Tumor Biology

, Volume 35, Issue 8, pp 7755–7763 | Cite as

Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy

  • Ming-Jen Sheu
  • Chien-Feng Li
  • Ching-Yih Lin
  • Sung-Wei Lee
  • Li-Ching Lin
  • Tzu-Ju Chen
  • Li-Jung Ma
Research Article


Neoadjuvant concurrent chemoradiation therapy (CCRT) is an increasingly common therapeutic strategy for rectal cancer. Clinically, it remains a major challenge to predict therapeutic response and patient outcomes after CCRT. Annexin I (ANXA1), encoded by ANXA1, is a Ca2+/phospholipid-binding protein that mediates actin dynamics and cellular proliferation, as well as suggesting tumor aggressiveness and predicting therapeutic response in certain malignancies. However, expression of ANXA1 has never been reported in rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of ANXA1 expression in patients with rectal cancer following neoadjuvant CCRT. We identified ANXA1 as associated with resistance to CCRT through data mining from a published transcriptomic dataset. Its immunoexpression was retrospectively assessed using H scores on pre-treatment biopsies from 172 rectal cancer patients treated with neoadjuvant CCRT followed by curative surgery. Results were correlated with clinicopathological features, therapeutic response, tumor regression grade (TRG), and metastasis-free survival (MeFS), as well as local recurrent-free survival (LRFS) and disease-specific survival (DSS). High expression of ANXA1 was associated with advanced pre-treatment tumor status (T3, T4, p = 0.022), advanced pre-treatment nodal status (N1, N2, p = 0.004), advanced post-treatment tumor status (T3, T4, p < 0.001), advanced post-treatment nodal status (N1, N2, p = 0.001) and inferior TRG (p = 0.009). In addition, high expression of ANXA1 emerged as an adverse prognosticator for DSS (p < 0.0001), LRFS (p = 0.0001) and MeFS (p = 0.0004). Moreover, high expression of ANXA1 also remained independently prognostic of worse DSS (hazard ratio [HR] = 3.998; p = 0.007), LRFS (HR = 3.206; p = 0.028) and MeFS (HR = 3.075; p = 0.017). This study concludes that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT.


ANXA1 Rectal cancer CCRT 



This study is supported by Chi Mei Medical Center (CMFHR10303) and the Ministry of Health and Welfare (MOHW103-TD-B-111-05)

Conflict Of Interest



  1. 1.
    Tian YF, Chen TJ, Lin CY, et al. SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential. Tumour Biol. 2013;34(2):1107–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Gérard J-P, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Bosset J-F, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal Cancer. N Engl J Med. 2006;355:1114–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Lim LH, Pervaiz S. Annexin 1: the new face of an old molecule. FASEB J. 2007;21:968–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Marie F, Solito E. Annexin 1 expression and phosphorylation are up-regulated during liver regeneration and transformation in antithrombin III SV40 T large antigen transgenic mice. Hepatology. 2000;31:371–80.CrossRefGoogle Scholar
  7. 7.
    Skouteris GG, Schroder CH. The hepatocyte growth factor receptor kinase-mediated phosphorylation of lipocortin-1 transduces the proliferating signal of the hepatocyte growth factor. J Biol Chem. 1996;271:27266–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Croxtall J, Flower R, Perretti M. The role of lipocortin 1 in the regulation of A549 cell proliferation and leukocyte migration. J Lipid Mediat. 1993;6:295–302.PubMedGoogle Scholar
  9. 9.
    Croxtall JD, Waheed S, Choudhury Q, Anand R, Flower RJ. N-terminal peptide fragments of lipocortin-1 inhibit A549 cell growth and block EGF-induced stimulation of proliferation. Int J Cancer. 1993;54:153–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Alldridge LC, Harris HJ, Plevin R, Hannon R, Bryant CE. The annexin protein lipocortin 1 regulates the MAPK/ERK pathway. J Biol Chem. 1999;274:37620–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Dorovkov MV, Ryazanov AG. Phosphorylation of annexin I by TRPM7 channel-kinase. J Biol Chem. 2004;279:50643–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Varticovski L, Chahwala SB, Whitman M, et al. Location of sites in human lipocortin I that are phosphorylated by protein tyrosine kinases and protein kinases A and C. Biochemistry. 1988;27:3682–90.PubMedCrossRefGoogle Scholar
  13. 13.
    Johnson MD, Kamso-Pratt J, Pepinsky RB, Whetsell Jr WO. Lipocortin-1 immunoreactivity in central and peripheral nervous system glial tumors. Hum Pathol. 1989;20:772–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Garcia Pedrero JM, Fernandez MP, Morgan RO, et al. Annexin A1 down-regulation in head and neck cancer is associated with epithelial differentiation status. Am J Pathol. 2004;164:73–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Rodrigo JP, Garcia-Pedrero JM, Fernandez MP, Morgan RO, Suarez C, Herrero A. Annexin A1 expression in nasopharyngeal carcinoma correlates with squamous differentiation. Am J Rhinol. 2005;19:483–7.PubMedGoogle Scholar
  16. 16.
    Silistino-Souza R, Rodrigues-Lisoni FC, Cury PM, et al. Annexin 1: differential expression in tumor and mast cells in human larynx cancer. Int J Cancer. 2007;120:2582–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Hu N, Flaig MJ, Su H, et al. Comprehensive characterization of annexin I alterations in esophageal squamous cell carcinoma. Clin Cancer Res. 2004;10:6013–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Hippo Y, Yashiro M, Ishii M, et al. Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res. 2001;61:889–95.PubMedGoogle Scholar
  19. 19.
    Ahn SH, Sawada H, Ro JY, Nicolson GL. Differential expression of annexin I in human mammary ductal epithelial cells in normal and benign and malignant breast tissues. Clin Exp Metastasis. 1997;15:151–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Masaki T, Tokuda M, Ohnishi M, et al. Enhanced expression of the protein kinase substrate annexin in human hepatocellular carcinoma. Hepatology. 1996;24:72–81.PubMedGoogle Scholar
  21. 21.
    Bai XF, Ni XG, Zhao P, et al. Overexpression of annexin 1 in pancreatic cancer and its clinical significance. World J Gastroenterol. 2004;10:1466–70.PubMedGoogle Scholar
  22. 22.
    Li CF, Shen KH, Huang LC, Huang HY, Wang YH, Wu TF. Annexin-I overexpression is associated with tumour progression and independently predicts inferior disease-specific and metastasis-free survival in urinary bladder urothelial carcinoma. Pathology. 2010;42(1):43–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Kang JS, Calvo BF, Maygarden SJ, Caskey LS, Mohler JL, Ornstein DK. Dysregulation of annexin I protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer. Clin Cancer Res. 2002;8:117–23.PubMedGoogle Scholar
  24. 24.
    Lin CY, Tian YF, Wu LC, et al. Rsf-1 expression in rectal cancer: with special emphasis on the independent prognostic value after neoadjuvant chemoradiation. J Clin Pathol. 2012;65(8):687–92.PubMedCrossRefGoogle Scholar
  25. 25.
    Bosset JF, Calais G, Mineur L, et al. Enhanced tumoricidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results of EORTC 22921. J Clin Oncol. 2005;23:5620e7.CrossRefGoogle Scholar
  26. 26.
    Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-T4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620e5.CrossRefGoogle Scholar
  27. 27.
    Bosset JF, Collette L, Calais G, et al. Chemotherapy with pre-operative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114e23.CrossRefGoogle Scholar
  28. 28.
    Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Adjuvant Breast and Bowel Project protocol R-03. Dis Colon Rectum. 1997;40:131e9.CrossRefGoogle Scholar
  29. 29.
    Valentini V, Coco C, Cellini N, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys. 1998;40:1067e75.CrossRefGoogle Scholar
  30. 30.
    Wagman R, Minsky BD, Cohen AM, et al. Sphincter preservation in rectal cancer with preoperative radiation therapy and coloanal anastomosis: long term follow-up. Int J Radiat Oncol Biol Phys. 1998;42:51e7.CrossRefGoogle Scholar
  31. 31.
    Lin CY, Sheu MJ, Li CF, et al.: Deficiency in asparagine synthetase expression in rectal cancers receiving concurrent chemoradiotherapy: negative prognostic impact and therapeutic relevance. Tumour Biol. 2014 Apr 13. [Epub ahead of print].Google Scholar
  32. 32.
    Alvarez-Martinez MT, Mani JC, Porte F, Faivre-Sarrailh C, Liautard JP, Sri WJ. Characterization of the interaction between annexin I and profilin. Eur J Biochem. 1996;238:777–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Rao J. Targeting actin remodeling profiles for the detection and management of urothelial cancers—a perspective for bladder cancer research. Front Biosci. 2002;7:e1–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 2007;39:305–18.PubMedCrossRefGoogle Scholar
  35. 35.
    Savagner P. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 2001;23:912–23.PubMedCrossRefGoogle Scholar
  36. 36.
    Wu YL, Jiang XR, Lillington DM, Newland AC, Kelsey SM. Upregulation of lipocortin 1 inhibits tumour necrosis factor-induced apoptosis in human leukaemic cells: a possible mechanism of resistance to immune surveillance. Br J Haematol. 2000;111:807–16.PubMedGoogle Scholar
  37. 37.
    Carollo M, Parente L, D’Alessandro N. Dexamethasone-induced cytotoxic activity and drug resistance effects in androgen-independent prostate tumor PC-3 cells are mediated by lipocortin 1. Oncol Res. 1998;10:245–54.PubMedGoogle Scholar
  38. 38.
    Papetti M, Augenlicht LH. MYBL2, a link between proliferation and differentiation in maturing colon epithelial cells. J Cell Physiol. 2011;226(3):785–91.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Swiderek E, Kalas W, Wysokinska E, Pawlak A, Rak J, Strzadala L. The interplay between epigenetic silencing, oncogenic KRas and HIF-1 regulatory pathways in control of BNIP3 expression in human colorectal cancer cells. Biochem Biophys Res Commun. 2013;441(4):707–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Wang X, Gong W, Qing H, et al. p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells. Tumour Biol. 2010;31(6):575–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Miyoshi N, Ishii H, Mimori K, et al. TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer. Ann Surg Oncol. 2010;17(4):967–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Koshiyama A, Ichibangase T, Imai K. Comprehensive fluorogenic derivatization-liquid chromatography/tandem mass spectrometry proteomic analysis of colorectal cancer cell to identify biomarker candidate. Biomed Chromatogr. 2013;27(4):440–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Eldai H, Periyasamy S, Al Qarni S, et al. Novel genes associated with colorectal cancer are revealed by high resolution cytogenetic analysis in a patient specific manner. PLoS One. 2013;8(10):e76251.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Clemo NK, Collard TJ, Southern SL, et al. BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappaB activity. Carcinogenesis. 2008;29(4):849–57.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Ming-Jen Sheu
    • 1
    • 2
  • Chien-Feng Li
    • 3
    • 4
    • 5
    • 6
  • Ching-Yih Lin
    • 1
    • 7
  • Sung-Wei Lee
    • 8
  • Li-Ching Lin
    • 9
  • Tzu-Ju Chen
    • 10
  • Li-Jung Ma
    • 3
  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineChi Mei Foundation Medical CenterTainanTaiwan
  2. 2.Department of Medicinal ChemistryChia Nan University of Pharmacy and ScienceTainanTaiwan
  3. 3.Department of PathologyChi Mei Medical CenterTainanTaiwan
  4. 4.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  5. 5.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  6. 6.Institute of Clinical MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  7. 7.Department of Leisure, Recreation, and Tourism ManagementSouthern Taiwan University of Science and TechnologyTainanTaiwan
  8. 8.Department of Radiation OncologyChi Mei Medical CenterTainanTaiwan
  9. 9.Department of Radiation OncologyChi Mei Medical CenterTainanTaiwan
  10. 10.Department of PathologyChi Mei Foundation Medical CenterTainanTaiwan

Personalised recommendations