Gene Expression Analysis Indicates Divergent Mechanisms in DEN-Induced Carcinogenesis in Wild Type and Bid-Deficient Livers

To elucidate the mechanism underlying special characteristic differences between a spontaneous seedling mutant ‘Huapi’ kumquat (HP) and its wild-type ‘Rongan’ kumquat (RA), the fruit quality, metabolic profiles, and gene expressions of the peel and flesh were comprehensively analyzed. Compared with RA, HP fruit has distinctive phenotypes such as glossy peel, light color, and few amounts of oil glands. Interestingly, HP also accumulated higher flavonoid (approximately 4.1-fold changes) than RA. Based on metabolomics analysis, we identified 201 differential compounds, including 65 flavonoids and 37 lipids. Most of the differential flavonoids were glycosylated by hexoside and accumulated higher contents in the peel but lower in the flesh of HP than those of RA fruit. For differential lipids, most of them belonged to lysophosphatidycholines (LysoPCs) and lysophosphatidylethanolamines (LysoPEs) and exhibited low abundance in both peel and flesh of HP fruit. In addition, structural genes associated with the flavonoid and lipid pathways were differentially regulated between the two kumquat varieties. Gene expression analysis also revealed the significant roles of UDP-glycosyltransferase (UGT) and phospholipase genes in flavonoid and glycerophospholipid metabolisms, respectively. These findings provide valuable information for interpreting the mutation mechanism of HP kumquat.

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Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000481506 ◽

2017 ◽

Vol 107 (1) ◽

pp. 1-23

Author(s):

Franziska Briest ◽

Irina Grass ◽

Dagmar Sedding ◽

Markus Möbs ◽

Friederike Christen ◽

...

Keyword(s):

Gene Expression ◽

Western Blot ◽

Neuroendocrine Tumors ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Neuroendocrine Neoplasms ◽

Wild Type ◽

Frequent Event ◽

P53 Response

Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo.Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors.

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