Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish
Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including <i>KRAS</i> mutations and inflammation, have been implicated in oncogenesis. However, the potentia...
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2021-08-01
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| author | Jeng-Wei Lu Yuxi Sun Pei-Shi Angelina Fong Liang-In Lin Dong Liu Zhiyuan Gong |
| author_facet | Jeng-Wei Lu Yuxi Sun Pei-Shi Angelina Fong Liang-In Lin Dong Liu Zhiyuan Gong |
| author_sort | Jeng-Wei Lu |
| collection | DOAJ |
| description | Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including <i>KRAS</i> mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between <i>KRAS</i> mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of <i>kras<sup>V</sup></i><sup>12</sup>, lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of <i>kras<sup>V</sup></i><sup>12</sup> transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in <i>kras<sup>V</sup></i><sup>12</sup> transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of <i>kras<sup>V</sup></i><sup>12</sup>, combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that <i>kras<sup>V</sup></i><sup>12</sup> expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, <i>kras<sup>V</sup></i><sup>12</sup> transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in <i>kras<sup>V</sup></i><sup>12</sup>-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that <i>kras<sup>V</sup></i><sup>12</sup> expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers. |
| first_indexed | 2024-03-10T08:59:34Z |
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| spelling | doaj.art-88e411ba8b734eca8d39e11ef544c0152023-11-22T06:52:48ZengMDPI AGBiomedicines2227-90592021-08-019897410.3390/biomedicines9080974Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic ZebrafishJeng-Wei Lu0Yuxi Sun1Pei-Shi Angelina Fong2Liang-In Lin3Dong Liu4Zhiyuan Gong5Department of Biological Sciences, National University of Singapore, Singapore 117543, SingaporeDepartment of Biological Sciences, National University of Singapore, Singapore 117543, SingaporeDepartment of Biological Sciences, National University of Singapore, Singapore 117543, SingaporeDepartment of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, TaiwanDepartment of Biology, Southern University of Science and Technology, Shenzhen 518055, ChinaDepartment of Biological Sciences, National University of Singapore, Singapore 117543, SingaporeIntestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including <i>KRAS</i> mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between <i>KRAS</i> mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of <i>kras<sup>V</sup></i><sup>12</sup>, lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of <i>kras<sup>V</sup></i><sup>12</sup> transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in <i>kras<sup>V</sup></i><sup>12</sup> transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of <i>kras<sup>V</sup></i><sup>12</sup>, combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that <i>kras<sup>V</sup></i><sup>12</sup> expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, <i>kras<sup>V</sup></i><sup>12</sup> transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in <i>kras<sup>V</sup></i><sup>12</sup>-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that <i>kras<sup>V</sup></i><sup>12</sup> expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers.https://www.mdpi.com/2227-9059/9/8/974colorectal cancerdextran sulfate sodiumlipopolysaccharides<i>kras<sup>V</sup></i><sup>12</sup>intestinal tumortransgenic zebrafish |
| spellingShingle | Jeng-Wei Lu Yuxi Sun Pei-Shi Angelina Fong Liang-In Lin Dong Liu Zhiyuan Gong Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish Biomedicines colorectal cancer dextran sulfate sodium lipopolysaccharides <i>kras<sup>V</sup></i><sup>12</sup> intestinal tumor transgenic zebrafish |
| title | Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish |
| title_full | Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish |
| title_fullStr | Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish |
| title_full_unstemmed | Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish |
| title_short | Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of <i>kras<sup>V</sup></i><sup>12</sup> in Transgenic Zebrafish |
| title_sort | lipopolysaccharides enhance epithelial hyperplasia and tubular adenoma in intestine specific expression of i kras sup v sup i sup 12 sup in transgenic zebrafish |
| topic | colorectal cancer dextran sulfate sodium lipopolysaccharides <i>kras<sup>V</sup></i><sup>12</sup> intestinal tumor transgenic zebrafish |
| url | https://www.mdpi.com/2227-9059/9/8/974 |
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