Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway

Abstract

Diabetes is a potential risk factor for gastric cancer (GC). Pin1, a peptidyl–prolyl cis/trans isomerase, promotes GC cell proliferation and migration. The role and underlying mechanism of the Pin1/BRD4 axis in hyperglycemia-induced proliferation and migration of GC cells were analyzed in vivo and in vitro. Proliferation and migration of GC cells were measured; Pin1 and BRD4 expression of the cell cycle were determined. Pin1 and BRD4 were downregulated by transfecting Pin1 shRNA lentivirus into GC cells and JQ1-intervention GC cells. Tumor formation and lung metastasis were assessed in vivo. Inhibition of Pin1 and BRD4 significantly suppressed high-glucose (HG)-induced GC cell proliferation and migration. HG enhanced G1/S cell-cycle transition, associated with increased Pin1 and BRD4 expression. Silencing Pin1 significantly downregulated the expression of BRD4 and NAP1L1 and upregulated that of P21 in GC cells. In vivo studies indicated that hyperglycemia promotes tumor growth and lung metastasis by inducing Pin1 and BRD4 expression. Thus, Pin1/BRD4 plays an important role in hyperglycemia-promoted tumor growth. The significance of these findings toward improved prognosis of diabetic patients with GC cannot be underestimated.

Diabetes and gastric cancer incidence and mortality in the Asia Cohort Consortium: A pooled analysis of more than a half million participants

“… 28 Hyperglycemia also enhances gastric carcinoma proliferation and migration via thr Pin1/BRD4 transcriptional pathway, involved in the hyperglycemia‐induced inflammatory process. 29 Second, H. pylori infection, a known risk factor for gastric cancer, is maintained in hyperglycemia, allowing the bacteria to grow and survive longer in patients with diabetes. 30 An in vitro study reported enhanced adhesion, growth, and viability of the H. pylori cytotoxin‐associated gene A antigen, an oncoprotein, under higher glucose concentrations.…”

“…First, insulin and hyperglycemia may directly promote gastric cancer by overstimulating tumorigenic pathways such as PI3K/AKT/mTOR, 27 insulin‐like growth factor‐1 (IGF‐1), strongly linked to insulin resistance, promotes gastric cancer cell proliferation and invasion via the Ras/RAF/MEK/ERK and JAK1/STAT3 cellular signaling pathways 28 . Hyperglycemia also enhances gastric carcinoma proliferation and migration via thr Pin1/BRD4 transcriptional pathway, involved in the hyperglycemia‐induced inflammatory process 29 . Second, H. pylori infection, a known risk factor for gastric cancer, is maintained in hyperglycemia, allowing the bacteria to grow and survive longer in patients with diabetes 30 .…”

NAP1L1 is a novel microtubule‐associated protein

“…These reports showed that NAP1L1 has multiple functions beyond the nucleosome assembly function. Such functions include proliferation, migration, invasion, and even thrombopoiesis (Freitag & Schwertz, 2022; Liang et al, 2022; Nagashio et al, 2020; Xiaohua et al, 2022; Yu et al, 2022). For example, the knockdown of NAP1L1 expression significantly reduced cell proliferation and cell cycle transformation in vitro and in vivo by disturbing hepatoma‐derived growth factor and c‐Jun signaling pathways that induce the expression of cell cycle factors such as cyclin D1 (Liu, Zhang, et al, 2022; Liu et al, 2021; Zhang et al, 2021).…”

“…These reports showed that NAP1L1 has multiple functions beyond the nucleosome assembly function. Such functions include proliferation, migration, invasion, and even thrombopoiesis (Freitag & Schwertz, 2022;Liang et al, 2022;Nagashio et al, 2020;Xiaohua et al, 2022;Yu et al, 2022).…”

The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer

“…Moreover, studies have reported that diabetes is associated with the incidence, mortality, and progression of various cancers 6,[11][12][13] . Experimental studies [14][15][16] have revealed that hyperglycemia per se, rather than the common risk factors between diabetes and cancer, worsens cancer. Hyperglycemia renders cancer cells more aggressive by exerting metabolic and oxidative stresses [16][17][18] .…”