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Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity

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Review

Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity

Shamshul Ansari et al. Int J Mol Sci.

Abstract

Gastric cancer is the third leading cause of cancer-related deaths and ranks as the fifth most common cancer worldwide. Incidence and mortality differ depending on the geographical region and gastric cancer ranks first in East Asian countries. Although genetic factors, gastric environment, and Helicobacter pylori infection have been associated with the pathogenicity and development of intestinal-type gastric cancer that follows the Correa's cascade, the pathogenicity of diffuse-type gastric cancer remains mostly unknown and undefined. However, genetic abnormalities in the cell adherence factors, such as E-cadherin and cellular activities that cause impaired cell integrity and physiology, have been documented as contributing factors. In recent years, H. pylori infection has been also associated with the development of diffuse-type gastric cancer. Therefore, in this report, we discuss the host factors as well as the bacterial factors that have been reported as associated factors contributing to the development of diffuse-type gastric cancer.

Keywords: contributing factors; diffuse gastric cancer; gastric cancer; hereditary diffuse gastric cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cell–cell adhesion through E-cadherin. The extracellular domain of E-cadherin from adjacent cells is involved in cell adhesion and tight junction. The cytoplasmic domain forming a protein complex with catenins (α-, β-, and p120-) regulates the cytoskeleton protein and actin, which is an important protein for normal cell integrity.
Figure 2
Figure 2
Pathogenicity and factors associated with the disruption of the normal cellular activity. Hyper-methylation of the CDH1 gene and mutational alteration in TP53 protein causes the impaired synthesis of E-cadherin. The truncated APC causes accumulation of β-catenin, which activates the β-catenin-dependent genes and Wnt pathway, altering normal cellular functions. The Wnt pathway after its activation causes the accumulation of β-catenins in cytoplasm and its translocation into the nucleus where it transcriptionally activates the transcription factors belonging to the TCF family. The recurrent mutation in RhoA is able to alter the RhoA pathway, which has a deleterious effect on E-cadherin.
Figure 3
Figure 3
H. pylori CagA has an inducible effect on the CDH1 methylation and TP53 mutational alteration. CagA can directly degrade the β-catenin from the E-cadherin-catenins complex. CagA can also degrade the E-cadherin directly. Bacterial HtrA protein can cleave the extracellular domain of E-cadherin.

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