Skip to main content

Advertisement

SpringerLink
Log in

Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

Hepatic annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical symptoms and plays a key role in development, metastasis, and drug resistance of lethal hepatocellular carcinoma (HCC). However, the prognostic significance of ANXA2 for HCC has not been elucidated up to now. In this study, ANXA2 was frequently found to be up-regulated in HCC tissues compared with benign liver disease (BLD) tissues, which was consistent with the results in serum samples and tissue specimens of patients with HCC. Furthermore, ANXA2 expression was significantly correlated with differentiated degree, intrahepatic metastasis, portal vein thrombus, and tumor node metastasis (TNM) staging. More importantly, increased ANXA2 level was first confirmed to be closely associated with shortened overall survival of HCC (χ 2 = 12.872, P = 0.005) and identified as an independent prognostic factor (hazard ratio 1.338, 95 % confidence interval (CI) 1.013 ~ 1.766, P = 0.040), suggesting that ANXA2 up-regulation might represent an acquired metastasis phenotype of HCC, help to screen out high-risk population for HCC, or more effectively treat a subset of postsurgical HCC patients positive for ANXA2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

HCC:

Hepatocellular carcinoma

ANXA2:

Annexin A2

BLD:

Benign liver diseases

TMA:

Tissue microarray

FFPE:

Formalin-fixed paraffin-embedded

ELISA:

Enzyme-linked immunosorbent assay

PBS:

Phosphate-buffered saline

qRT-PCR:

Quantitative real-time polymerase chain reaction

IHC:

Immunohistochemistry

SD:

Standard deviation

tPA:

Tissue plasminogen activator

AFP:

Alpha-fetoprotein

References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.

    Article  PubMed  Google Scholar 

  2. Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat. 2009;16(7):453–63.

    Article  CAS  PubMed  Google Scholar 

  3. Ichikawa T, Sano K, Morisaka H. Diagnosis of pathologically early HCC with EOB-MRI: experiences and current consensus. Liver Cancer. 2014;3(2):97–107.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Shoreibah MG, Bloomer JR, McGuire BM, Massoud OI. Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. Am J Med Sci. 2014;347(5):415–9.

    Article  PubMed  Google Scholar 

  5. Sun H, Zhu MS, Wu WR, Shi XD, Xu LB. Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: the jury is still out. World J Hepatol. 2014;6(12):830–5.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang CY, Lin CF. Annexin A2: its molecular regulation and cellular expression in cancer development. Dis Markers. 2014;2014:308976.

    PubMed  PubMed Central  Google Scholar 

  7. Chaiteerakij R, Addissie BD and Roberts LR. Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2013.

  8. Zhao YJ, Ju Q, Li GC. Tumor markers for hepatocellular carcinoma. Mol Clin Oncol. 2013;1(4):593–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jour G, Gullet A, Liu M, Hoch BL. Prognostic relevance of Federation Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma: a study of 50 cases. Mod Pathol. 2015;28(1):37–47.

    Article  CAS  PubMed  Google Scholar 

  10. Llovet JM, Bruix J. Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology. 2000;32(3):679–80.

    Article  CAS  PubMed  Google Scholar 

  11. Luo CH, Liu QQ, Zhang PF, Li MY, Chen ZC, Liu YF. Prognostic significance of annexin II expression in non-small cell lung cancer. Clin Transl Oncol. 2013;15(11):938–46.

    Article  CAS  PubMed  Google Scholar 

  12. Yang T, Peng H, Wang J, Yang J, Nice EC, Xie K, et al. Prognostic and diagnostic significance of annexin A2 in colorectal cancer. Colorectal Dis. 2013;15(7):e373–81.

    Article  CAS  PubMed  Google Scholar 

  13. Waisman DM. Annexin II, tetramer: structure and function. Mol Cell Biochem. 1995;149–150:301–22.

    Article  PubMed  Google Scholar 

  14. Hedhli N, Falcone DJ, Huang B, Cesarman-Maus G, Kraemer R, Zhai H, et al. The annexin A2/S100A10 system in health and disease: emerging paradigms. J Biomed Biotechnol. 2012;2012:406273.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vedeler A, Hollas H, Grindheim AK, Raddum AM. Multiple roles of annexin A2 in post-transcriptional regulation of gene expression. Curr Protein Pept Sci. 2012;13(4):401–12.

    Article  CAS  PubMed  Google Scholar 

  16. Mohammad HS, Kurokohchi K, Yoneyama H, Tokuda M, Morishita A, Jian G, et al. Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma. Int J Oncol. 2008;33(6):1157–63.

    CAS  PubMed  Google Scholar 

  17. Gao PJ, Shi Y, Gao YH, Liu YW, Tan Y. The receptor for beta(2)GP I on membrane of hepatocellular carcinoma cell line SMMC-7721 is annexin II. World J Gastroenterol. 2007;13(24):3364–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang HJ, Yao DF, Yao M, Huang H, Wu W, Yan MJ, et al. Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma. World J Gastroenterol. 2012;18(41):5897–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sun Y, Gao G, Cai J, Wang Y, Qu X, He L, et al. Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma. Carcinogenesis. 2013;34(3):595–604.

    Article  CAS  PubMed  Google Scholar 

  20. Zhao P, Zhang W, Tang J, Ma XK, Dai JY, Li Y, et al. Annexin II promotes invasion and migration of human hepatocellular carcinoma cells in vitro via its interaction with HAb18G/CD147. Cancer Sci. 2010;101(2):387–95.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang W, Zhao P, Xu XL, Cai L, Song ZS, Cao DY, et al. Annexin A2 promotes the migration and invasion of human hepatocellular carcinoma cells in vitro by regulating the shedding of CD147-harboring microvesicles from tumor cells. PLoS One. 2013;8(8), e67268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang C, Guo Y, Wang J, Min Z. Annexin A2 knockdown inhibits hepatoma cell growth and sensitizes hepatoma cells to 5-fluorouracil by regulating betacatenin and cyclin D1 expression. Mol Med Rep. 2015;11(3):2147–52.

    CAS  PubMed  Google Scholar 

  23. Ministry of Health of the People’s Republic of C. Updated standards for the diagnosis and treatment of primary liver cancer. Zhonghua Gan Zang Bing Za Zhi. 2012;20(6):419–26.

    Google Scholar 

  24. o Y. [Management of clinical diagnosis, and antiviral therapy for HBV-related cirrhosis]. Zhonghua Gan Zang Bing Za Zhi. 2014;22(5):327-335.

  25. M PN. World Medical Association publishes the Revised Declaration of Helsinki. Natl Med J India. 2014;27(1):56.

    PubMed  Google Scholar 

  26. Luo RZ, Cai PQ, Li M, Fu J, Zhang ZY, Chen JW, et al. Decreased expression of PTPN12 correlates with tumor recurrence and poor survival of patients with hepatocellular carcinoma. PLoS One. 2014;9(1), e85592.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang HJ, Yao DF, Yao M, Huang H, Wang L, Yan MJ, et al. Annexin A2 silencing inhibits invasion, migration, and tumorigenic potential of hepatoma cells. World J Gastroenterol. 2013;19(24):3792–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Q, Ni Q, Wang X, Zhu H, Wang Z, Huang J. High expression of RAB27A and TP53 in pancreatic cancer predicts poor survival. Med Oncol. 2015;32(1):372.

    Article  PubMed  Google Scholar 

  29. Breuhahn K, Schirmacher P. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J Gastroenterol. 2008;14(11):1690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kwon MJ, Shin YK. Epigenetic regulation of cancer-associated genes in ovarian cancer. Int J Mol Sci. 2011;12(2):983–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang X, Liu S, Guo C, Zong J, Sun MZ. The association of annexin A2 and cancers. Clin Transl Oncol. 2012;14(9):634–40.

    Article  CAS  PubMed  Google Scholar 

  32. Lokman NA, Ween MP, Oehler MK, Ricciardelli C. The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron. 2011;4(2):199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu Z, Ling Q, Wang J, Xie H, Xu X, Zheng S. Annexin A2 is not a good biomarker for hepatocellular carcinoma in cirrhosis. Oncol Lett. 2013;6(1):125–9.

    PubMed  PubMed Central  Google Scholar 

  34. Longerich T, Haller MT, Mogler C, Aulmann S, Lohmann V, Schirmacher P, et al. Annexin A2 as a differential diagnostic marker of hepatocellular tumors. Pathol Res Pract. 2011;207(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  35. Sharma M, Ownbey RT, Sharma MC. Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation. Exp Mol Pathol. 2010;88(2):278–86.

    Article  CAS  PubMed  Google Scholar 

  36. Nedjadi T, Kitteringham N, Campbell F, Jenkins RE, Park BK, Navarro P, et al. S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility. Br J Cancer. 2009;101(7):1145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao P, Zhang W, Wang SJ, Yu XL, Tang J, Huang W, et al. HAb18G/CD147 promotes cell motility by regulating annexin II-activated RhoA and Rac1 signaling pathways in hepatocellular carcinoma cells. Hepatology. 2011;54(6):2012–24.

    Article  CAS  PubMed  Google Scholar 

  38. de Graauw M, Cao L, Winkel L, van Miltenburg MH, le Devedec SE, Klop M, et al. Annexin A2 depletion delays EGFR endocytic trafficking via cofilin activation and enhances EGFR signaling and metastasis formation. Oncogene. 2014;33(20):2610–9.

    Article  PubMed  Google Scholar 

  39. Emoto K, Sawada H, Yamada Y, Fujimoto H, Takahama Y, Ueno M, et al. Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer Res. 2001;21(2B):1339–45.

    CAS  PubMed  Google Scholar 

  40. Zimmermann U, Woenckhaus C, Pietschmann S, Junker H, Maile S, Schultz K, et al. Expression of annexin II in conventional renal cell carcinoma is correlated with Fuhrman grade and clinical outcome. Virchows Arch. 2004;445(4):368–74.

    Article  CAS  PubMed  Google Scholar 

  41. Jia JW, Li KL, Wu JX, Guo SL. Clinical significance of annexin II expression in human non-small cell lung cancer. Tumour Biol. 2013;34(3):1767–71.

    Article  CAS  PubMed  Google Scholar 

  42. Ma RL, Shen LY and Chen KN. Coexpression of ANXA2, SOD2 and HOXA13 predicts poor prognosis of esophageal squamous cell carcinoma. Oncol Rep. 2014;PMID: 24626613.

  43. Zhang Q, Zhao Z, Ma Y, Wang H, Ma J, He X, et al. Combined expression of S100A4 and Annexin A2 predicts disease progression and overall survival in patients with urothelial carcinoma. Urol Oncol. 2014;32(6):798–805.

    Article  CAS  PubMed  Google Scholar 

  44. Seckinger A, Meissner T, Moreaux J, Depeweg D, Hillengass J, Hose K, et al. Clinical and prognostic role of annexin A2 in multiple myeloma. Blood. 2012;120(5):1087–94.

    Article  CAS  PubMed  Google Scholar 

  45. Alonso-Alconada L, Santacana M, Garcia-Sanz P, Muinelo-Romay L, Colas E, Mirantes C, Monge M, Cueva J, Oliva E, Soslow RA, Lopez MA, Palacios J, Prat J, Valls J, Krakstad C, Salvesen H, Gil-Moreno A, Lopez-Lopez R, Dolcet X, Moreno-Bueno G, Reventos J, Matias-Guiu X and Abal M. Annexin-A2 as predictor biomarker of recurrent disease in endometrial cancer. Int J Cancer. 2014;PMID: 25219463.

  46. Takano S, Togawa A, Yoshitomi H, Shida T, Kimura F, Shimizu H, et al. Annexin II overexpression predicts rapid recurrence after surgery in pancreatic cancer patients undergoing gemcitabine-adjuvant chemotherapy. Ann Surg Oncol. 2008;15(11):3157–68.

    Article  PubMed  Google Scholar 

  47. Ding T, Yang L, Wang Y, Yuan J, Chen T, Cai X. Down-regulation of annexin II in prostate cancer is associated with Gleason score, recurrence, metastasis and poor prognosis. Mol Med Rep. 2010;3(5):781–7.

    CAS  PubMed  Google Scholar 

  48. Rodrigo JP, Lequerica-Fernandez P, Rosado P, Allonca E, Garcia-Pedrero JM, de Vicente JC. Clinical significance of annexin A2 downregulation in oral squamous cell carcinoma. Head Neck. 2011;33(12):1708–14.

    Article  PubMed  Google Scholar 

  49. Liu X, Ma D, Jing X, Wang B, Yang W, Qiu W. Overexpression of ANXA2 predicts adverse outcomes of patients with malignant tumors: a systematic review and meta-analysis. Med Oncol. 2015;32(1):392.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81401988), the Academic Program Development of Jiangsu Higher Education Institution (PAPD), and the International S&T Cooperation Program of China (2013DFA32150).

Conflicts of interest

None

Author information

Author notes

    Authors and Affiliations

    1. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China

      Haijian Zhang, Wei Wu, Liwei Qiu, Wenli Sai, Junling Yang, Wenjie Zheng & Dengfu Yao

    2. Department of Immunology, Medical School of Nantong University, Nantong, China

      Min Yao

    3. Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, China

      Jianfei Huang

    Authors
    1. Haijian Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Min Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wei Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Liwei Qiu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Wenli Sai
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Junling Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Wenjie Zheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jianfei Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Dengfu Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jianfei Huang or Dengfu Yao.

    Additional information

    Haijian Zhang and Min Yao contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, H., Yao, M., Wu, W. et al. Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma. Tumor Biol. 36, 9373–9383 (2015). https://doi.org/10.1007/s13277-015-3678-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-015-3678-6

    Keywords

    Search

    Navigation