Page 41 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

autocrine or paracrine regulator. Especially in stem cell niche Processing of Shh to its active form (19 kilodaltons) in parietal cells becomes compromised in the absence of gastric acid [44, 45] Atrophy of parietal and zymogenic (chief cell) lineages result in hypochlorhydria and reduced serum pepsinogen I (A) levels compared to pepsinogen II (C)[46-52]. These zymogens are proteins encoded by different gene loci that are used clinically to identify pre-neoplastic changes in the stomach[52]. Pepsinogens A and C are converted to the enzymatically active aspartic proteinases, pepsin A and pepsin C, through intramolecular self- cleavage[52, 53]. Pepsinogen A is produced primarily in the mouse corpus by parietal cells, whereas pepsinogen C is mainly produced by both mucous neck and chief cells throughout the stomach[44]. This result is consistent with the exclusive expression of pepsinogen A in the human corpus and not the antrum, whereas pepsinogen C marks mucous cells of both the antrum and corpus (www.proteinatlas.org). Pepsin A prefers to cleave proteins at hydrophobic and aromatic residues, particularly at phenylalanine (F) when the pH is less than 2. By contrast, pepsin C recognizes a broader consensus site and uses more comprehensive pH spectrum than pepsin A[53, 54]. Explicitly, it's shown using site-directed mutagenesis that pepsin A cleaves the nascent 45-kilodalton Shh polypeptide at residue 200 (SGGCF200|P) to generate the active 19-kilodalton form, whereas pepsin C does not cleave SHH peptide[44]. This may account for absence of Shh expression in atrohic gastritis.
Regulation of Gastrin and Gastric Acidity by Shh
Several studies have examined the impact of blocking Hedgehog signalling in vivo, for instance by employing a transgenic mouse that secretes a natural -inhibitor of Hedgehogs called HHIP employing the parietal cell-specific H+, K+-ATPase β subunit promotor[65]. This approach showed that loss of Hedgehog signalling in parietal cells reduces H+, K+-ATPase gene expression and gastric acid secretion[65]. Usually, hypochlorhydria stimulates gastrin gene expression through a decrease in Somatostatin levels[66] Accordingly, increased plasma gastrin occurred in the HHIP transgenic mice, concomitant with reduced somatostatin expression. Both antral G and D cells possess primary cilia, organelles protruding from the plasma membrane, essential for transducing Hedgehog signalling[67, 68]. Therefore, gastric endocrine cells may well be capable of responding directly to Shh. Functionally, this idea is supported by the observation that that transgenic overexpression of GLI2 suppresses gastrin gene expression[69]. Taken together, the
Gastric cancer and the Hedgehog Signalling
Gastric cancer and Hedgehog signalling
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