Changes in p⁵³ and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric‐cardia carcinogenesis

Abstract

The objective of this study was to quantify the changes in p53 and cyclin D1 protein levels in different stages of human esophageal and gastric cardia carcinogenesis in a high-risk population in Henan, China. Immunoreactivity of p53, cyclin D1 and proliferating-cell nuclear antigen (PCNA) was observed in the cell nuclei of esophageal and gastric cardia biopsies. The number of p53-immunostaining-positive cells was low in normal epithelia, slightly increased in basal-cell hyperplasia (BCH), markedly increased in dysplasia (DYS) (10-fold), and further increased in squamous-cell carcinoma (SCC) (40-fold). This pattern of change was similar to that of cell proliferation as indicated by PCNA immunostaining. On the other hand, the number of cyclin D1-immunostaining-positive cells did not increase from BCH to DYS, although a slight increase from DYS to SCC was noted. In the gastric cardia, again, the pattern of change of p53-positive cells in different stages of lesions paralleled the pattern of cell proliferation. The number of p53-positive cells was very low, much lower than that of PCNA-positive cells, in normal, chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG); therefore, the increase of p53-positive cells from CAG to DYS was more dramatic (100-fold). From DYS to adenocarcinoma (AC), the p53-positive and the PCNA-positive cells increased 4-fold. On the other hand, the number of cyclin D1-positive cells did not increase in pre-cancerous lesions, but increased slightly in AC. This study demonstrates that p53 protein accumulation increased with the progression of pre-cancerous lesions, especially in the genesis of dysplasia, both in the esophagus and in the gastric cardia. Our approach of quantitative immunohistochemistry sheds light on the mechanisms of genesis of esophageal and gastric-cardia cancers, which frequently occur together in many high-incidence areas.

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

“…42 Further support for the notion that cyclin D1 alterations occur relatively early in carcinogenesis is derived from a related study of premalignant lesions of the upper aerodigestive tract, in which cyclin D1 overexpression was observed in 14 of 28 dysplastic lesions (50%) that were localized to the basal and parabasal layers. 43 Despite chemoprevention with retinoids, cyclin D1 expression was not altered in 12 of 14 patients, with 8 patients showing histologic progression to invasive carcinoma on follow-up biopsies.…”

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

“…Accumulation of this complex leads to the activation of the kinases that phosphorylate and inactivate the tumor suppressor retinoblastoma, a necessary step for cell cycle progression through G1-to-S phases (Harbour and Dean, 2000). The expression levels of cyclin D1 have been shown to be rate limiting in cellular proliferation induced by a variety of stimuli (Ohtsubo and Roberts, 1993;Quelle et al, 1993;Albanese et al, 1995;Watanabe et al, 1996), and an increased expression of cyclin D1 has been observed in several tumors (Wang et al, 1994;Arber et al, 1996;Zhang et al, 1997;Albanese et al, 1999).…”

Histochemical studies on intestinal metaplasia adjacent to gastric cardia adenocarcinoma in subjects at high-incidence area in Henan, north China

“…In China, epidemiologically, gastric cardia adenocarcinoma (GCA) shares a very similar geographic distribution with esophageal squamous cell carcinoma (SCC), especially in Linzhou (formerly Linxian County), Henan Province, north China, the highest incidence area of SCC in the world [1,2] . However, the incidence of adenocarcinoma arising from the distal stomach is very low in this area [3,4] .…”