To investigate the expression and clinical significance of ephrin type-A receptor 2 and epithelial-mesenchymal transition-related proteins in primary hepatocellular carcinoma.
Methods
Tissues from 52 primary hepatocellular carcinomas and 12 human normal liver tissues were detected for expression of ephrin type-A receptor 2, E-cadherin, and N-cadherin by immunochemistry. Cinicopathological features of hepatocellular carcinoma and tumor recurrence after operation were studied for the association with these molecular expressions and E-N cadherin switch.
Results
Increased expressions of ephrin type-A receptor 2 and N-cadherin and reduced expression of E-cadherin were significantly detected in hepatocellular carcinoma compared with normal liver tissues. Univariate analysis showed that there were close associations between unfavorable clinicopathological features and expressions of ephrin type-A receptor 2, E-cadherin, N-cadherin, and E-N cadherin switch. Ephrin type-A receptor 2 and E-cadherin expressions were confirmed as independent prognostic factors when corrected with age, gender, AFP, HBsAg, liver cirrhosis, tumor size, nodules, capsule, portal vein invasion, cell differentiation, and TNM stage.
Conclusions
The overexpression of ephrin type-A receptor 2 protein is correlated with the number of tumors, capsular integrity, portal vein cancer thrombus and clinical stages. Epithelial-mesenchymal transition regulated by ephrin type-A receptor 2 is involved in the aggressive clinicopathological features and prognosis, suggesting that the receptor may play an important role in the progression and metastasis of hepatocellular carcinoma.
DaiM., RenJ.S., LiN., LiQ., YangL., ChenY.H.: [estimation and prediction on cancer related incidence and mortality in china, 2008]. Zhonghua Liu Xing Bing Xue Za Zhi, 33: 57–61, 2012.
2.
Waly RaphaelS., YangdeZ., YuxiangC.: Hepatocellular carcinoma: Focus on different aspects of management. ISRN Oncol, 2012: 421673, 2012.
3.
YuanW., ChenZ., WuS., GuoJ., GeJ., YangP., HuangJ.: Silencing of EphA2 inhibits invasion of human gastric cancer SGC-7901 cells in vitro and in vivo. Neoplasma, 59: 105–113, 2012.
4.
UdayakumarD., ZhangG., JiZ., NjauwC.N., MrozP., TsaoH.: EphA2 is a critical oncogene in melanoma. Oncogene, 30: 4921–4929, 2011.
5.
HouF., YuanW., HuangJ., QianL., ChenZ., GeJ., WuS., ChenJ., WangJ.: Overexpression of EphA2 correlates with epithelial-mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients. Med Oncol, 29: 2691–2700, 2012.
6.
YuanW.J., GeJ., ChenZ.K., WuS.B., ShenH., YangP., HuB., ZhangG.W., ChenZ.H.: Over-expression of EphA2 and ephrinA-1 in human gastric adenocarcinoma and its prognostic value for postoperative patients. Dig Dis Sci, 54: 2410–2417, 2009.
7.
KataokaH., IgarashiH., KanamoriM., IharaM., WangJ.D., WangY.J., LiZ.Y., ShimamuraT., KobayashiT., MaruyamaK., NakamuraT., AraiH., KajimuraM., HanaiH., TanakaM., SugimuraH.: Correlation of EphA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci, 95: 136–141, 2004.
8.
NakajimaS., DoiR., ToyodaE., TsujiS., WadaM., KoizumiM., TulachanS.S., ItoD., KamiK., MoriT., KawaguchiY., FujimotoK., HosotaniR., ImamuraM.: N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res, 10: 4125–4133, 2004.
9.
Walker-DanielsJ., CoffmanK., AzimiM., RhimJ.S., BostwickD.G., SnyderP., KernsB.J., WatersD.J., KinchM.S.: Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate, 41: 275–280, 1999.
10.
YangP., YuanW., HeJ., WangJ., YuL., JinX., HuY., LiaoM., ChenZ., ZhangY.: Overexpression of epha2, mmp-9, and mvd-cd34 in hepatocellular carcinoma: Implications for tumor progression and prognosis. Hepatol Res, 39: 1169–1177, 2009.
OrsulicS., KemlerR.: Expression of Eph receptors and ephrins is differentially regulated by E-cadherin. J Cell Sci, 113(Pt 10): 1793–1802, 2000.
13.
HessA.R., SeftorE.A., GrumanL.M., KinchM.S., SeftorR.E., HendrixM.J.: Ve-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: Implications for vasculogenic mimicry. Cancer Biol Ther, 5: 228–233, 2006.
14.
GaoZ.H.: Predictive markers for postsurgical recurrence of hepatocellular carcinoma. J Surg Oncol, 92: 274–275, 2005.
15.
CuiX.D., LeeM.J., YuG.R., KimI.H., YuH.C., SongE.Y., KimD.G.: EfnA1 ligand and its receptor EphA2: Potential biomarkers for hepatocellular carcinoma. Int J Cancer, 126: 940–949, 2010.
16.
IshikawaM., MiyaharaR., SonobeM., HoriuchiM., MennjuT., NakayamaE., KobayashiM., KikuchiR., KitamuraJ., ImamuraN., HuangC.L., DateH.: Higher expression of EphA2 and Ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma. Lung Cancer, 76: 431–438, 2012.
17.
WykoskyJ., DebinskiW.: The EphA2 receptor and EphrinA1 ligand in solid tumors: Function and therapeutic targeting. Mol Cancer Res, 6: 1795–1806, 2008.
18.
ChoS.B., LeeK.H., LeeJ.H., ParkS.Y., LeeW.S., ParkC.H., KimH.S., ChoiS.K., RewJ.S.: Expression of E- and N-cadherin and clinicopathology in hepatocellular carcinoma. Pathol Int, 58: 635–642, 2008.
19.
IslamS., CareyT.E., WolfG.T., WheelockM.J., JohnsonK.R.: Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion. J Cell Biol, 135: 1643–1654, 1996.
20.
AsanoK., DuntschC.D., ZhouQ., WeimarJ.D., BordelonD., RobertsonJ.H., PourmotabbedT.: Correlation of N-cadherin expression in high-grade gliomas with tissue invasion. J Neurooncol, 70: 3–15, 2004.
21.
AgathanggelouA., BiecheI., Ahmed-ChoudhuryJ., NickeB., DammannR., BakshS., GaoB., MinnaJ.D., DownwardJ., MaherE.R., LatifF.: Identification of novel gene expression targets for the ras association domain family 1 (rassf1a) tumor suppressor gene in non-small cell lung cancer and neuroblastoma. Cancer Res, 63: 5344–5351, 2003.
22.
KashimaT., NakamuraK., KawaguchiJ., TakanashiM., IshidaT., AburataniH., KudoA., FukayamaM., GrigoriadisA.E.: Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo. Int J Cancer, 104: 147–154, 2003.
23.
HagiharaA., MiyamotoK., FurutaJ., HiraokaN., WakazonoK, SekiS., FukushimaS., TsaoM.S., SugimuraT., UshijimaT.: Identification of 27 5' cpg islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene, 23: 8705–8710, 2004.
24.
ZhanD.Q., WeiS., LiuC., LiangB.Y., JiG.B., ChenX.P., XiongM., HuangZ.Y.: Reduced N-cadherin expression is associated with metastatic potential and poor surgical outcomes of hepatocellular carcinoma. J Gastroenterol Hepatol, 27: 173–180, 2012.
QuattrocchiL., GreenA.R., MartinS., DurrantL., DeenS.: The cadherin switch in ovarian high-grade serous carcinoma is associated with disease progression. Virchows Arch, 459: 21–29, 2011.
27.
ArakiK., ShimuraT., SuzukiH., TsutsumiS., WadaW., YajimaT., KobayahiT., KuboN., KuwanoH.: E/N-cadherin switch mediates cancer progression via TGF-beta-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma. Br J Cancer, 105: 1885–1893, 2011.
28.
JagerT., BeckerM., EisenhardtA., TilkiD., TotschM., SchmidK.W., RomicsI., RubbenH., ErgunS., SzarvasT.: The prognostic value of cadherin switch in bladder cancer. Oncol Rep, 23: 1125–1132, 2010.
29.
HaoL., HaJ.R., KuzelP., GarciaE., PersadS.: Cadherin switch from E- to N-cadherin in melanoma progression is regulated by the PI3K/PTEN pathway through twist and snail. Br J Dermatol, 166: 1184–1197, 2012.
30.
NiemanM.T., PrudoffR.S., JohnsonK.R., WheelockM.J.: N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol, 147: 631–644, 1999.
31.
KuphalS., BosserhoffA.K.: Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma. Oncogene, 25: 248–259, 2006.
