Essential role of gastric gland mucin in preventing gastric cancer in mice

信州大学博士（医学）・学位論文・平成24年3月31日授与（甲第916号）・唐澤文寿Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal alpha 1,4-linked N-acetylglucosamine residues (alpha GlcNAc). Previously, we identified human alpha 1,4-N-acetylglucosaminyltransferase (alpha 4GnT), which is responsible for the O-glycan biosynthesis and characterized alpha GlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt(-/-) mice to better understand its role in vivo. A4gnt(-/-) mice showed complete lack of alpha GlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori infection. Microarray and quantitative RT-PCR analysis revealed upregulation of genes encoding inflammatory chemokine ligands, proinflammatory cytokines, and growth factors, such as Ccl2, Il-11, and Hgf in the gastric mucosa of A4gnt(-/-) mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced alpha GlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of alpha GlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, alpha GlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation.ArticleJOURNAL OF CLINICAL INVESTIGATION. 122(3):923-934 (2012)journal articl

Pulmonary adenocarcinoma possibly developed from the cut-end of small-sized adenocarcinoma in the lung periphery as recurrence 13 years after its wedge resection

Abstract Background It is a big topic for general thoracic surgery whether still curability can be obtained by limited resection for peripheral small-sized nodules of non-small cell lung cancer (NSCLC) in the current era of frequent computed tomography (CT) use. Accumulation of information on problematic cases would be meaningful for surgeons to select better surgical procedures. Case presentation A 69-year-old man was pointed out an enlarged 2.1-cm solid nodule on the edge of staple line of the residual right upper lobe by chest CT. He had past history of the lung cancer surgery, wedge resection of the same right upper lobe 13 years ago. The pathological findings were 1.1-cm, p-TlbN0M0, p-stage IA2-adenocarcinoma. Thereafter, he received no adjuvant therapy. This time, the trans-bronchial lung biopsy revealed adenocarcinoma. After the completion lobectomy of the residual right upper lobe, the tumor was diagnosed as adenocarcinoma consistent with recurrence of small-sized adenocarcinoma in the lung periphery developed from the cut-end because of similarities between present and previous tumors on histopathology and p53-positivity. Conclusions When limited resection has been performed for small-sized NSCLC presenting solid nodule on thin-slice CT images, long-term postoperative follow-up time will be necessary for monitoring, considering the possibility of cut-end recurrence

Essential role of gastric gland mucin in preventing gastric cancer in mice

Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). Previously, we identified human α1,4-N-acetylglucosaminyltransferase (α4GnT), which is responsible for the O-glycan biosynthesis and characterized αGlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt(–/–) mice to better understand its role in vivo. A4gnt(–/–) mice showed complete lack of αGlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori infection. Microarray and quantitative RT-PCR analysis revealed upregulation of genes encoding inflammatory chemokine ligands, proinflammatory cytokines, and growth factors, such as Ccl2, Il-11, and Hgf in the gastric mucosa of A4gnt(–/–) mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced αGlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of αGlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, αGlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation