Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

Abstract

Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis revealed that hypoxia signaling was induced by mutant p53 in 2 gastric cancer cell lines. Using real-time in vivo imaging, we confirmed that hypoxia reporter activity was elevated during the initiation of mutant p53 gastric cancer xenografts. Unlike HIF co-factor ARNT, HIF1α was required for primary tumor growth in mutant p53 gastric cancer. These findings elucidate the contribution of missense p53 mutations in gastroesophageal malignancy and indicate that hypoxia signaling rather than mutant p53 itself may serve as a therapeutic vulnerability in these deadly set of cancers.

• Authors: Nilay Sethi, Osamu Kikuchi, James McFarland, Yanxi Zhang, Max Chung, Nicholas Kafker, Mirazul Islam, Benjamin Lampson, Abhishek Chakraborty, William G Kaelin Jr, Adam J Bass
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 15 (08 08 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31391338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARNT protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• TP53 protein, human
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• Aryl Hydrocarbon Receptor Nuclear Translocator

Topics

• Adenocarcinoma (genetics, pathology)
• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (metabolism)
• Carcinogenesis (genetics)
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• DNA Mutational Analysis
• Datasets as Topic
• Esophageal Mucosa (pathology)
• Esophageal Neoplasms (genetics, pathology)
• Gastric Mucosa (pathology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intravital Microscopy
• Mice
• Mutation, Missense
• Signal Transduction (genetics)
• Stomach Neoplasms (genetics, pathology)
• Transcription, Genetic
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays