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Identification of Calreticulin as a Prognosis Marker and Angiogenic Regulator in Human Gastric Cancer |
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| Authors: | Chiung-Nien Chen MD PhD Cheng-Chi Chang PhD Ting-En Su Wen-Ming Hsu MD PhD Yung-Ming Jeng MD Ming-Chih Ho MD PhD Fon-Jou Hsieh MD Po-Huang Lee MD PhD Min-Liang Kuo PhD Hsinyu Lee PhD King-Jen Chang MD PhD |
| Affiliation: | 1. Department of Surgery, Angiogenesis Research Center, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Road, Taipei, 100, Taiwan 2. Department of Dentistry, School of Medicine, National Taiwan University, Taipei, Taiwan 3. Department of Life Science, Institute of Zoology, Angiogenesis Research Center, National Taiwan University, 1 Roosevelt Rd., Sec. 4, Taipei, 106, Taiwan 4. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan 5. Department of Obstetrics, National Taiwan University Hospital, Taipei, Taiwan 6. Department of Toxicology, School of Medicine, National Taiwan University, Taipei, Taiwan |
| 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. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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