Regulation of GKN1 expression in gastric carcinogenesis: A problem to resolve (Review)

Abstract

Gastrokine 1 (GKN1) is a protein expressed on the surface mucosa cells of the gastric antrum and fundus, which contributes to maintaining gastric homeostasis, inhibits inflammation and is a tumor suppressor. The expression of GKN1 decreases in mucosa that are either inflamed or infected by Helicobacter pylori, and is absent in gastric cancer. The measurement of circulating GKN1 concentration, the protein itself, or the mRNA in gastric tissue may be of use for the early diagnosis of cancer. The mechanisms that modulate the deregulation or silencing of GKN1 expression have not been completely described. The modification of histones, methylation of the GKN1 promoter, or proteasomal degradation of the protein have been detected in some patients; however, these mechanisms do not completely explain the absence of GKN1 or the reduction in GKN1 levels. Only NKX6.3 transcription factor has been shown to be a positive modulator of GKN1 transcription, although others also have an affinity with sequences in the promoter of this gene. While microRNAs (miRNAs) are able to directly or indirectly regulate the expression of genes at the post-transcriptional level, the involvement of miRNAs in the regulation of GKN1 has not been reported. The present review analyzes the information reported on the determination of GKN1 expression and the regulation of its expression at the transcriptional, post-transcriptional and post-translational levels; it proposes an integrated model that incorporates the regulation of GKN1 expression via transcription factors and miRNAs in H. pylori infection.

Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer

“…The specific outer inflammatory protein antigen (OipA) receptor has not been identified [91]. The OipA of H. pylori stimulates the phosphorylation of signal transducer and activator of transcription 1 (STAT-1) [92]. The nonreceptor tyrosine kinase associated with cytokine receptor so-called Janus kinase (JAK) phosphorylates the STAT.…”

Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer

“…The topmost molecular network in the intestinal subtype on IPA network analysis showed increased expression of SULF1 [ 62 ], HGF [ 63 , 64 ], SPARC [ 65 , 66 , 67 ], SERPINH1 [ 68 ], and IGFBP7 [ 69 , 70 ], which have been shown to contribute to the growth and survival of tumor cells, tumor invasion, metastasis, and poor survival in gastric cancer ( Supplementary Figure S2 ). AKR1B10 [ 71 ], GKN1 [ 72 , 73 ], TFF2 [ 74 , 75 ], SULT1E1, ADH1C, ADHFE1, ADH7, REG3A, LIPF, ATP4A, ATP4B, and PGC were found to show decreased expression. These proteins have been shown to play a role in tumor suppression and inhibit gastric carcinogenesis and metastasis [ 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].…”

“…H. pylori -infected gastric mucosa or inflammation in the mucosa results in a decreased expression of GKN1. GKN1 expression is lost in gastric cancer [ 72 , 73 ]. TFF2 expression is found to be markedly decreased in gastric cancer, the downregulation of which was found to be regulated by promoter hypermethylation.…”

Women with chronic follicular gastritis positive for Helicobacter pylori express lower levels of GKN1

“…On the other hand, there may be a negative regulation of the GKN1 transcript translation by non-coding RNAs [17] or degradation of the protein by ubiquitination [18]. These and other mechanisms can act synergistically and cause decrease or silencing of GKN1 expression in the gastric tissue [19].…”