Published online Nov 15, 2021. doi: 10.4251/wjgo.v13.i11.1755
Peer-review started: June 30, 2021
First decision: July 18, 2021
Revised: July 30, 2021
Accepted: September 29, 2021
Article in press: September 29, 2021
Published online: November 15, 2021
Zinc is an element with multiple functions. Zinc deficiency can lead to overexpression of several genes related to immune response, apoptosis, cell proliferation, and transcriptional regulation. Dietary zinc deficiency has been shown to be associated with the development of esophageal cancer in humans, but the exact mechanism of action is not known.
Esophageal squamous cell carcinoma is a deadly disease with a 5-year survival rate of only 10%. Because of the absence of early symptoms, patients with esophageal squamous cell carcinoma ESCC are usually diagnosed at a late stage and, therefore, have a poor prognosis. To improve the prevention and treatment of this deadly cancer, understanding its causes and discovering new early biomarkers are essential for chemoprevention and therapeutic options.
The aim of this study was to investigate the effects of dietary zinc deficiency on the growth, development, and proliferation of esophageal squamous cells in mice. In addition, we investigated the pathway of zinc deficiency-induced proliferation of esophageal squamous cells by detecting the expression of five predictive biomarkers, namely proliferating cell nuclear antigen (PCNA), mitogen-activated protein kinase p38 (p38MAPK), nuclear factor kappa B (NF-κB) p105, NF-κB p65, and cyclooxygenase (COX)-2 protein.
Thirty C57BL/6 mice were randomly divided into three groups: a zinc-sufficient (ZS) group, zinc-deficient (ZD) group, and zinc-replenished (ZR) group. For weeks 1–10, zinc levels in the mice diets were 30.66–30.89 mg/kg in the ZS group and 0.66–0.89 mg/kg in the ZD and ZR groups. During weeks 10–12, the ZR group was switched to the ZS diet; the other two groups had no changes in their diets. Changes in body weight, serum, and esophageal tissue zinc concentrations were assessed as well as differences in the expression of PCNA, p38MAPK, NF-κB p105, NF-κB p65, and COX-2 proteins in the esophageal mucosa.
The body weight and zinc concentration in the serum and esophageal mucosa were significantly lower in the ZD and ZR groups than in the ZS group. In ZD mice, there was a marked proliferation of basal cells in the esophageal mucosa, resulting in a disturbance in the arrangement of basal cells in layers 2–4, a thickening of the squamous layer, and a significant increase in the expression of the above-mentioned five proteins involved in proliferation and inflammation in the esophageal mucosa.
The results indicated that the ZD diet decreased the growth rate and promoted the proliferation of esophageal squamous cells in mice. The mechanism of proliferation was related to the induced overexpression of COX-2, P38, PCNA, and NF-κB (p105 and p65), and the ZR diet reduced the expression of PCNA, NF-κB p105, and COX-2, thereby reversing this process.
In this study, all five proteins were detected by immunohistochemistry staining, which is a semi-quantitative method. In future studies, we will try to increase the sample size and use a quantitative approach to make the results more meaningful.