Tumor Biology

, Volume 35, Issue 2, pp 1343–1350 | Cite as

High expression of MACC1 predicts poor prognosis in patients with osteosarcoma

  • Kai Zhang
  • Yonggang Zhang
  • Huimin Zhu
  • Na Xue
  • Jie Liu
  • Chao Shan
  • Qing Zhu
Research Article


Increasing evidence has demonstrated that high metastasis-associated in colon cancer-1 (MACC1) level is tightly associated with the development, progression, and poor prognosis of a variety of tumors. However, the relationship between MACC1 and the occurrence, development, and progression of osteosarcoma (OS) remains to be clarified. To facilitate and deepen the understanding of the associations of MACC1 with the development and progression of OS, in the current study, we detected the expressions of MACC1 mRNA and protein, and investigated the relationship between MACC1 expression and prognosis of the patients with OS. Our findings demonstrated that expressions of MACC1 mRNA and protein in OS tissues were significantly higher than those in paired normal bone tissues (P < 0.05). Additionally, the level of MACC1 mRNA in the patients with higher clinical stage and distant metastasis was markedly higher than those with lower clinical stage and without metastasis (P < 0.05). Furthermore, high MACC1 level was closely correlated with clinical stage and distant metastasis (P < 0.05), but not related to the patients’ age, gender, tumor size, and anatomical location (P > 0.05). Stepwise investigation revealed that survival time of the patients with high MACC1 level was obviously lower than that with low MACC1 level (P < 0.05). Collectively, our data suggest that MACC1 may play important roles in the development and progression of OS, and thus may be considered as a novel molecular target for therapy of the patients with OS.


Metastasis-associated in colon cancer-1 Osteosarcoma Metastasis Prognosis 


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics. CA Cancer J Clin. 2008;58(2):71–96.PubMedCrossRefGoogle Scholar
  2. 2.
    Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Hayden JB, Hoang BH. Osteosarcoma: basic science and clinical implications. Orthop Clin North Am. 2006;37(1):1–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Ham SJ, Schraffordt Koops H, van der Graaf WT, van Horn JR, Postma L, Hoekstra HJ. Historical, current and future aspects of osteosarcoma treatment. Eur J Surg Oncol. 1998;24(6):584–600.PubMedCrossRefGoogle Scholar
  5. 5.
    Papagelopoulos PJ, Galanis EC, Vlastou C, Nikiforidis PA, Vlamis JA, Boscainos PJ, et al. Current concepts in the evaluation and treatment of osteosarcoma. Orthopedics. 2000;23(8):858–67. quiz 868–859.PubMedGoogle Scholar
  6. 6.
    Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006;32(6):423–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Ta HT, Dass CR, Choong PF, Dunstan DE. Osteosarcoma treatment: state of the art. Cancer Metastasis Rev. 2009;28(1–2):247–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Bispo Junior RZ, Camargo OP. Prognostic factors in the survival of patients diagnosed with primary non-metastatic osteosarcoma with a poor response to neoadjuvant chemotherapy. Clinics (Sao Paulo). 2009;64(12):1177–86.CrossRefGoogle Scholar
  9. 9.
    Zhukov NV, Tjulandin SA. Targeted therapy in the treatment of solid tumors: practice contradicts theory. Biochemistry (Mosc). 2008;73(5):605–18.CrossRefGoogle Scholar
  10. 10.
    Kokoszynska K, Krynski J, Rychlewski L, Wyrwicz LS. Unexpected domain composition of MACC1 links MET signaling and apoptosis. Acta Biochim Pol. 2009;56(2):317–23.PubMedGoogle Scholar
  11. 11.
    Puntervoll P, Linding R, Gemund C, Chabanis-Davidson S, Mattingsdal M, Cameron S, et al. ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins. Nucleic Acids Res. 2003;31(13):3625–30.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Quevillon E, Silventoinen V, Pillai S, Harte N, Mulder N, Apweiler R, et al. InterProScan: protein domains identifier. Nucleic Acids Res. 2005;33:W116–20. Web Server issue.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Iakoucheva LM, Radivojac P, Brown CJ, O′Connor TR, Sikes JG, Obradovic Z, et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 2004;32(3):1037–49.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med. 2009;15(1):59–67.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang Y, Zhang H, Cai J, Fang L, Wu J, Ye C, et al. Overexpression of MACC1 and Its significance in human breast cancer progression. Cell Biosci. 2013;3(1):16.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Wang L, Wu Y, Lin L, Liu P, Huang H, Liao W, et al. Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion. Int J Cancer. 2013;133(6):1419–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Gao J, Ding F, Liu Q, Yao Y. Knockdown of MACC1 expression suppressed hepatocellular carcinoma cell migration and invasion and inhibited expression of MMP2 and MMP9. Mol Cell Biochem. 2013;376(1–2):21–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Qu JH, Chang XJ, Lu YY, Bai WL, Chen Y, Zhou L, et al. Overexpression of metastasis-associated in colon cancer 1 predicts a poor outcome of hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 2012;18(23):2995–3003.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang R, Shi H, Chen Z, Wu Q, Ren F, Huang H. Effects of metastasis-associated in colon cancer 1 inhibition by small hairpin RNA on ovarian carcinoma OVCAR-3 cells. J Exp Clin Cancer Res. 2011;30:83.PubMedCrossRefGoogle Scholar
  20. 20.
    Shirahata A, Shinmura K, Kitamura Y, Sakuraba K, Yokomizo K, Goto T, et al. MACC1 as a marker for advanced colorectal carcinoma. Anticancer Res. 2010;30(7):2689–92.PubMedGoogle Scholar
  21. 21.
    Shimokawa H, Uramoto H, Onitsuka T, Chundong G, Hanagiri T, Oyama T, et al. Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence. J Thorac Cardiovasc Surg. 2011;141(4):895–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Shirahata A, Sakata M, Kitamura Y, Sakuraba K, Yokomizo K, Goto T, et al. MACC 1 as a marker for peritoneal-disseminated gastric carcinoma. Anticancer Res. 2010;30(9):3441–4.PubMedGoogle Scholar
  23. 23.
    Zhu M, Xu Y, Mao X, Gao Y, Shao L, Yan F: Overexpression of metastasis-associated in colon cancer-1 associated with poor prognosis in patients with esophageal cancer. Pathol Oncol Res 2013, (in press).Google Scholar
  24. 24.
    Shirahata A, Fan W, Sakuraba K, Yokomizo K, Goto T, Mizukami H, et al. MACC 1 as a marker for vascular invasive hepatocellular carcinoma. Anticancer Res. 2011;31(3):777–80.PubMedGoogle Scholar
  25. 25.
    Stein U. MACC1—a novel target for solid cancers. Expert Opin Ther Targets. 2013;17(9):1039–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Machida T, Fujita T, Ooo ML, Ohira M, Isogai E, Mihara M, et al. Increased expression of proapoptotic BMCC1, a novel gene with the BNIP2 and Cdc42GAP homology (BCH) domain, is associated with favorable prognosis in human neuroblastomas. Oncogene. 2006;25(13):1931–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25(4):402–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhao H, Yang J, Fan T, Li S, Ren X. RhoE functions as a tumor suppressor in esophageal squamous cell carcinoma and modulates the PTEN/PI3K/Akt signaling pathway. Tumour Biol. 2012;33(5):1363–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Yuan D, Liu B, Liu K, Zhu G, Dai Z, Xie Y. Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma. J Surg Oncol. 2013;108(3):157–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Boardman LA. Overexpression of MACC1 leads to downstream activation of HGF/MET and potentiates metastasis and recurrence of colorectal cancer. Genome Med. 2009;1(4):36.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Meng F, Li H, Shi H, Yang Q, Zhang F, Yang Y, et al. MACC1 down-regulation inhibits proliferation and tumourigenicity of nasopharyngeal carcinoma cells through Akt/beta-catenin signaling pathway. PLoS One. 2013;8(4):e60821.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Rech A, Castro Jr CG, Mattei J, Gregianin L, Di Leone L, David A, et al. [Clinical features in osteosarcoma and prognostic implications]. J Pediatr (Rio J). 2004;80(1):65–70.CrossRefGoogle Scholar
  33. 33.
    Cianfrocca M, Goldstein LJ. Prognostic and predictive factors in early-stage breast cancer. Oncologist. 2004;9(6):606–16.PubMedCrossRefGoogle Scholar
  34. 34.
    Jatoi I, Hilsenbeck SG, Clark GM, Osborne CK. Significance of axillary lymph node metastasis in primary breast cancer. J Clin Oncol. 1999;17(8):2334–40.PubMedGoogle Scholar
  35. 35.
    Madu CO, Lu Y. Novel diagnostic biomarkers for prostate cancer. J Cancer Educ. 2010;1:150–77.CrossRefGoogle Scholar
  36. 36.
    Swanson RS, Compton CC, Stewart AK, Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol. 2003;10(1):65–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients. Ann Surg. 2002;236(4):416–21. discussion 421.PubMedCrossRefGoogle Scholar
  38. 38.
    Wang M, Wang L, Ren T, Xu L, Wen Z. IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells. Cancer Biol Ther. 2013;14(2):155–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Qiu J, Huang P, Liu Q, Hong J, Li B, Lu C, et al. Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma. J Transl Med. 2011;9:166.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Feugeas O, Guriec N, Babin-Boilletot A, Marcellin L, Simon P, Babin S, et al. Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol. 1996;14(2):467–72.PubMedGoogle Scholar
  41. 41.
    Rosier RN, Teot LA, Hicks DG, Schwartz C, O’Keefe RJ, Puzas JE. Multiple drug resistance in osteosarcoma. Iowa Orthop J. 1995;15:66–73.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH, et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol. 1999;17(9):2781–8.PubMedGoogle Scholar
  43. 43.
    Onda M, Matsuda S, Higaki S, Iijima T, Fukushima J, Yokokura A, et al. ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer. 1996;77(1):71–8.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Kai Zhang
    • 1
  • Yonggang Zhang
    • 1
  • Huimin Zhu
    • 2
  • Na Xue
    • 3
  • Jie Liu
    • 2
  • Chao Shan
    • 2
  • Qing Zhu
    • 3
  1. 1.Department of OrthopaedicsChinese PLA General Hospital and Chinese PLA Medical SchoolBeijingChina
  2. 2.Department of Spine surgery, Henan People’s Armed Police Corps HospitalZhengzhouChina
  3. 3.Department of Stomatologythe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina

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