Does TP53 mutation promote ovarian cancer metastasis to omentum by regulating lipid metabolism?

Abstract

TP53 (Tumor Protein 53, previously known as p53) is probably the best known of all tumor suppressor genes, and is mutated in nearly all (96%) high-grade serous ovarian cancer (HGS-OvCa), which is the most common histopathological type of epithelial ovarian cancer (EOC). Recently, TP53 is found to involve in regulating cell metabolic pathways besides its classical tumor suppressive functions. In addition, emerging evidence suggests that mutant TP53 is associated with cancer metastasis. Through summarizing and comparing the roles of wild-type TP53 and mutant TP53 in the progression of various types of cancer, we hypothesize that mutant TP53 in HGS-OvCa cells interacts with sterol regulatory element-binding proteins (SREBPs) and guanidinoacetate N-methyltransferase (GAMT), leading to increased gene expression of key enzymes involved in fatty acids (FAs) and cholesterol biosynthesis and the inhibition of fatty acid oxidation (FAO), thus promotes lipid anabolism to accelerate tumor growth and progression. Elevated platelet number in patients' tumor microenvironment results in increased TGF-β production. Then, TGF-β acts in concert with mutant TP53 to promote HGS-OvCa metastasis by assembling a mutant-TP53/p63/Smads protein complex, in which p63's functions as metastasis suppressor are antagonized, and by enhancing the activities of the Slug/Snail and Twist families to drive induce EMT-like transition. Then adipocyte-derived IL-8 facilitates the metastasis of transformative cancer cells to abdominal adipose tissue (e.g., omentum). Once metastasis is established, mutant TP53 together with adipocyte-derived IL-8 upregulates Fatty acid-binding protein 4 (FABP4) expression and then promotes FAs absorption from adipocytes to support rapid tumor growth in adipocyte-rich metastatic environments. In summary, these indicate that mutant TP53 may play determinant roles in the progression of HGS-OvCa.

• Authors: Jing Hu, Zhiqiang Liu, Xipeng Wang
• Journal: Medical hypotheses (Med Hypotheses) Vol. 81 Issue 4 Pg. 515-20 (Oct 2013) ISSN: 1532-2777 [Electronic] United States
• PMID: 23880140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• FABP4 protein, human
• Fatty Acid-Binding Proteins
• Interleukin-8
• Sterol Regulatory Element Binding Proteins
• Transforming Growth Factor beta
• Tumor Suppressor Protein p53
• Guanidinoacetate N-Methyltransferase

Topics

• Fatty Acid-Binding Proteins
• Female
• Gene Expression Regulation, Neoplastic (genetics, physiology)
• Guanidinoacetate N-Methyltransferase (metabolism)
• Humans
• Interleukin-8 (metabolism)
• Lipid Metabolism (genetics, physiology)
• Mutation (genetics)
• Neoplasm Metastasis (genetics)
• Omentum (pathology)
• Ovarian Neoplasms (physiopathology)
• Peritoneal Neoplasms (genetics, secondary)
• Sterol Regulatory Element Binding Proteins (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)