We investigated the effects of PPARα activators fenofibrate and WY-14643 as well as the PPARα inhibitor GW6471 on the PI3K/Akt/PTEN pathway of intestinal cell differentiation. Our previous study showed that all these compounds increased the expression of villin, a specific marker of intestinal cell differentiation in HT-29 and Caco2 cells. Our current results confirmed the central role of lipid messenger phosphatidylinositol-4,5-bisphosphate (PIP2), a known player in brush border formation, in mediating the effects of tested PPARα ligands. Although all tested compounds increased its levels, surprisingly, each of them affected different PIP2-metabolizing enzymes, especially the levels of PIP5K1C and PTEN. Moreover, we found a positive relationship between the expression of PPARα itself and PIP2 as well as PIP5K1C. By contrast, PPARα was negatively correlated with PTEN. However, the expression of antigens of interest was independent of PPARα subcellular localization, suggesting that it is not directly involved in their regulation. In colorectal carcinoma tissues we found a decrease in PTEN expression, which was accompanied by a change in its subcellular localization. This change was also observed for the regulatory subunit of PI3K. Taken together, our data revealed that fenofibrate, WY-14643, and GW6471 affected different members of the PI3K/Akt/PTEN pathway. However, these effects were PPARα-independent.

• Klíčová slova
• carcinogenesis, fibrates, intestinal cell differentiation, phosphatidylinositol-4,5-bisphosphate,
• Publikační typ
• časopisecké články MeSH

The Cdx2 homeobox gene is important in assigning positional identity during the finely orchestrated process of embryogenesis. In adults, regenerative responses to tissues damage can require a replay of these same developmental pathways. Errors in reassigning positional identity during regeneration can cause metaplasias-normal tissue arising in an abnormal location-and this in turn, is a well-recognized cancer risk factor. In animal models, a gain of Cdx2 function can elicit a posterior shift in tissue identity, modeling intestinal-type metaplasias of the esophagus (Barrett's esophagus) and stomach. Conversely, loss of Cdx2 function can elicit an anterior shift in tissue identity, inducing serrated-type lesions expressing gastric markers in the colon. These metaplasias are major risk factors for the later development of esophageal, stomach and colon cancer. Leukemia, another cancer in which Cdx2 is ectopically expressed, may have mechanistic parallels with epithelial cancers in terms of stress-induced reprogramming. This review will address how animal models have refined our understanding of the role of Cdx2 in these common human cancers.

• Klíčová slova
• Cdx, animal models, cancer, metaplasia,
• MeSH
• ezofágus patologie   MeSH
• homeoboxové geny genetika   MeSH
• kolon patologie   MeSH
• lidé MeSH
• metaplazie genetika   patologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory jícnu genetika   patologie   MeSH
• nádory tračníku genetika   patologie   MeSH
• nádory žaludku genetika   patologie   MeSH
• progrese nemoci MeSH
• regulace genové exprese u nádorů * MeSH
• transkripční faktor CDX2 genetika   metabolismus   MeSH
• žaludek patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• transkripční faktor CDX2 MeSH