Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Expression and Clinical Significance of REPS2 in Human Esophageal Squamous Cell Carcinoma

  • Zhang, Hang (Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University) ;
  • Duan, Chao-Jun (Medical Science Institute, Xiangya Hospital, Central South University) ;
  • Zhang, Heng (Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University) ;
  • Cheng, Yuan-Da (Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University) ;
  • Zhang, Chun-Fang (Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University)
  • Published : 2013.05.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: REPS2 plays important roles in inhibiting cell proliferation, migration and in inducing apoptosis of cancer cells, now being identified as a useful biomarker for favorable prognosis in prostate and breast cancers. The purpose of this study was to assess REPS2 expression and to explore its role in esophageal squamous cell carcinoma (ESCC). Methods: Protein expression of REPS2 in ESCCs and adjacent non-cancerous tissues from 120 patients was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, thirty paired ESCC tissues and four ESCC cell lines and one normal human esophageal epithelial cell line were evaluated for REPS2 mRNA and protein expression levels by quantitative RT-PCR and Western blotting. Results: REPS2 mRNA and protein expression levels were down-regulated in ESCC tissues and cell lines. Low protein levels were significantly associated with primary tumour, TNM stage, lymph node metastasis and recurrence (all, P < 0.05). Survival analysis demonstrated that decreased REPS2 expression was significantly associated with shorter overall survival and disease-free survival (both, P < 0.001), especially in early stage ESCC patients. When REPS2 expression and lymph node metastasis status were combined, patients with low REPS2 expression/lymph node (+) had both poorer overall and disease-free survival than others (both, P < 0.001). Cox multivariate regression analysis further revealed REPS2 to be an independent prognostic factor for ESCC patients. Conclusions: Our findings demonstrate that downregulation of REPS2 may contribute to malignant progression of ESCC and represent a novel prognostic marker and a potential therapeutic target for ESCC patients.

Keywords

References

  1. Badway JA, Baleja JD (2011). Reps2: a cellular signaling and molecular trafficking nexus. Int J Biochem Cell Biol, 43, 1660-3. https://doi.org/10.1016/j.biocel.2011.08.014
  2. Bashir M, Kirmani D, Bhat HF, et al (2010). P66shc and its downstream Eps8 and Rac1 proteins are upregulated in esophageal cancers. Cell Commun Signal, 8, 13. https://doi.org/10.1186/1478-811X-8-13
  3. Chai J, Jamal MM (2012). Esophageal malignancy: A growing concern. World J Gastroenterol, 18, 6521-6. https://doi.org/10.3748/wjg.v18.i45.6521
  4. Chang GT, Blok LJ, Steenbeek M, et al (1997). Differentially expressed genes in androgen-dependent and -independent prostate carcinomas. Cancer Res, 57, 4075-81.
  5. Chen H, Fre S, Slepnev VI, et al (1998). Epsin is an EH-domainbinding protein implicated in clathrin-mediated endocytosis. Nature, 394, 793-7. https://doi.org/10.1038/29555
  6. Chen SB, Weng HR, Wang G, et al (2013). Prognostic factors and outcome for patients with esophageal squamous cell carcinoma underwent surgical resection alone: evaluation of the seventh edition of the american joint committee on cancer staging system for esophageal squamous cell carcinoma. J Thorac Oncol, 8, 495-501. https://doi.org/10.1097/JTO.0b013e3182829e2c
  7. Doolan P, Clynes M, Kennedy S, et al (2009). TMEM25, REPS2 and Meis 1: favourable prognostic and predictive biomarkers for breast cancer. Tumour Biol, 30, 200-9. https://doi.org/10.1159/000239795
  8. Feng JG, Liu Q, Qin X, et al (2012). Clinicopathological pattern and Annexin A2 and Cdc42 status in patients presenting with differentiation and lymphnode metastasis of esophageal squamous cell carcinomas. Mol Biol Rep, 39, 1267-74. https://doi.org/10.1007/s11033-011-0859-2
  9. Ikeda M, Ishida O, Hinoi T, et al (1998). Identification and characterization of a novel protein interacting with Ralbinding protein 1, a putative effector protein of Ral. J Biol Chem, 273, 814-21. https://doi.org/10.1074/jbc.273.2.814
  10. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  11. Joneson T, Bar-Sagi D (1999). Suppression of Ras-induced apoptosis by the Rac GTPase. Mol Cell Biol, 19, 5892-901.
  12. Jullien-Flores V, Dorseuil O, Romero F, et al (1995). Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. J Biol Chem, 270, 22473-77. https://doi.org/10.1074/jbc.270.38.22473
  13. Kariya K, Koyama S, Nakashima S, et al (2000). Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation. J Biol Chem, 275, 18399-406. https://doi.org/10.1074/jbc.M000521200
  14. Loudig O, Brandwein-Gensler M, Kim RS, et al (2011). Illumina whole-genome complementary DNA-mediated annealing, selection, extension and ligation platform: assessing its performance in formalin-fixed, paraffin-embedded samples and identifying invasion pattern-related genes in oral squamous cell carcinoma. Hum Pathol, 42, 1911-22. https://doi.org/10.1016/j.humpath.2011.02.011
  15. Morinaka K, Koyama S, Nakashima S, et al (1999). Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis. Oncogene, 18, 5915-22. https://doi.org/10.1038/sj.onc.1202974
  16. Nakashima S, Morinaka K, Koyama S, et al (1999). Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. EMBO J, 18, 3629-42. https://doi.org/10.1093/emboj/18.13.3629
  17. Oosterhoff JK, Kuhne LC, Grootegoed JA, Blok LJ (2005). EGF signalling in prostate cancer cell lines is inhibited by a high expression level of the endocytosis protein REPS2. Int J Cancer, 113, 561-7. https://doi.org/10.1002/ijc.20612
  18. Oosterhoff JK, Penninkhof F, Brinkmann AO, et al (2003). REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells. Oncogene, 22, 2920-25. https://doi.org/10.1038/sj.onc.1206397
  19. Oshiro T, Koyama S, Sugiyama S, et al (2002). Interaction of POB1, a downstream molecule of small G protein Ral, with PAG2, a paxillin-binding protein, is involved in cell migration. J Biol Chem, 277, 38618-26. https://doi.org/10.1074/jbc.M203453200
  20. Penninkhof F, Grootegoed JA, Blok LJ (2004). Identification of REPS2 as a putative modulator of NF-kappaB activity in prostate cancer cells. Oncogene, 23, 5607-15. https://doi.org/10.1038/sj.onc.1207750
  21. Rincon SA, Ye Y, Villar-Tajadura MA, et al (2009). Pob1 participates in the Cdc42 regulation of fission yeast actin cytoskeleton. Mol Biol Cell, 20, 4390-9. https://doi.org/10.1091/mbc.E09-03-0207
  22. Rodriguez-Rocha H, Garcia Garcia A, Zavala-Flores L, et al (2012). Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease. Antioxid Redox Signal, 17, 1676-93. https://doi.org/10.1089/ars.2011.4474
  23. Singhal SS, Yadav S, Drake K, et al (2008). Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1. J Biol Chem, 283, 19714-29. https://doi.org/10.1074/jbc.M708703200
  24. Tomassi L, Costantini A, Corallino S, et al (2008). The central proline rich region of POB1/REPS2 plays a regulatory role in epidermal growth factor receptor endocytosis by binding to 14-3-3 and SH3 domain-containing proteins. BMC Biochem, 9, 21. https://doi.org/10.1186/1471-2091-9-21
  25. Toya M, Iino Y, Yamamoto M (1999). Fission yeast Pob1p, which is homologous to budding yeast Boi proteins and exhibits subcellular localization close to actin patches, is essential for cell elongation and separation. Mol Biol Cell, 10, 2745-57. https://doi.org/10.1091/mbc.10.8.2745

Cited by

  1. Activating Transcription Factor 4 Promotes Esophageal Squamous Cell Carcinoma Invasion and Metastasis in Mice and Is Associated with Poor Prognosis in Human Patients vol.9, pp.7, 2014, https://doi.org/10.1371/journal.pone.0103882