The overexpression of glypican-5 promotes cancer cell migration and is associated with shorter overall survival in non-small cell lung cancer

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Abstract

Although the correlation between glypican-5 (GPC5) and lung cancer is well known, the effect of GPC5 expression on non-small cell lung cancer (NSCLC) survival remains to be determined. In the present study, GPC5 expression in A549, H3255, and SPC-A1 NSCLC cell lines was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. GPC5 mRNA and protein expression levels were found to be higher in A549 and H3255 cells compared with SPC-A1 cells. The role of GPC5 in NSCLC cell migration was evaluated in vitro by shRNA-mediated knockdown or the overexpression of GPC5 through scratch and transwell assays. The mean migration rates of cancer cells transfected with pRNAT-shRNA-GPC5-1 were reduced compared with the controls in A549 (P<0.001) and H3255 (P=0.001), while the migration rate of SPC-A1 with GPC5 overexpression was higher than that of the control (P=0.001). The downregulation of GPC5 impeded the transmigration of A549 and H3255 while the upregulation of GPC5 expression promoted the transmembrane invasion of SPC-A1. Furthermore, a panel of formalin-fixed paraffin-embedded NSCLC tissues from 127 patients undergoing curative resection (stages I, II and III) between January, 2003 and December, 2008 were obtained in order to investigate the correlation between GPC5 expression and clinicopathological factors using immunohistochemical methods. The results demonstrated that high GPC5 expression levels in NSCLC were associated with respiratory symptoms in lung cancer diagnosis, poor differentiation, vascular invasion, regional lymph node metastasis and a higher TNM stage. Using the Kaplan-Meier method, NSCLC patients with high levels of GPC5 expression demonstrated a significantly shorter overall survival time compared with those with low GPC5 expression levels (median postsurgical survival time: 14.0 months vs. 59.0 months, P=0.001). GPC5 expression was also identified as an independent prognostic factor by Cox regression analysis [adjusted hazard ratio: 2.18; 95% confidence interval (CI): 1.35-3.52; P=0.001]. This study suggested that increased levels of GPC5 expression are a poor prognostic marker for NSCLC.

Figures

  • Figure 1. Glypican-5 (GPC5) expression in three non-small cell lung cancer (NSCLC) cell lines. (A and B) GPC5 expression in A549 and H3255 was higher than that in SPC-A1; (C and D) Expression of GPC5 was elevated in SPC-A1 following transfection of pEGFP/GPC5; GPC5 expression was downregulated following transfection with all three shRNAs. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
  • Table I. Characteristics of 127 non-small cell lung cancer patients.
  • Figure 2. High glypican-5 (GPC5) expression levels lead to the increased motility of non-small cell lung cancer cells. (A) In vitro scratch assay, A549 and H3255 migrated markedly slower following transfection with pRNAT-shRNA-GPC5-1 compared with parental cells transfected with control vectors. SPC-A1 demonstrated a higher migration rate following transfection with pEGFP/GPC5. The histogram reveals significant changes to the cell migration rate within the time frame of the scratch experiment. (B) Transmigration was impeded in A549 and H3255 cells with the downregulation of GPC5 through pRNAT-shRNAGPC5-1. Transmigration was promoted in SPC-A1 with the upregulation of GPC5 expression through pEGFP/GPC5.
  • Figure 3. Microscopic views of positively stained immunohistochemical sections in non-small cell lung cancer. (Original magnification, x400.) (A and B) Positive
  • Table II. Univariate analysis.
  • Figure 4. Overall survival in relation to glypican-5 (GPC5) expression levels. Patients with high levels of GPC5 expression had a shorter overall survival times [14.0 months (95% CI: 9.0-19.0) vs. 59.0 months (95% CI: 30.2-87.8), P=0.001].

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Li, Y., Miao, L., Cai, H., Ding, J., Xiao, Y., Yang, J., & Zhang, D. (2013). The overexpression of glypican-5 promotes cancer cell migration and is associated with shorter overall survival in non-small cell lung cancer. Oncology Letters, 6(6), 1565–1572. https://doi.org/10.3892/ol.2013.1622

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