Decreased Eph receptor‑A1 expression is related to grade in ovarian serous carcinoma

  • Authors:
    • Yunfeng Jin
    • Yi Zou
    • Linling Wan
    • Mingming Lu
    • Ya Liu
    • Guoqin Huang
    • Jiandong Wang
    • Qinghua Xi
  • View Affiliations

  • Published online on: January 31, 2018     https://doi.org/10.3892/mmr.2018.8528
  • Pages: 5409-5415
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Eph receptor‑A1 (EphA1) was the first member of the erythropoietin producing hepatocellular carcinoma (Eph) family of receptor tyrosine kinases. Although the roles of EphA1 in the tumorigenesis of various human cancers have been investigated, few studies have focused on ovarian carcinoma. The present study aimed to explore the profile of EphA1 expression in ovarian carcinomas, to analyzed the association between EphA1 expression and clinicopathologic parameters, and to investigate the roles of overexpressed EphA1 in ovarian cancer cells. EphA1 protein was detected in ovarian cancer cell lines and in a set of formalin‑fixed tissues, including normal fallopian tube, ovarian benign serous cystadenoma, borderline serous tumors and serous carcinoma. Ovarian cancer cell lines HO8910 and A2780 were transiently transfected with EphA1‑pCMV6‑GFP plasmid, and the proliferation and apoptosis of cells were measured. The association between EphA1 expression and clinicopathological parameters was statistically analyzed. EphA1 expression was negative in HO8910 and weakly positive in A2780 cells. The proliferation rate was significantly reduced in ovarian cancer cells after transfection with EphA1 plasmid compared with cells transfected with mock plasmid or untreated cells, but no obvious alteration in apoptosis was detected among these groups. EphA1 expression was positively detected in all normal fallopian tubes (10/10, 100%) and ovarian benign serous cystadenomas (12/12, 100%) as well as in some borderline serous tumors (9/15, 60%) and ovarian serous carcinomas (33/76, 43.42%). EphA1 expression was associated with grade of ovarian serous carcinomas, with loss of EphA1 more often observed in high‑grade tumors (P=0.016) and high Ki67 index tumors (P=0.007). These data suggest that EphA1 might be a useful marker for distinguishing low grade from high‑grade ovarian serous carcinoma.

Introduction

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer, accounting for over 90% of ovarian cancers, and is one of the three most common cancers in females (1,2). EOC is associated with high morbidity and mortality rates owing to the typical late stage of the disease at diagnosis; up to 75% of females with EOC are diagnosed at advanced stages because there are few symptoms in the early stage (3). Ovarian serous carcinoma is the most common histological type of ovarian cancer, accounting for 70–80% of all newly diagnosed patients, and the most common and most aggressive subtype of EOC (4). Over the past 30 years, advances in surgery and chemotherapy have had little impact on overall patient survival, and current treatment leads to relapse in the majority of patients. This situation calls for investigation of the pathogenesis of ovarian serous carcinoma and identification of molecular markers for early diagnosis and treatment.

Erythropoietin producing hepatocellular carcinoma (Eph) receptors constitute the largest subfamily of receptor tyrosine kinases that bind membrane-bound ligands called ephrins (5). The Eph/ephrin interactions emanate their signals in a bidirectional manner into adjacent cells, followed by internalization and degradation of the complexes (6). Eph/ephrin signaling is proposed to participate in a wide spectrum of developmental processes through its capacity to regulate cellular adhesion, migration, or repulsion and tissue/cell boundary formation (711). Beyond their initial role in developmental processes, Ephs and ephrins are also involved in a broad range of processes directly related to tumor progression and metastasis (6,1215).

Eph receptor-A1 (EphA1), the first member of the Eph receptor tyrosine kinase family to be discovered, was isolated as a gene that was amplified in a carcinoma cell line and shown to be located on chromosome 7q34 (16). EphrinA1 is the highest affinity binding ligand for EphA1, although EphA1 also binds ephrinA3 and A4 with lower affinity. Whole-mount in situ hybridization showed overlapping expression of EphA1, ephrinA1, and ephrinA3 in the streak and the posterior paraxial mesoderm during early mouse development (17). Activation of EphA1 can inhibit cell spreading and migration in a Rho-ROCK-dependent manner (18). These results suggested that interaction of EphA1 and ephrinA1/A3 plays a role in tumor development. EphA1 expression has been detected in several types of human cancer. EphA1 mRNA and protein were detected in human epidermis at a high level, but EphA1 protein expression was reduced in non-melanoma skin cancers derived from the epidermis (19). In a previous study, we explored EphA1 expression in colorectal cancer, gastric cancer, and renal carcinoma and analyzed the correlation between EphA1 expression and clinicopathological parameters (2022). Our data suggest that EphA1 is expressed in human cancers at highly varying levels. Expression of EphA1 protein has not yet been determined in ovarian serous carcinoma. The purpose of this study is to investigate the expression of EphA1 protein in ovarian serous adenocarcinoma and its association with clinical parameters.

Materials and methods

Cell lines and tissue samples

Human ovarian cancer cell lines HO8910 and A2780 used in the present study were purchased from the cell resource center of the Shanghai Institute of life Sciences, Chinese Academy of Sciences. HO8910 and A2780 were maintained in RPMI 1640 medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Gibco; Invitrogen), 100 U/ml penicillin, and 100 mg/ml streptomycin in a 5% CO2 and 95% atmosphere at 37°C with cell culture plates (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

Clinical specimens were collected from the Department of Pathology of Affiliated Hospital of Nantong University from January 2001 to January 2013. Samples consisted of 10 normal fallopian tubes (age, 24–50 years; average, 43.1), 12 ovarian benign serous cystadenoma tumor tissues (age, 23–62 years; average, 38.5), 15 borderline serous tumors (age, 22–51 years; average, 34.5) and 76 ovarian serous carcinoma tissues (age, 27–69 years; average, 48.7). Generally, matched normal (or non-tumor) and tumor tissue from same patient are subjected to detection when we investigate a gene expression profile in certain cancer. However, serous ovarian carcinoma is very special. First of all, according to recent research results, serous ovarian carcinoma is not derived from ovarian epithelial cells, but from fallopian tube (23). Secondly, there usually almost no normal ovarian surface epithelial was available in ovarian tumor tissues. Formalin-fixed and paraffin-embedded tumor tissues were sectioned at 4-µm thickness. Each tumor was classified according to WHO Classification Tumors of Female Reproduction Organs (23). Data were acquired with approval from the Ethics Committee of the Affiliated Hospital of Nantong University.

EphA1 plasmid transfection

The plasmid EphA1-pCMV6-GFP eukaryotic expression vector kit was purchased from OriGene Technologies, Inc (Rockville, MD, USA). HO8910 and A2780 cells were each divided into three groups: EphA1 transfected group (EphA1-TG), mock group (MG), and untransfected group (UTG). The MG group and the EphA1-TG group were transiently transfected with plasmid pCMV6-GFP and plasmid EphA1-pCMV6-GFP respectively using Lipofectamine 2000 according to the manufacturer's instructions. The UTG group did not receive any treatment. The transfection rate for EphA1-pCMV6-GFP and mock was checked by observation of GFP with a fluorescence microscope and by RT-PCR amplification of EphA1 mRNA. The protocol for amplification of EphA1 mRNA was the same as in our previous report (20). For EphA1, the sense primer is 5′-ATCTTTGGGCTGCTGCTTGG-3′ and the antisense primer is 5′-GCTTGTCCTCTCGATCCACATC-3′. For housekeeping gene GAPDH, the sense primer is 5′-CCAGGTGGTCTCCTCTGACTT-3′ and the antisense primer is 5′-GTTGCTGTAGCCAAATTCGTTGT-3′.

Determination of cell viability (MTT assay)

HO8910 and A2780 cells were seeded in 96-well flat-bottomed plates with 5,000 cells per well in 100 µl of complete RPMI 1640 medium, followed by incubation at 37°C (5% CO2 and 95% air) for 24 h to allow the cells to reach 70% confluence. The cells were transiently transfected and cultured for 48 h. The supernatant was carefully removed, and 100 µl medium and 20 µl of a 5 mg/ml MTT solution (Thermo Fisher Scientific, Inc.) were added to each well and incubated for 4 h at 37°C. The excess MTT was then aspirated. Viable cells internalize the MTT into their mitochondria. The formazan crystals formed in cells were dissolved by addition of 150 µl of dimethyl sulfoxide (DMSO). After shaking for 1 h, the absorbance was measured at 540 nm in a multiwall scanning spectrophotometer.

Apoptosis

Apoptosis of cells after transfection for 72 h with EphA1-pCMV6-GFP and mock plasmid was detected using an Annexin V-FITC apoptosis detection kit (Qiagen GmbH, Hilden, Germany). In brief, cells were collected after digestion with 0.25% trypsin and rinsed. The cells were resuspended in binding buffer with 5 µl Annexin V-FITC and 5 µl propidium iodide (PI). After incubation at room temperature for 10 min in the dark, Annexin V-FITC/PI binding was measured by flow cytometry (excitation, 488 nm; emission, 530 nm) using the phycoerythrin emission signal detector (FL1 for detection of FITC, and FL2 for detection of PI).

Immunocytochemical (ICC) and immunohistochemical (IHC) staining

ICC and IHC staining was performed by the Envision method. For ICC staining, cells were grown on glass coverslips to 70% confluence, washed with PBS, and fixed with cold 75% ethanol for 10 min on ice. The cells were incubated in 3% H2O2 for 10 min and then at 4°C overnight with an anti-EphA1 polyclonal antibody (AO1047a, ABGENT) at a 1:100 dilution in Antibody Diluent (Zymed; Invitrogen). After a wash with PBS, the cells were incubated with secondary antibody (Dako, Ely, UK) for 20 min at room temperature. Color development was performed with 3,3-diaminobenzidine (DAB). Nuclei were lightly counterstained with hematoxylin.

For IHC staining, 4-µm thick sections were deparaffinized in xylene. After rehydration through a graded ethanol series, the sections were autoclaved in 10 mM citrate buffer (pH 6.0) at 120°C for 2 min for antigen retrieval and then cooled to 30°C and washed with PBS (pH 7.3). After non-specific sites had been blocked with 3% H2O2 for 10 min, the sections were incubated at 4°C overnight with an anti-EphA1 polyclonal antibody and washed with PBS. The subsequent steps were the same as for ICC. Two pathologists independently assessed the immunostained slides, and any differences in the staining scores were resolved by consensus.

IHC scoring and quantification

Cytoplasmic staining was considered positive staining. The scoring for percentage of immunoreactive tumor cells was as follows: 0, 0%; 1, <20%; 2, 20–50%; and 3, >50%. The staining intensity was scored and stratified as follows: 0, negative; 1, weak; 2, moderate; and 3, strong. A final immunoreactivity score (IRS) was obtained for each of the cases by multiplying the percentage score and the intensity score. Protein expression levels were further analyzed by classifying IRS values as negative (IRS value <4) or positive (IRS value ≥4) (24).

Statistical analysis

Cell experiments were repeated three times and data were expressed as mean ± standard deviation (mean ± standard deviation). Results were analyzed by one-way ANOVA. The χ2 test (Fisher's exact test) was used to assess the associations of EphA1 protein expression with clinicopathological variables. Two-sided P-values <0.05 were considered statistically significant. All analyses were performed by SPSS software (version 16.0; SPSS, Inc., Chicago, IL, USA).

Results

Expression of EphA1 in ovarian cancer cell lines

EphA1 expression in human ovarian cancer cell lines HO8901 and A2780 was examined by immunocytochemistry. EphA1 staining was located in the cytoplasm. The expression of EphA1 protein was negative in HO8910 cells and weakly positive in A2780 cells (Fig. 1).

Transfection of EphA1 gene

The ovarian cancer cells were observed using a fluorescence microscope after transient transfection with pCMV6-GFP or EphA1-pCMV6-GFP plasmids. Green fluorescence was observed in ovarian cancer cells transfected with EphA1-TG and MG, but not in UTG (Fig. 2A). EphA1 mRNA expression in cells of the EphA1-TG group was detected by RT-PCR (127 bp), with GAPDH mRNA as an internal control (416 bp) (Fig. 2B).

Proliferation of HO8910 and A2780 cell lines after EphA1 transfection

The MTT assay was performed to determine the proliferative effect of HO8910 and A2780 ovarian cancer cells transfected with EphA1 and the data were analyzed using two-sample independent t-test. The proliferation rate of both HO8910-EphA1-TG and A2780-EphA1-TG cells was significantly reduced compared with that in mock and untransfected groups (Fig. 3).

Apoptosis in HO8910 and A2780 cell lines after EphA1 transfection

Apoptosis was measured in HO8910 and A2780 ovarian cancer cells using flow cytometry. There was no significant difference in apoptosis among the EphA1 transfected group, mock, and untransfected groups for both HO8910 and A2780 cells (Fig. 4).

EphA1 expression in normal fallopian tube and ovarian serous tumors

EphA1 staining in normal fallopian tube, ovarian benign serous cystadenoma, borderline serous tumors and serous carcinoma was located predominantly in the cytoplasm with diffuse positive expression (Fig. 5). Positive EphA1 staining was detected in all normal fallopian tubes (10/10) and ovarian benign serous cystadenomas (12/12). EphA1 protein was positively detected in some samples of borderline serous tumors (9/15) and ovarian serous carcinoma (33/76) (Table I).

Table I.

EphA1 expression in normal fallopian tubes, ovarian benign serous cystadenomas, and serous carcinomas.

Table I.

EphA1 expression in normal fallopian tubes, ovarian benign serous cystadenomas, and serous carcinomas.

EphA1

GroupNo.NegativePositivePositive (%)
Normal fallopian tube10  010100.00
Serous cystadenoma12  012100.00
Borderline serous tumors15  6  9   60.00
Serous carcinoma764333   43.42

[i] Eph1A1, Eph receptor-A1.

EphA1 expression correlated with clinicopathological features

The relationship between EphA1 expression and clinicopathological parameters was shown in Table II. Statistical analysis of the association between EphA1 expression and clinicopathological features revealed a significant relationship between EphA1 expression and tumor grade (P=0.016) and Ki67 (P=0.007). No significant association of EphA1 expression and other features was found in this study.

Table II.

Relationship between EphA1 expression and clinicopathologic parameters in ovarian serous carcinomas.

Table II.

Relationship between EphA1 expression and clinicopathologic parameters in ovarian serous carcinomas.

EphA1

ParametersNo.+Positive %χ2P-value
Clinical stages
  I+II15  6  960.00
  III+ IV61372439.342.0910.148
Grade
  Low12  3  975.00
  High64402437.505.7840.016
Metastasis
  Yes30191136.67
  No46242247.830.9200.337
Position of tumors
  Single32161650.00
  Double44271738.640.9740.324
Maximum diameter (cm)
  ≤529131655.17
  5–102115  628.57
  ≥101711  635.293.9380.140
  No data  9  4  5
Age (years)
  ≤5030171343.33
  50–551612  425.00
  ≥5530141653.333.4100.182
Ki67
  >20%52351768.42
  ≤20%24  81631.587.7150.007

[i] Eph1A1, Eph receptor-A1.

Discussion

Roles of the receptor tyrosine kinases in both normal physiology and oncogenesis have been well established. The genes that encode Eph receptors, the largest subfamily of receptor tyrosine kinases, are primarily considered to be classic oncogenes. Overexpression of EphA1 has been reported in several human cancers (2527); however, reduced expression of EphA1 also has been detected in prostate cancer cell lines (28), basal cell carcinomas and squamous cell carcinomas of the skin (19), and colorectal cancer (20). Therefore, whether EphA1 is an oncogene has been questioned. We previously reported that EphA1 expression was associated with metastasis in esophageal squamous cell carcinoma (29), Gleason score in prostate cancer (30), invasion and metastasis in colorectal cancer (20), and metastasis in gastric cancer (21). Comprehensive studies show obvious differences in EphA1 expression among different tissues and different tumor types.

In this study, EphAl expression was negative in HO8910 and weakly positive in A2780 ovarian cancer cells. In addition, loss of EphA1 expression was found in most ovarian serous carcinoma tissues compared with normal fallopian tube and benign tumor. Our data suggest that EphAl is downregulated in ovarian serous carcinoma. In contrast, Wong et al reported that EphA1 mRNA was upregulated in EOC with positive immunostaining of ephrin receptor A1 (31) and Herath et al reported that overexpression of EphA1 mRNA strongly correlated with the high-affinity ligand ephrin A1 in advanced ovarian cancer (32). We interpret the difference in results between these papers and ours as follows: First, the experimental samples used by Herath et al (32) and Wong et al (31) included ovarian serous, mucinous, endometrioid, and clear cell cancer, whereas we focused on ovarian serous cancer. Second, mechanisms regulating EphA1 protein level may be important in ovarian cancer and EphA1 mRNA expression may show an inconsistent trend. The possible mechanisms need to be further explored. We previously proved that hypermethylation of a CpG island in the EphA1 promoter region leads to downregulation of EphA1 in colorectal cancer (20). We therefore deduced that methylation of DNA might be one of the mechanisms for reduced expression of EphA1 in ovarian serous cancers. Other possible regulatory mechanisms include EphA1 mutation, microRNA, deacetylation, and gene deletion. We plan to intensively investigate these molecular mechanisms in future studies.

Ki67 is a marker of proliferation expressed exclusively during active phases of the cell cycle. It is commonly assessed by IHC in clinical settings to judge cell proliferative activity. It has been correlated with clinical outcome and is considered to be an indicator of prognosis. Interestingly, our data show that loss of EphA1 was more often observed in high Ki67 index tumors (P=0.007). On the other hand, the MTT proliferation assay showed that overexpression of EhpA1 gene inhibited the proliferation of HO8910 and A2780 tumor cells, this is consistent with what observed in tumor tissues. Overexpression of EphA1 in ovarian cancer cell lines did not affect cell apoptosis. Our results suggest that EphA1 may play a role in ovarian cancer as a tumor suppressor but is not a key suppressor gene in ovarian tumorigenesis.

Histologic grade has been shown to be an important prognostic factor in cases of ovarian serous carcinoma. Although the ovarian grading system has evolved over the years, there is no universally accepted classification. The Federation of Gynecology and Obstetrics (FIGO) grading system typically analyzes architectural pattern, nuclear/cytologic atypia, mitotic index, or a combination of these features. Molecular pathological research has contributed to improved knowledge of the different subtypes of ovarian cancer. The World Health Organization Classification System of Ovarian Cancer, published in 2014 by Kurman et al (23), eliminated the older practice of grading serous tumors on a continuum (grade 1, 2, or 3) and instead differentiates low-grade serous and high-grade serous ovarian cancers as two distinct diseases. It is now widely accepted that low-grade and high-grade serous tumors are essentially distinct diseases exhibiting distinct genetic alterations, molecular patterns, and clinical behaviors. Low-grade serous carcinoma develops from well-recognized precursors and behaves in an indolent fashion. It is characterized by specific mutations including KRAS, BRAF, and ERBB2 and is relatively genetically stable (1). In contrast, high-grade serous ovarian carcinoma is characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based chemotherapy (33). Although high-grade and low-grade serous carcinomas are usually easily distinguished, it may be difficult to discriminate between them in some carcinomas and can especially challenging in small tissue samples (34). This is the first study demonstrating that EphA1 protein is significantly correlated with tumor grade in ovarian serous carcinoma, with negative expression of EphA1 more often found in ovarian high-grade serous cancers (P=0.016). Our data suggest that EphA1 may be a new molecular marker for grading ovarian serous carcinoma.

In conclusion, EphA1 expression is decreased in ovarian serous carcinoma compared with normal fallopian tube and benign ovarian serous cystadenoma. Decreased EphA1 expression was more often detected in high-grade tumors. Our data suggest that EphA1 may be a new marker for grading and prognosis in ovarian serous adenocarcinoma.

Acknowledgements

The authors wish to thank the patients who participated in this study. This study was supported by grants from the National Natural Science Foundation of China (grant no. 81371611) and the National Basic Research Priorities Program 973 Project (grant no. 2014CB744504) from the Ministry of Science and Technology of China.

References

1 

Ciucci A, Zannoni GF, Buttarelli M, Martinelli E, Mascilini F, Petrillo M, Ferrandina G, Scambia G and Gallo D: Ovarian low and high grade serous carcinomas: Hidden divergent features in the tumor microenvironment. Oncotarget. 7:68033–68043. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Seebacher V, Reinthaller A, Koelbl H, Concin N, Nehoda R and Polterauer S: The impact of the duration of adjuvant chemotherapy on survival in patients with epithelial ovarian cancer-a retrospective study. PLoS One. 12:e01692722017. View Article : Google Scholar : PubMed/NCBI

4 

Takekuma M, Wong KK and Coleman RL: A long-term surviving patient with recurrent low-grade serous ovarian carcinoma treated with the MEK1/2 inhibitor, selumetinib. Gynecol Oncol Res Pract. 3:52016. View Article : Google Scholar : PubMed/NCBI

5 

Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee. Cell. 90:403–404. 1997. View Article : Google Scholar : PubMed/NCBI

6 

Pasquale EB: Eph receptors and ephrins in cancer: Bidirectional signalling and beyond. Nat Rev Cancer. 10:165–180. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Drescher U: The Eph family in the patterning of neural development. Curr Biol. 7:R799–R807. 1997. View Article : Google Scholar : PubMed/NCBI

8 

Mellitzer G, Xu Q and Wilkinson DG: Eph receptors and ephrins restrict cell intermingling and communication. Nature. 400:77–81. 1999. View Article : Google Scholar : PubMed/NCBI

9 

Xu Q, Mellitzer G, Robinson V and Wilkinson DG: In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature. 399:267–271. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Holmberg J, Clarke DL and Frisén J: Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature. 408:203–206. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Cooke J, Moens C, Roth L, Durbin L, Shiomi K, Brennan C, Kimmel C, Wilson S and Holder N: Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain. Development. 128:571–580. 2001.PubMed/NCBI

12 

Herath NI and Boyd AW: The role of Eph receptors and ephrin ligands in colorectal cancer. Int J Cancer. 126:2003–2011. 2010.PubMed/NCBI

13 

Takano H, Nakamura T, Tsuchikawa T, Kushibiki T, Hontani K, Inoko K, Takahashi M, Sato S, Abe H, Takeuchi S, et al: Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice. Oncotarget. 6:41063–41076. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Husa AM, Magić Ž, Larsson M, Fornander T and Pérez-Tenorio G: EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer. Oncotarget. 7:21362–21380. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Mateo-Lozano S, Bazzocco S, Rodrigues P, Mazzolini R, Andretta E, Dopeso H, Fernández Y, Del Llano E, Bilic J, Suárez-López L, et al: Loss of the EPH receptor B6 contributes to colorectal cancer metastasis. Sci Rep. 7:437022017. View Article : Google Scholar : PubMed/NCBI

16 

Hirai H, Maru Y, Hagiwara K, Nishida J and Takaku F: A novel putative tyrosine kinase receptor encoded by the eph gene. Science. 238:1717–1720. 1987. View Article : Google Scholar : PubMed/NCBI

17 

Duffy SL, Steiner KA, Tam PP and Boyd AW: Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development. Gene Expr Patterns. 6:719–723. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Yamazaki T, Masuda J, Omori T, Usui R, Akiyama H and Maru Y: EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci. 122:243–255. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Hafner C, Becker B, Landthaler M and Vogt T: Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer. Mod Pathol. 19:1369–1377. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Dong Y, Wang J, Sheng Z, Li G, Ma H, Wang X, Zhang R, Lu G, Hu Q, Sugimura H and Zhou X: Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol. 22:151–160. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Wang J, Dong Y, Wang X, Ma H, Sheng Z, Li G, Lu G, Sugimura H and Zhou X: Expression of EphA1 in gastric carcinomas is associated with metastasis and survival. Oncol Rep. 24:1577–1584. 2010.PubMed/NCBI

22 

Wang X, Liu Y, Cao G, Zhang X, Xu H, Xu H and Wang J: Expression of the EphA1 protein is associated with Fuhrman nuclear grade in clear cell renal cell carcinomas. Int J Clin Exp Pathol. 8:6821–6827. 2015.PubMed/NCBI

23 

Kurman RJ, Carcangiu ML, Herrington CS and Young RH: WOH Classification of Tumours of Female Reproductive Organs. International Agency for Research on Cancer; Lyon: 2014

24 

Miyazaki K, Inokuchi M, Takagi Y, Kato K, Kojima K and Sugihara K: EphA4 is a prognostic factor in gastric cancer. BMC Clin Pathol. 13:192013. View Article : Google Scholar : PubMed/NCBI

25 

Fox BP and Kandpal RP: Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun. 318:882–892. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Nakagawa M, Inokuchi M, Takagi Y, Kato K, Sugita H, Otsuki S, Kojima K, Uetake H and Sugihara K: Erythropoietin-producing hepatocellular A1 is an independent prognostic factor for gastric cancer. Ann Surg Oncol. 22:2329–2335. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Giaginis C, Tsoukalas N, Bournakis E, Alexandrou P, Kavantzas N, Patsouris E and Theocharis S: Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: Associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. BMC Clin Pathol. 14:82014. View Article : Google Scholar : PubMed/NCBI

28 

Fox BP, Tabone CJ and Kandpal RP: Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines. Biochem Biophys Res Commun. 342:1263–1272. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Wang J, Ma J, Dong Y, Shen Z, Ma H, Wang X, Shi S, Wu J, Lu G, Peng L and Zhoud X: High expression of EphA1 in esophageal squamous cell carcinoma is associated with lymph node metastasis and advanced disease. APMIS. 121:30–37. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Peng L, Wang H, Dong Y, Ma J, Wen J, Wu J, Wang X, Zhou X and Wang J: Increased expression of EphA1 protein in prostate cancers correlates with high Gleason score. Int J Clin Exp Pathol. 6:1854–1860. 2013.PubMed/NCBI

31 

Wong YL, Dali AZ, Mohamed Rose I, Jamal R and Mokhtar NM: Potential molecular signatures in epithelial ovarian cancer by genome wide expression profiling. Asia Pac J Clin Oncol. 12:e259–e268. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Herath NI, Spanevello MD, Sabesan S, Newton T, Cummings M, Duffy S, Lincoln D, Boyle G, Parsons PG and Boyd AW: Over-expression of Eph and ephrin genes in advanced ovarian cancer: Ephrin gene expression correlates with shortened survival. BMC cancer. 6:1442006. View Article : Google Scholar : PubMed/NCBI

33 

Mignogna C, Staropoli N, Botta C, De Marco C, Rizzuto A, Morelli M, Di Cello A, Franco R, Camastra C, Presta I, et al: Aurora kinase a expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients. J Ovarian Res. 9:312016. View Article : Google Scholar : PubMed/NCBI

34 

Gu Y, Li F, Qian N, Chen X, Wang H and Wang J: Expression of EphB6 in ovarian serous carcinoma is associated with grade, TNM stage and survival. J Clin Pathol. 69:448–453. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April-2018
Volume 17 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Jin Y, Zou Y, Wan L, Lu M, Liu Y, Huang G, Wang J and Xi Q: Decreased Eph receptor‑A1 expression is related to grade in ovarian serous carcinoma. Mol Med Rep 17: 5409-5415, 2018
APA
Jin, Y., Zou, Y., Wan, L., Lu, M., Liu, Y., Huang, G. ... Xi, Q. (2018). Decreased Eph receptor‑A1 expression is related to grade in ovarian serous carcinoma. Molecular Medicine Reports, 17, 5409-5415. https://doi.org/10.3892/mmr.2018.8528
MLA
Jin, Y., Zou, Y., Wan, L., Lu, M., Liu, Y., Huang, G., Wang, J., Xi, Q."Decreased Eph receptor‑A1 expression is related to grade in ovarian serous carcinoma". Molecular Medicine Reports 17.4 (2018): 5409-5415.
Chicago
Jin, Y., Zou, Y., Wan, L., Lu, M., Liu, Y., Huang, G., Wang, J., Xi, Q."Decreased Eph receptor‑A1 expression is related to grade in ovarian serous carcinoma". Molecular Medicine Reports 17, no. 4 (2018): 5409-5415. https://doi.org/10.3892/mmr.2018.8528