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Identification of Calreticulin as a Prognosis Marker and Angiogenic Regulator in Human Gastric Cancer

Annals of Surgical Oncology volume 16, pages 524–533 (2009)Cite this article

Abstract

The purpose of this study was to identify genes of interest for a subsequent functional and clinical cohort study using complementary (c)DNA microarrays. cDNA microarray hybridization was performed to identify differentially expressed genes between tumor and nontumor specimens in 30 gastric cancer patients. Subsequent functional studies of the selected gene were carried out, including cell cycle analysis, cell migration analysis, analyses of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF), and oligo-microarray studies using two pairs of stable cell lines of the selected gene. Another independent cohort study of 79 gastric cancer patients was conducted to evaluate the clinical significance of the selected gene in human gastric cancer. Calreticulin (CRT) was selected for further investigation. Two pairs of stable cell lines of CRT overexpression and CRT knockdown were constructed to perform functional studies. CRT enhanced gastric cancer cell proliferation and migration. Overexpressed CRT upregulated the expression and secretion of PlGF and VEGF. CRT had a reciprocal effect on connective tissue growth factor (CTGF) expression. Positive immunohistochemical staining of calreticulin was significantly correlated with high microvessel density (MVD) (p = 0.014), positive serosal invasion (p = 0.013), lymph node metastasis (p = 0.002), perineural invasion (p = 0.008), and poor patient survival (p = 0.0014). Multivariate survival analysis showed that CRT, MVD, and serosal invasion were independent prognosticators. We conclude that CRT overexpression enhances angiogenesis, and facilitates proliferation and migration of gastric cancer cells, which is in line with the association of CRT with MVD, tumor invasion, lymph node metastasis, and survival in gastric cancer patients.

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Acknowledgments

Supported by grants from National Taiwan University Hospital (95A06), the National Science Council (NSC95-2314-B002-151-MY3) and the Department of Industrial Technology, Ministry of Economic Affairs (95-EC-17-A-19-S1-016), Taipei, Taiwan. The authors would like to thank the Second Core Lab at National Taiwan University Hospital for providing technical assistance and Chia-I Chen for manuscript preparation.

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Authors and Affiliations

  1. Department of Surgery, Angiogenesis Research Center, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Road, Taipei, 100, Taiwan

    Chiung-Nien Chen MD, PhD, Wen-Ming Hsu MD, PhD, Ming-Chih Ho MD, PhD, Po-Huang Lee MD, PhD & King-Jen Chang MD, PhD

  2. Department of Dentistry, School of Medicine, National Taiwan University, Taipei, Taiwan

    Cheng-Chi Chang PhD

  3. Department of Life Science, Institute of Zoology, Angiogenesis Research Center, National Taiwan University, 1 Roosevelt Rd., Sec. 4, Taipei, 106, Taiwan

    Ting-En Su & Hsinyu Lee PhD

  4. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Yung-Ming Jeng MD

  5. Department of Obstetrics, National Taiwan University Hospital, Taipei, Taiwan

    Fon-Jou Hsieh MD

  6. Department of Toxicology, School of Medicine, National Taiwan University, Taipei, Taiwan

    Min-Liang Kuo PhD

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  1. Chiung-Nien Chen MD, PhD
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  2. Cheng-Chi Chang PhD
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  3. Ting-En Su
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  4. Wen-Ming Hsu MD, PhD
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  5. Yung-Ming Jeng MD
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  7. Fon-Jou Hsieh MD
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  8. Po-Huang Lee MD, PhD
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  9. Min-Liang Kuo PhD
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  10. Hsinyu Lee PhD
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  11. King-Jen Chang MD, PhD
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Corresponding authors

Correspondence to Hsinyu Lee PhD or King-Jen Chang MD, PhD.

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Chen, CN., Chang, CC., Su, TE. et al. Identification of Calreticulin as a Prognosis Marker and Angiogenic Regulator in Human Gastric Cancer. Ann Surg Oncol 16, 524–533 (2009). https://doi.org/10.1245/s10434-008-0243-1

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  • DOI: https://doi.org/10.1245/s10434-008-0243-1

Keywords

  • Gastric Cancer
  • Vascular Endothelial Growth Factor
  • Gastric Cancer Cell
  • Gastric Cancer Patient
  • Connective Tissue Growth Factor