DDIT4 overexpression associates with poor prognosis in lung adenocarcinoma

Li Song; Zhiyao Chen; Menghua Zhang; Mingli Zhang; Xiaoyun Lu; Chunsun Li; Liyan Miao

doi:10.7150/jca.60118

DDIT4 overexpression associates with poor prognosis in lung adenocarcinoma

J Cancer. 2021 Sep 3;12(21):6422-6428. doi: 10.7150/jca.60118. eCollection 2021.

Authors

Li Song^{1

2}, Zhiyao Chen¹, Menghua Zhang¹, Mingli Zhang¹, Xiaoyun Lu³, Chunsun Li³, Liyan Miao¹

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China, 215006.
² Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong 226361, Jiangsu, China.
³ Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong 226361, Jiangsu, China.

Abstract

Objectives: DNA damage inducible transcript 4 (DDIT4) plays a key role in different cancers, but the role of DDIT4 in lung adenocarcinoma (LUAD) is not completely understood. The aim of this study was to evaluate the utility of DDIT4 as a prognostic biomarker for LUAD. Methods: First, DDIT4 mRNA expression in LUAD cell lines (A549, H1299 and HBE) and tissues (89 cases) was assessed by RT-PCR. Next, DDIT4 protein expression in LUAD tissues and normal tissues was assessed by immunohistochemistry (75 cases). Then, the correlation between DDIT4 expression and overall survival was analyzed using the Kaplan-Meier method. After that, we verified the utility of the DDIT4 gene as a prognostic marker of lung cancer in the TCGA database (1133 cases). Finally, the possible mechanism of the DDIT4 gene as a prognostic marker of LUAD was preliminarily explored. Results: mRNA levels of DDIT4 in HBE cells were significantly lower than in A549 and H1299 cells (P<0.05), and expression of the DDIT4 gene in cancer tissues was significantly higher than in adjacent tissues (P<0.0001). Immunohistochemical staining results showed that high expression of DDIT4 accounted for approximately 68.0% of LUAD tissues. DDIT4 expression was significantly correlated with differentiation (P < 0.05). However, it was not correlated with sex, age, smoking, tumor size, lymph node metastasis, or TNM stage (P>0.05). The survival analysis demonstrated that high DDIT4 expression was correlated with shorter overall survival (P < 0.05). Univariate and multivariate analyses indicated that DDIT4 was an independent predictor of overall survival for LUAD, which was confirmed by data from the TCGA database. Finally, we found that DDIT4 gene expression was significantly increased in the hypoxic environment compared to the normal oxygen environment, indicating that the DDIT4 gene may play an important role in the hypoxic microenvironment of tumor tissue. Conclusion: High expression levels of DDIT4 correlated with poor overall survival in patients with LUAD, and DDIT4 was an independent predictor of overall survival. These findings provide new insight for understanding the development of LUAD.

Keywords: DDIT4; Lung adenocarcinoma; Prognosis.