Bei- jing Genomics Institute (Beijing, China) as fol-lows: MTAP forward primer, 5’-CAGGCGAACAT-

Figure 1. Expression change comparing resistant and sensitive cell lines. The expression of MTAP was significantly reduced in resistant cell lines (*P<0.05, **P<0.01).



probe in the probe set, as it was MTAP (Affy- metrix ID: 231984_at), the hazard ratio (HR) and logrank P value were calculated. In the survival analysis, the median were used as the cutoff value and the significance threshold was set at P<0.05 [17].

Results

Reduced expression of MTAP was related to platinum-resistance

By qRT-PCR, we detected the expression differ-ence in ovarian cancer cell lines, the results showed that MTAP was down regulated in platinum-resistant cell lines: A2780/DDP (P= 0.021), A2780/CBP (P=0.002) and SKOV3/DDP (P=0.008), in contrast to their parental cell lines A2780 and SKOV3, respectively, as shown in Figure 1. Then we examined the expression difference of MTAP between platinum-resistant and platinum-sensitive epithelial ovarian cancer tissues, the expression of MTAP in platinum-resistant group (7/10) was signifi-cantly lower compared with platinum-sensitive group (4/10) (Figure 2A, P=0.003). To further verify the result, we run the data extracted from TCGA database on the expression of MTAP between platinum-resistant and platinum-sen-sitive tissues of OC patients. The results showed that expression of MTAP in platinum-resistant group was reduced compared with platinum-sensitive group, the P value was 0.024, as shown in Figure 2B.

CTGGGCTTT-3’, reverse primer, 5’-GGACTGAG- GTCTCATAGTGGT-3’; GAPDH forward primer, 5’-GAAGGTGAAGGTCGGAGT-3’, reverse primer: 5’-GAAGATGGTGATGGGATTT-3’. The reaction was conducted following the procedure: pre-degeneration at 95°C for 30 s, and then 40 amplification cycles of 95°C for 5 s, and 60°C for 30 s using StepOnePlusTM Software v2.3 (ABI, Foster City, CA, USA) quantitative Real-Time PCR instrument. GAPDH was used as ref-erence. Each sample was analyzed in triplicate. Comparative threshold cycle (CT) method-fold change (2-ΔΔCT) was used to analyze relative fold changes.

Bioinformatics analysis

Then we searched The Cancer Genome Atlas (TCGA, http://cancergenome.nih.gov) database to get the expression data of MTAP and divid- ed it into two groups according to the clinical chemotherapy response information: platinum-resistant group (n=90) and platinum-sensitive group (n=197). The gene/protein-gene/protein interaction network was generated by Gene- MANIA (http://genemania.org/); the Coremine Medical online tool (http://www.coremine.com/medical/) was used to annotate the biological processes. To analyze the prognostic value of MTAP in ovarian cancer, the central server of Kaplan-Meier plotter (KM plotter) for ovarian cancer (www.kmplot.com/ovar) was used to calculate and plot Kaplan-Meier survival plots to assess the correlation between survival and gene expression. We chose the JetSet [16] best

Figure 2. Expression differences of MTAP between platinum-resistant and platinum-sensitive tissues in ovarian can-cer. The expression of MTAP was significantly reduced in chemo-resistant tissues. A. Was the data from 20 ovarian cancer tissues collected by us; B. Represented the data from TCGA database (*P<0.05, **P<0.01).



Prediction and analysis of function based on gene/protein-gene/protein interactions

To further demonstrate the function of MTAP, we collected the drug-resistance related genes in ovarian cancer using the search terms “Ovarian Neoplasms”, “Drug Resistance”, and “Drug Resistance and Ovarian Neoplasm” from the PubMed online database (https://www.ncbi.nlm.nih.gov/pubmed), and the interaction networks between MTAP and drug resistance-related genes in ovarian cancer were analyzed using the GeneMANIA tool. The results revealed that MTAP was interacted with 21 genes in total (Figure 3), and 12 of them had been verified in reports to have correlation with drug-resistance in ovarian cancer: APC, WNT signaling pathway regulator (APC), mito-gen-activated protein kinase1 (MAPK1), nucle-ar factor kappa B subunit 1 (NFKB1), PLAG1 like zinc finger 1 (PLAGL1), URI1, prefoldin like chaperone (URI1), ATM serine/threonine kinase (ATM), ATR serine/threonine kinase (ATR),

biological function and importance in disease due to the cross-referenced gene and protein names. Therefore, we used the Coremine Me- dical and set the probabilistic value lower than 0.009 to annotate MTAP with respect to biological processes. As shown in Figure 4, 23 biological processes closely associated with ovarian cancer, drug resistance, and the MTAP was annotated, suggesting its mutual involve-ment in drug resistance in ovarian cancer. Among the 23 processes, four (growth, cell growth, cell proliferation and cell division) were cell-growth related, three (metabolic process, polyamine biosynthetic, biosynthetic process) were cell-metabolism related, three (cell cycle, regulation of cell cycle and S phase) were cell-cycle related, and three (methylation, DNA methylation and demethylation) were cell-methyla-tion related. Among these, the correlation of the MTAP’s metabolic function and drug resis-tance is in accordance with the previous study in which MTAP was shown to affect cell metabo-lism regulation in cancer therapy [21].

Figure 3. The gene/protein interaction networks of MTAP based on the Gen-eMANIA online tool.

Cyclin-dependent kinase in- hibitor 2A gene (CDKN2A), check point kinase 2 (CHEK2), death associated protein kinase 1 (DAPK1), F-box pro-tein32 (FBXO32) and phos-phatase and tensin homolog (PTEN). Such as CDKN2A, whose down-regulation in ovarian cancers represented an unfavorable prognosis, and had an underlying interaction in paclitaxel resis-tance in cancer therapy [18, 19]. The presence of a germ-line or somatic mutation in CHEK2 gene, one of the ho- mologous recombination genes, was strongly associated with primary platinum sensi-tivity [20]. In additional, MTAP was also interacting with a long non-coding RNA RP11-145E5.5, which hasn’t been reported before.

Functional prediction based on the annotated biological process

Coremine Medical, an online tool, which can help to under-stand the terms relevant to



tients get chemoresistance after standard treatment, which reduces the treatment out-come and the 5-year survival rate. In general, the potential mechanisms of chemoresistance are decreased drug uptake, disordered DNA damage repair system, obstructed apoptosis pathway or activated cell survival pathway [23]. This study analyzed the association between MTAP level and platinum based chemotherapy response as well as prognosis in OC by using public databases and basic experiments.

For ovarian cancer, to validate a prognostic bio-marker is a major challenge in large indepen-dent patient cohorts. TCGA database conclude thousands of ovarian cancer microarray datas-ets released to the public. The data have been reported to be used in analyzing the relation-ship between the data and the chemotherapy response, the prognosis, the gene-gene inter-actions and the microRNA analysis [24]. There- fore, we retrieved the expression data of MTAP in ovarian cancer from TCGA to verify our results. In addition, we implemented an online tool KM plotter to identify biomarkers related to ovarian cancer patients’ survival. KM plotter database is set up using gene expression data and survival information of 1648 ovarian can-cer patients downloaded from Gene Expression Omnibus (GEO) and TCGA. The prognostic value was analyzed by dividing the patients into two groups according to various quantile expres-sions of the gene [17]. Then the PFS or OS was compared between the two groups, and

Reduced expression of MTAP was related to worse prognosis

Based on the data obtained from KM plotter, we proceeded to investigate the relationship between MTAP expression and clinical out-come. We identified 1,648 patients in GEO (12 independent datasets) and TCGA. In theses patients, 1,364 patients get a platinum-based chemotherapy and 780 received paclitaxel, besides, 763 patients were treated with both platinum and paclitaxel. Then we used Jetset to filter for probe set quality and include only reliable and specific probe sets in the statisti-cal evaluation. In all the patients no matter what chemotherapy they were given from 13 independent datasets, down-regulated MTAP was significantly associated with patients’ worse progression-free survival (PFS, HR=0.79, P=0.027) and overall survival (OS, HR=0.72, P=0.0033), as shown in Figure 5. Then we com-pared the prognosis of patients treated with different chemotherapy, in the patients treated based on platinum, MTAP’s down-regulation was correlated to OS (HR=0.68, P=0.0045), and marginally with PFS (HR=0.81, P=0.051). When running data on the patients treated with platinum and paclitaxel, only OS was sig-nificant (HR=0.69, P=0.02), no apparent signifi-cance was found in PFS (P=0.26). In the patients treated based on paclitaxel, lower expres-sion of MTAP significantly correlated with OS (HR=0.68, P=0.017), but had no significance with PFS (P=0.24), as shown in Figure 6.

Figure 4. Diagram of the annotated biological processes of MTAP and the correlation with drug resistance in ovarian cancer using the Coremine Medi-cal online tool.

Discussion

OC is the fifth most common cause of cancer-related death in women. Chemotherapy based on platinum compound and taxane after cytoreduc-tive surgery is the standard treatment in clinic. The platinum-based agent cisplatin has made a great contribution in cancer therapy, especially in testicular and ovarian can-cer, since its inception over 40 years ago [22]. However, multiple drug resistance is the main cause of the failure of the ovarian cancer chemotherapy at present stage. Mostly, ovarian cancer pa-



Figure 5. The relationship between the expression of MTAP and all the ovarian cancer patients’ prognosis computed by Kaplan-Meier plotter online tool. Low expression of MTAP correlated with poor PFS and OS (MTAP, methylthio-adenosine phosphorylase; HR, hazard ratio; OS, overall survival; PFS, progression-free survival).

a Kaplan-Meier survival plot was generated with statistical significance. The relationship between MTAP and PFS and OS in ovarian can-cer was analyzed in this study by this way.

In our study, the expression of MTAP was significantly down regulated in platinum-resistant ovarian cancer cell lines and tissues. Subse- quently, we verified the results by computed the data extracted from TCGA database since the small sample size of our own. As was ex- pected, MTAP was low expressed in platinum resistant patients compared to platinum sensi-tive patients. So we proposed that MTAP could be a potential predictor for platinum based chemotherapy response. To predict the func-tion of MTAP and the relation with drug resis-tance in ovarian cancer, based on the gene/protein-gene/protein analysis and the text mining performed by the GeneMANIA and the Coremine Medical online tool, we found 54.5% of the genes interacted with MTAP were drug resistance-related genes in ovarian cancer, such as CDKN2A, CHEK2, PTEN, NFKB1 etc [25, 26]. In addition, MTAP could be involved in the regulation of drug resistance through modulating cell-growth, cell-cycle, cell-metabo-lism, cell-methylation etc, which have close relationship with drug resistance. Therefore, we could come up with the conclusion that MTAP was associated with the regulation of drug-resistance in ovarian cancer, especially platinum resistance.

Afterwards, we detected the relationship between the expression of MTAP and prognosis in epithelial ovarian cancer. Due to the small number of our own sample size and some patients were lost to follow-up, we did this by running on KM plotter. In all the OC patients, we found MTAP’s down expression was signifi-cantly associated with ovarian cancer patients’ adverse PFS and OS. When the patients were set apart according to the chemotherapy treat-ment, the results changed. In the platinum group, MTAP’s down-regulation was correlated with poor OS and marginally with poor PFS. But when added in the paclitaxel group, that is to say, in the platinum plus paclitaxel and pacli-taxel groups, its down-regulation was signifi-cantly correlated with adverse OS but no PFS. We supposed that MTAP’s down-regulation was more related to platinum treatment than pacli-taxel, the data from the paclitaxel group con-founded the final result. On the whole, MTAP’s down regulation had a significant relationship with an unfavorable survival prognosis, espe-cially in the patients treated with platinum, which was consistent with previously reported results. Su etc [11] found patients with a low MTAP expression level had poor OS and dis-ease-free survival, and the MTAP expression level retained an independent prognostic power in NSCLC. In cutaneous malignant melanoma, loss of MTAP expression was significantly asso-ciated with worse OS, and even more impor-tantly, its expression had a clear correlation



Over the past, many strategies were proposed to overcome MTAP-deficient tumors. There

with interferon response, which could offer direct therapeutic implications [27].

Figure 6. Survival diagrams for the gene of MTAP based on Kaplan-Meier plotter online tool. Kaplan-Meier survival plots showed that low expression of MTAP resulted in a worse OS, while no apparent significance was found between low expression of MTAP and PFS (MTAP, methylthioadenosine phosphorylase; HR, hazard ratio; OS, overall survival; PFS, progression-free survival).



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were experiments in vitro revealed that MTAP-deficient tumors enhanced sensitivity to inhibi-tors of de novo purine biosynthesis. A more recent proposal methylthioadenosine (MTA), a natural substrate of MTAP generated during polyamine biosynthesis, combined with an anti-metabolic purine or pyrimidine analog, such as the guanine analog 6-thioguanine (6-TG), 5-fluo-rouracil (5-FU), demonstrated to be a success-ful application of the strategy in treating hema-tological tumor or solid tumor [28-30]. There- fore, MTA combined with a toxic purine or pyrim-idine to treat platinum resistant patients with MTAP deficiency maybe a novel strategy in OC, which still need more studies to verify.

In the present study, we lay out various data from different points to demonstrate that MTAP has a strong connection with drug resistance of ovarian cancer and it could be a potential bio-marker for predicting platinum based chemo-therapy response. Furthermore, low expression of MTAP is associated with a poor prognosis in OC. However, our study also has some limita-tions. The sample size is relatively small; more-over, detailed mechanisms for MTAP affecting OC platinum resistance and prognosis remain unclear and require further study. Overall, MTAP may serve as an important biomarker to predict platinum based chemotherapy response and prognosis for OC patients.

Acknowledgements

This work was supported by the National Na- tural Science Foundation of China (no. 815- 72579 and 81660430) and Natural Science Foundation of Guangxi, China (no. 2014- GXNSFAA118147).

Disclosure of conflict of interest

None.

Address correspondence to: Dr. Li Li, Department of Gynecologic Oncology, The Affiliated Tumor Hos- pital of Guangxi Medical University, 71 Hedi Road, Nanning 530021, Guangxi Province, P. R. China. E-mail: [email protected]

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