Abstract
Background
Our previous study observed that the expression of RASSF6, a member of the Ras-association domain family, was down-regulated in gastric cancer cells. The present study further investigated the clinical significance of RASSF6 in gastric cancer.
Methods
Using real-time PCR, Western blot analysis, tissue microarray (TMA), and immunohistochemical staining, we evaluated RASSF6 mRNA and protein levels in tumor tissues and in the paired adjacent normal mucosa from patients with gastric cancers at different stages.
Results
RASSF6 mRNA and protein levels were decreased in gastric cancer tissues compared with the adjacent normal mucosa. Immunohistochemical detection of RASSF6 in a TMA that contained 264 paired specimens showed that a decreased cytoplasmic RASSF6 expression was significantly associated with the extent of cancer invasion, lymph node metastasis, distant metastasis, tumor histological grade, advanced clinical stage, and Ki-67 proliferative index. Moreover, RASSF6 expression in metastatic lymph nodes was lower than in the paired primary tumors. Patients with RASSF6-negative tumors had extremely higher disease recurrence rates and poorer survival than patients with RASSF6-positive tumors even after radical surgery. Stratification analysis revealed RASSF6 as an independent predictor for tumor recurrence in patients with gastric cancers irrespective of tumor stage.
Conclusions
RASSF6 might contribute to the progression of gastric carcinogenesis and may function as a novel independent prognostic marker for the prediction of the recurrence of cancer in patients after curative operations.
Similar content being viewed by others
References
Leung WK, Wu MS, Kakugawa Y, et al. Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 2008;9:279–87.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin. 2010;60:277–300.
Cunningham D, Oliveira J. Gastric cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19:ii23–4.
de Maat MF, van de Velde CJ, Umetani N, et al. Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer. J Clin Oncol. 2007;25(31):4887–94.
MacDonald JS. Gastric cancer: new therapeutic options. N Engl J Med. 2006;355:76–7.
Hundahl SA, Wanebo HJ. Changing gastric cancer treatment in the United States and the pursuit of quality. Eur J Surg Oncol. 2005;31:605–15.
Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.
Ishii HH, Gobe GC, Ebihara Y. P53 is an indicator of tumor progression in early but not advanced gastric carcinomas. Hepatogastroenterology. 2007;54(79):2159–63.
Scartozzi M, Galizia E, Freddari F, Berardi R, Cellerino R, Cascinu S. Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. Cancer Treat Rev. 2004;30(5):451–9.
Kim JH, Kim MK, Lee HE, et al. Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer. Mod Pathol. 2007;20:835–42.
Lieto E, Ferraraccio F, Orditura M, et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 2008;15(1):69–79.
Wang Q, Wen YG, Li DP, et al. Refined mapping of loss of heterozygosity in Chinese sporadic gastric carcinoma. Afr J Biotechnol. 2010;9(35):5754–61.
Wen YG, Wang Q, Zhou CZ, Qiu GQ, Peng ZH, Tang HM. Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3 K/AKT pathway. Oncol Rep. 2010;24:89–95.
Eckfeld K, Hesson L, Vos MD, Bieche I, Latif F, Clark GJ. RASSF4/AD037 is a potential Ras effector/tumor suppressor of the RASSF family. Cancer Res. 2004;64:8688–93.
Weyden LVD, Adams DJ. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007;1776:58–85.
Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization, Biochim Biophys Acta. 2009;1796:114–28.
Allen NPC, Donninger H, Vos MD, et al. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene. 2007;26:6203–11.
Ikeda M, Hirabayashi S, Fujiwara N, et al. Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways. Exp Cell Res. 2007;313:1484–95.
Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.
Tsamandas AC, Kardamakis D, Tsiamalos P, et al. The potential role of Bcl-2 expression, apoptosis and cell proliferation (Ki-67 expression) in cases of gastric carcinoma and correlation with classic prognostic factors and patient outcome. Anticancer Res. 2009;29(2):703–9.
Sobin LH, Wittekind C. TNM classification of malignant tumors, 6th edn. New York: Wiley-Liss; 2002.
Ajani J, D’Amico TA, Hayman JA, Meropol NJ, Minsky B, National Comprehensive Cancer Network. Gastric cancer: Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2003;1(1):28–39.
Bachmann IM, Puntervoll HE, Otte AP, Akslen LA. Loss of BMI-1 expression is associated with clinical progress of malignant melanoma. Mod Pathol. 2008;21:583–90.
Liu XP, Tsushimi K, Tsushimi M, Kawauchi S, Oga A, Furuya T, Sasaki K. Expression of p21(WAF1/CIP1) and p53 proteins in gastric carcinoma: Its relationships with cell proliferation activity and prognosis. Cancer Lett. 2001;170:183–9.
Yan DW, Li DW, Yang YX, et al. Ubiquitin D is correlated with colon cancer progression and predicts recurrence for stage II–III disease after curative surgery. Br J Cancer. 2010;103(7):961–9.
Agathanggelou A, Cooper WN, Latif F. Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res. 2005;65:3497–508.
Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MI B 1 and MI B 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.
Niimi C, Goto H, Ohmiya N, Niwa Y, Hayakawa T, Nagasaka T, Nakashima N. Usefulness of p53 and Ki-67 immunohistochemical analysis for preoperative diagnosis of extremely well-differentiated gastric adenocarcinoma. Am J Clin Pathol. 2002;118:683–92.
Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8:86–94.
Briasoulis E, Liakakos T, Dova L, Fatouros M, Tsekeris P, Roukos DH, Kappas AM. Selecting a specific pre- or postoperative adjuvant therapy for individual patients with operable gastric cancer. Expert Rev Anticancer Ther. 2006;6:931–9.
Jüttner S, Wissmann C, Jöns T, et al. Vascular endothelial growth factor-D and its receptor VEGF-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006;24:228–40.
Huang KH, Chen JH, Wu CW, Lo SS, Hsieh MC, Li AF, Lui WY. Factors affecting recurrence in node-negative advanced gastric cancer. J Gastroenterol Hepatol. 2009;24:1522–6.
Baksh S, Tommasi S, Fenton S, et al. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death. Mol Cell. 2005;18:637–50.
Vos MD, Dallol A, Eckfeld K, et al. The RASSF1A tumor suppressor activates Bax via MOAP-1. J Biol Chem. 2006;281:4557–63.
Hull J, Rowlands K, Lockhart E, Sharland M, Moore C, Hanchard N, Kwiatkowski DP. Haplotype mapping of the bronchiolitis susceptibility locus near IL8. Hum Genet. 2004;114:272–9.
Acknowledgement
This project was supported by the Medical Guidance Research Project of the Science and Technology Commission of Shanghai Municipality (10411967300) and the Doctor Innovation Fund of Shanghai Jiao Tong University School of Medicine (BXJ201045).
Conflict of interest
The authors disclosed no commercial or financial interest in the subject of study.
Author information
Authors and Affiliations
Corresponding author
Additional information
Yugang Wen and Quan Wang have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Wen, Y., Wang, Q., Zhou, C. et al. Decreased Expression of RASSF6 Is a Novel Independent Prognostic Marker of a Worse Outcome in Gastric Cancer Patients after Curative Surgery. Ann Surg Oncol 18, 3858–3867 (2011). https://doi.org/10.1245/s10434-011-1668-5
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-011-1668-5