High Expression of PHGDH Predicts Poor Prognosis in Non-Small Cell Lung Cancer

Jinhong Zhu, Jianqun Ma, Xudong Wang, Tianjiao Ma, Shu Zhang, Wei Wang, Xiaoyu Zhou, Jiahai Shi, Jinhong Zhu, Jianqun Ma, Xudong Wang, Tianjiao Ma, Shu Zhang, Wei Wang, Xiaoyu Zhou, Jiahai Shi

Abstract

Tumors have exceptionally high demands for energy and anabolism because of their rapid growth. The de novo serine synthesis pathway initiated by phosphoglycerate dehydrogenase (PHGDH) has been recognized as a hallmark of metabolic adaption in carcinogenesis. The oncogenic role and prognostic value of PHGDH have been investigated in multiple cancer types, including breast cancer, melanoma, cervical cancer, and colon cancer. Due to the importance of PHGDH in cancer, we attempted to determine the clinical significance of PHGDH in 319 patients with non-small cell lung cancer (NSCLC). We evaluated the mRNA and protein expression levels of PHGDH gene, using quantitative reverse transcriptase polymerase chain reaction and tissue array-based immunohistochemistry, respectively. Significantly increased PHGDH expression in mRNA and protein levels was identified in tumor tissues versus matched adjacent nontumor tissues. More interestingly, immunohistochemical expression of PHGDH was significantly associated with lymph node metastasis (P=.021) and TNM stage (P=.016). Kaplan-Meier survival analysis indicated that NSCLC patients with low levels of PHGDH outperformed patients with high levels of PHGDH regarding 5-year overall survival. Significantly longer survival in the former suggested the prognostic implication of PHGDH in NSCLC. Multivariate survival analysis using Cox regression model demonstrated that high PHGDH levels and advanced TNM stage (III+IV) were independent predictors of prognosis in NSCLC. Moreover, bioinformatics analysis confirmed the increase in PHGDH transcripts (data from The Cancer Genome Atlas) and its prognostic value (Kaplan-Meier plotter) in NSCLC. In conclusion, this study suggested the clinical implication of PHGDH in NSCLC. PHGDH may be a promising therapeutic target in NSCLC.

Copyright © 2016. Published by Elsevier Inc.

Figures

Figure 1
Figure 1
Bioinformatics analysis. (A) PHGDH gene. (B) TCGA data indicated a significantly higher PHGDH mRNA expression in tumor tissue than in normal tissues. (Left panel) 108 pairs of tumor and lung tissues (paired t test: P < .0001); (right panel) 108 tumor tissues versus 1014 normal tissues (Student's t test: P < .0001). (C) (left panel) Overall, the KM-plotter showed that patients with PHGDHhigh tumors had significantly shorter survival than those with PHGDHlow tumors (n = 1926, log-rank test: P < .001). (Middle panel) PHGDHhigh was significantly associated with reduced survival in adenocarcinoma (n = 720, HR = 1.38, 95% CI = 1.1-1.75; log-rank test: P = .006); (right panel) no significant difference in survival was observed in squamous cell carcinoma (n = 524, HR = 1.17, 95% CI = 0.92-1.48; log-rank test: P = .2).
Figure 2
Figure 2
Immunohistochemical expression of PHGDH in lung tissue microarray cores. (A1, A2) lung adenocarcinoma, strong cytoplasmic expression (red arrow); (B1, B2) squamous cell carcinoma of the lung, strong positive staining in cytoplasm (red arrow); (C1, C2) normal lung tissue, cytoplasm of alveolar epithelial cells, negative staining (green arrow). Original magnification ×40 (bar = 500 μm) in A1, B1, and C1; ×400 (bar = 50 μm) in A2, B2, and C2.
Figure 3
Figure 3
Significantly higher mRNA expression levels of PHGDH were observed in NSCLC than in tumor adjacent normal tissues (P < .0001). One-step qRT-PCR was used to examine PHGDH mRNA expression levels. Relative mRNA expression of PHGDH was normalized to GAPDH.
Figure 4
Figure 4
Kaplan-Meier survival curves of NSCLC patients. (A) Patients with PHGDHhigh (green) had significantly shortened survival time when compared with those with PHGDHlow tumor (blue). (B) Patients with node metastasis (green) tended to survive shorter than patients without node metastasis (blue). (C) Advanced TNM stages (brown, II; green, III + IV) were significantly correlated with inferior OS.

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