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Calreticulin and Cancer

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Pathology & Oncology Research

Abstract

Calreticulin (CRT) as a multi-functional endoplasmic reticulum protein is involved in a spectrum of cellular processes which ranges from calcium homeostasis and chaperoning to cell adhesion and finally malignant formation and progression. Previous studies have shown a contributing role for CRT in a range of different cancers. This present review will focus on the possible roles of CRT in the progression of malignant proliferation and the mechanisms involved in its contribution to cancer invasion.

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References

  1. Michalak M et al (1999) Calreticulin: one protein, one gene, many functions. Biochem J 344(2):281–292

    Article  CAS  PubMed  Google Scholar 

  2. Goicoechea S et al (2002) The anti-adhesive activity of thrombospondin is mediated by the N-terminal domain of cell surface calreticulin. J Biol Chem 277(40):37219–37228

    Article  CAS  PubMed  Google Scholar 

  3. Michalak M et al (1992) Calreticulin. Biochem J 285(3):681–692

    CAS  PubMed  Google Scholar 

  4. Michalak M, Robert Parker JM, Opas M (2002) Ca2+ signaling and calcium binding chaperones of the endoplasmic reticulum. Cell Calcium 32(5–6):269–278

    Article  CAS  PubMed  Google Scholar 

  5. Rojiani MV et al (1991) In vitro interaction of a polypeptide homologous to human Ro/SS-A antigen (calreticulin) with a highly conserved amino acid sequence in the cytoplasmic domain of integrin alpha subunits. Biochemistry 30:9859–9866

    Article  CAS  PubMed  Google Scholar 

  6. Burns K et al (1994) Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 367(6462):476–480

    Article  CAS  PubMed  Google Scholar 

  7. Gelebart P, Opas M, Michalak M (2005) Calreticulin, a Ca2+−binding chaperone of the endoplasmic reticulum. Int J Biochem Cell Biol 37(2):260–266

    Article  CAS  PubMed  Google Scholar 

  8. Qiu Y, Michalak M (2009) Transcriptional control of the calreticulin gene in health and disease. Int J Biochem Cell Biol 41(3):531–538

    Article  CAS  PubMed  Google Scholar 

  9. Gold LI et al (2010) Calreticulin: non-endoplasmic reticulum functions in physiology and disease. FASEB J 24(3):665–683

    Article  CAS  PubMed  Google Scholar 

  10. Nanney LB et al (2008) Calreticulin enhances porcine wound repair by diverse biological effects. Am J Pathol 173(3):610–630

    Article  CAS  PubMed  Google Scholar 

  11. Gu VY et al (2008) Calreticulin in human pregnancy and pre-eclampsia. Mol Hum Reprod 14(5):309–315

    Article  CAS  PubMed  Google Scholar 

  12. Pagh R et al (2008) The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with MBL through the binding site for MBL-associated serine proteases. FEBS J 275(3):515–526

    Article  CAS  PubMed  Google Scholar 

  13. Yokoyama M, Hirata K-I (2005) New function of calreticulin: calreticulin-dependent mRNA destabilization. Circ Res 97(10):961–963

    Article  CAS  PubMed  Google Scholar 

  14. McCauliffe DP et al (1992) The 5’-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters. J Biol Chem 267(4):2557–2562

    CAS  PubMed  Google Scholar 

  15. Waser M et al (1997) Regulation of calreticulin gene expression by calcium. J Cell Biol 138(3):547–557

    Article  CAS  PubMed  Google Scholar 

  16. Nguyen TQ, Donald Capra J, Sontheimer RD (1996) Calreticulin is transcriptionally upregulated by heat shock, calcium and heavy metals. Mol Immunol 33(4–5):379–386

    Article  CAS  PubMed  Google Scholar 

  17. Michalak M et al (2009) Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 417(3):651–666

    Article  CAS  PubMed  Google Scholar 

  18. Qiu Y et al (2008) Regulation of the calreticulin gene by GATA6 and Evi-1 transcription factorsâ€. Biochemistry 47(12):3697–3704

    Article  CAS  PubMed  Google Scholar 

  19. Guo L et al (2001) COUP-TF1 antagonizes Nkx2.5-mediated activation of the calreticulin gene during cardiac development. J Biol Chem 276:2797–2801

    Article  CAS  PubMed  Google Scholar 

  20. Lynch J et al (2005) Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca2+−dependent signaling cascade. J Cell Biol 170:37–47

    Article  CAS  PubMed  Google Scholar 

  21. Vig S et al (2012) C/EBPα mediates the transcriptional suppression of human calreticulin gene expression by TNFα. Int J Cell Biol 44(1):113–122

    Article  CAS  Google Scholar 

  22. Opas M et al (1991) Regulation of expression and intracellular distribution of calreticulin, a major calcium binding protein of nonmuscle cells. J Cell Physiol 149(1):160–171

    Article  CAS  PubMed  Google Scholar 

  23. Yoon G-S et al (2000) Nuclear matrix of calreticulin in hepatocellular carcinoma. Cancer Res 60(4):1117–1120

    CAS  PubMed  Google Scholar 

  24. Gold LI, et al. (2006) Overview of the role for calreticulin in the enhancement of wound healing through multiple biological effects. The journal of investigative dermatology. Symposium proceedings/the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research 11(1):57–65

  25. Huang J-B et al (2004) Identification of channels promoting calcium spikes and waves in HT1080 tumor cells. Cancer Res 64(7):2482–2489

    Article  CAS  PubMed  Google Scholar 

  26. Pallero MA et al (2008) Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. FASEB J 22(11):3968–3979

    Article  CAS  PubMed  Google Scholar 

  27. Kageyama K et al (2002) Overexpression of calreticulin modulates protein kinase B/Akt signaling to promote apoptosis during cardiac differentiation of cardiomyoblast H9c2 cells. J Biol Chem 277(22):19255–19264

    Article  CAS  PubMed  Google Scholar 

  28. Okunaga T et al (2006) Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells. Cancer Res 66(17):8662–8671

    Article  CAS  PubMed  Google Scholar 

  29. Lim S, et al. (2008) Enhanced calreticulin expression promotes calcium-dependent apoptosis in postnatal cardiomyocytes. 25:390–396

  30. Bini L et al (1997) Protein expression profiles in human breast ductal carcinoma and histologically normal tissue. Electrophoresis 18(15):2832–2841

    Article  CAS  PubMed  Google Scholar 

  31. Chahed K et al (2005) Expression of fibrinogen E-fragment and fibrin E-fragment is inhibited in the human infiltrating ductal carcinoma of the breast: the two-dimensional electrophoresis and MALDI-TOF-mass spectrometry analyses. Int J Oncol 27(5):1425–1431

    CAS  PubMed  Google Scholar 

  32. Kageyama S et al (2004) Identification by proteomic analysis of calreticulin as a marker for bladder cancer and evaluation of the diagnostic accuracy of its detection in urine. Clin Chem 50(5):857–866

    Article  CAS  PubMed  Google Scholar 

  33. Ayodele A et al (2000) Polypeptide expression in prostate hyperplasia and prostate adenocarcinoma. Anal Cell Pathol 21(1):1–9

    Google Scholar 

  34. Kim Y et al (2004) Glucoronic acid is a novel inducer of heat shock response. Mol Cell Biochem 259(1):23–33

    Article  CAS  PubMed  Google Scholar 

  35. Hong S-H et al (2004) An autoantibody-mediated immune response to calreticulin isoforms in pancreatic cancer. Cancer Res 64(15):5504–5510

    Article  CAS  PubMed  Google Scholar 

  36. Du X-L et al (2007) Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. J Mol Med 85(8):863–875

    Article  CAS  PubMed  Google Scholar 

  37. Nishimori T et al (2006) Proteomic analysis of primary esophageal squamous cell carcinoma reveals downregulation of a cell adhesion protein, periplakin. Proteomics 6(3):1011–1018

    Article  CAS  PubMed  Google Scholar 

  38. Chen CN et al (2009) Association between color doppler vascularity index, angiogenesis-related molecules, and clinical outcomes in gastric cancer. J Surg Oncol 99(7):402–408

    Article  PubMed  Google Scholar 

  39. Vougas K et al (2008) Two-dimensional electrophoresis and immunohistochemical study of calreticulin in colorectal adenocarcinoma and mirror biopsies. J Blacan Union Oncol 13(1):101–107

    CAS  Google Scholar 

  40. White TK, Zhu Q, Tanzer ML (1995) Cell surface calreticulin is a putative mannoside lectin which triggers mouse melanoma cell spreading. J Biol Chem 270(27):15926–15929

    Article  CAS  PubMed  Google Scholar 

  41. Dissemond J et al (2004) Differential downregulation of endoplasmic reticulum-residing chaperones calnexin and calreticulin in human metastatic melanoma. Cancer Lett 203(2):225–231

    Article  CAS  PubMed  Google Scholar 

  42. Helbling D et al (2005) CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood 106(4):1369–1375

    Article  CAS  PubMed  Google Scholar 

  43. Chen CN et al (2009) Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer. Ann Surg Oncol 16(2):524–533

    Article  CAS  PubMed  Google Scholar 

  44. Lwin Z-M, et al. (2010) Clinicopathological significance of calreticulin in breast invasive ductal carcinoma. Mod Pathol

  45. Eric A et al (2009) Effects of humoral immunity and calreticulin overexpression on postoperative course in breast cancer. Pathol Oncol Res 15(1):89–90

    Article  CAS  PubMed  Google Scholar 

  46. Pabst T et al (2001) AML1-ETO downregulates the granulocytic differentiation factor C/EBP[alpha] in t(8;21) myeloid leukemia. Nat Med 7(4):444–451

    Article  CAS  PubMed  Google Scholar 

  47. Lu Y-C et al (2011) Changes in tumor growth and metastatic capacities of j82 human bladder cancer cells suppressed by down-regulation of calreticulin expression. Am J Pathol 179:1425–1433

    Article  CAS  PubMed  Google Scholar 

  48. Hayashi E et al (2005) Proteomic profiling for cancer progression: differential display analysis for the expression of intracellular proteins between regressive and progressive cancer cell lines. Proteomics 5(4):1024–1032

    Article  CAS  PubMed  Google Scholar 

  49. Zhu J (1996) Ultraviolet B irradiation and cytomegalovirus infection synergize to induce the cell surface expression of 52-kD/Ro antigen. Clin Exp Immunol 1(103):47–53

    Article  Google Scholar 

  50. Alur M et al (2009) Suppressive roles of calreticulin in prostate cancer growth and metastasis. Am J Pathol 175(2):882–890

    Article  CAS  PubMed  Google Scholar 

  51. Porcellini S et al (2006) Regulation of peripheral T cell activation by calreticulin. J Exp Med 203(2):461–471

    Article  CAS  PubMed  Google Scholar 

  52. Dupuis M et al (1993) The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med 177(1):1–7

    Article  CAS  PubMed  Google Scholar 

  53. Andrin C et al (1998) Interaction between a Ca2+−binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules†. Biochemistry 37(29):10386–10394

    Article  CAS  PubMed  Google Scholar 

  54. Sipione S et al (2005) Impaired cytolytic activity in calreticulin-deficient CTLs. J Immunol 174(6):3212–3219

    CAS  PubMed  Google Scholar 

  55. Obeid M et al (2007) Ecto-calreticulin in immunogenic chemotherapy. Immunol Rev 220:22–34

    Article  CAS  PubMed  Google Scholar 

  56. Obeid M et al (2007) Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from “silent” to immunogenic. Cancer Res 67(17):7941–7944

    Article  CAS  PubMed  Google Scholar 

  57. Clarke C, Smyth MJ (2007) Calreticulin exposure increases cancer immunogenicity. Nat Biotechnol 25(2):192–193

    Article  CAS  PubMed  Google Scholar 

  58. Zhou P et al (2008) Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan. Blood 111(2):549–557

    Article  CAS  PubMed  Google Scholar 

  59. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  60. Hayashida Y et al (2006) Calreticulin represses E-cadherin gene expression in Madin-Darby Canine kidney cells via slug. J Biol Chem 281(43):32469–32484

    Article  CAS  PubMed  Google Scholar 

  61. Fresno Vara JA et al (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204

    Article  PubMed  Google Scholar 

  62. Xu Q et al (2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24(36):5552–5560

    Article  CAS  PubMed  Google Scholar 

  63. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809

    Article  CAS  PubMed  Google Scholar 

  64. Luo M-L et al (2006) Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance. Cancer Res 66(24):11690–11699

    Article  CAS  PubMed  Google Scholar 

  65. Weaver AM (2008) Cortactin in tumor invasiveness. Cancer Lett 265(2):157–166

    Article  CAS  PubMed  Google Scholar 

  66. Du XL et al (2009) Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma. Oncogene 28(42):3714–3722

    Article  CAS  PubMed  Google Scholar 

  67. Dedhar S et al (1994) Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367(6462):480–483

    Article  CAS  PubMed  Google Scholar 

  68. Green S et al (1988) The N-terminal DNA-binding ‘zinc finger’ of the oestrogen and glucocorticoid receptors determines target gene specificity. EMBO J 7(10):3037–3044

    CAS  PubMed  Google Scholar 

  69. Platet N et al (2000) Unliganded and liganded estrogen receptors protect against cancer invasion via different mechanisms. Mol Endocrinol 14(7):999–1009

    Article  CAS  PubMed  Google Scholar 

  70. Lusche DF, Wessels D, Soll DR (2009) The effects of extracellular calcium on motility, pseudopod and uropod formation, chemotaxis, and the cortical localization of myosin II in Dictyostelium discoideum. Cell Motil Cytoskeleton 66(8):567–587

    Article  CAS  PubMed  Google Scholar 

  71. Fache S et al (2005) Calcium mobilization stimulates Dictyostelium discoideum shear-flow-induced cell motility. J Cell Sci 118(15):3445–3458

    Article  CAS  PubMed  Google Scholar 

  72. Chantome A et al (2009) KCa2.3 channel-dependent hyperpolarization increases melanoma cell motility. Exp Cell Res 315(20):3620–3630

    Article  CAS  PubMed  Google Scholar 

  73. Titushkin I, Cho M (2009) Regulation of cell cytoskeleton and membrane mechanics by electric field: role of linker proteins. Biophys J 96(2):717–728

    Article  CAS  PubMed  Google Scholar 

  74. Nakamura K et al (2001) Functional specialization of calreticulin domains. J Cell Biol 154(5):961–972

    Article  CAS  PubMed  Google Scholar 

  75. Mesaeli N et al (1999) Calreticulin is essential for cardiac development. J Cell Biol 144(5):857–868

    Article  CAS  PubMed  Google Scholar 

  76. Camacho P, Lechleiter JD (1995) Calreticulin inhibits repetitive intracellular Ca2+ waves. Cell 82(5):765–771

    Article  CAS  PubMed  Google Scholar 

  77. Arnaudeau S et al (2002) Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria. J Biol Chem 277(48):46696–46705

    Article  CAS  PubMed  Google Scholar 

  78. Orr AW et al (2003) Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration. J Cell Sci 116(14):2917–2927

    Article  CAS  PubMed  Google Scholar 

  79. Li SS, Forslöw A, Sundqvist K-G (2005) Autocrine regulation of T cell motility by calreticulin-thrombospondin-1 interaction. J Immunol 174(2):654–661

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Genetic Medicine Research Center, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia

    Mohammadreza Zamanian, Abhi Veerakumarasivam, Syahril Abdullah & Rozita Rosli

  2. UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia

    Syahril Abdullah & Rozita Rosli

  3. Medical Genetics Group, Genetics Department, Reproductive Biomedicine Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Mohammadreza Zamanian

  4. Perdana University Graduate School of Medicine, Perdana University, Serdang, 43400, Selangor Darul Ehsan, Malaysia

    Abhi Veerakumarasivam

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  1. Mohammadreza Zamanian
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  2. Abhi Veerakumarasivam
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  3. Syahril Abdullah
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  4. Rozita Rosli
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Correspondence to Rozita Rosli.

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Zamanian, M., Veerakumarasivam, A., Abdullah, S. et al. Calreticulin and Cancer. Pathol. Oncol. Res. 19, 149–154 (2013). https://doi.org/10.1007/s12253-012-9600-2

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  • DOI: https://doi.org/10.1007/s12253-012-9600-2

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