High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer

Abstract

The developmental pluripotency-associated 4 (Dppa4) gene serves critical roles in cell self-renewal, as well as in cancer development and progression. However, the regulatory role of Dppa4 in non-small-cell lung cancer (NSCLC) and its underlying mechanisms remain elusive. The aim of the present study was to investigate the biological function of Dppa4 in NSCLC and its underlying mechanism of action. Dppa4 expression was measured in NSCLC tissue samples and cell lines, and its effect on cell proliferation and the expression of glycolytic enzymes was determined. In addition, the underlying mechanisms of Dppa4-induced alterations in glycolysis were analyzed. Univariate and multivariate analyses were also performed to analyze the prognostic significance of clinicopathological characteristics. Dppa4 was found to be highly expressed in NSCLC tissues and cell lines. Furthermore, it was observed that Dppa4 was correlated with the degree of tumor differentiation and TNM stage. Univariate and multivariate analyses identified Dppa4 expression and clinical stage as prognostic factors for NSCLC patients. Kaplan-Meier analysis further revealed that patients with lower Dppa4 expression exhibited a better prognosis. In NSCLC cells, Dppa4 knockdown inhibited cell proliferation, while Dppa4 overexpression enhanced cell proliferation, which was likely mediated by glycolysis promotion. Dppa4 knockdown had no evident effect on the majority of enzymes examined; however, glucose transporter type 4 (GLUT-4) and pyruvate kinase isozyme M2 were significantly upregulated, and hexokinase II (HK-II) and lactate dehydrogenase B (LDHB) were downregulated following Dppa4 knockdown. By contrast, Dppa4 overexpression resulted in downregulation of GLUT-4, and upregulation of HK-II, enolase and LDHB, whereas it had no effect on other enzymes. Since the most evident effect was observed on LDHB, further functional experiments demonstrated that this enzyme reversed the promoting effects of Dppa4 in NSCLC. In conclusion, Dppa4 promotes NSCLC progression, partly through glycolysis by LDHB. Thus, the Dppa4-LDHB axis critically contributes to glycolysis in NSCLC cells, thereby promoting NSCLC development and progression.

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells

“… (A) Higher glucose uptake has been measured by Lim et al [107] in B7-H3 knockdown cells grown in normoxic or perturbed conditions (hypoxia) for 24 h, (B) Li et al [105] has shown that glucose uptake increases significantly in Dppa4 overexpressed cancer cell, and (C) Our computational results depict similar behavior of glucose uptake in cancer cells compared to that in normal and perturbed ones. …”

“…As a result, higher lactate production ( Fig. 18 B) has been found here [105] . Lim et al [107] has also found similar higher lactate production ( Fig.…”

“…17 B). This experiment [105] has also shown that LDH has significantly been up regulated ( Fig. 16 A) in Dppa4 overexpressed cancer cells.…”

“…In this context, Lim et al [107] has measured higher glucose uptake ( Fig. 17 A) in B7-H3 knockdown cells grown in normoxic or perturbed conditions (hypoxia) for 24 h. Besides, Li et al [105] has shown that glucose uptake increases significantly in Dppa4 overexpressed cancer cells ( Fig. 17 B).…”

“… Li et al [105] has shown that (A) LDH has significantly been up regulated in Dppa4 overexpressed cancer cell, (C) Expression of hexokinase (HK) mRNA levels have been found higher in cancer [106] compared to normal liver tissue, (E) Higher glut1 mRNA levels has been found as 92-fold higher in Meta specimens [106] compared to normal liver tissue. Similar altered behaviors of (B) LDH, (D) HK and (F) glut1 have been found in our computational results.…”