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Published on: July 20, 2019
A pan-cancer analysis implicates human NKIRAS1 as a tumor-suppressor gene
Thomas S Postler1, Anqi Wang2,3, Francesco G Brundu2,3
1Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032.
Abstract:
The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 (NKIRAS1) and κB-Ras 2 (NKIRAS2) are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human NKIRAS1 alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of NKIRAS1 in human tumors that do not carry oncogenic RAS mutations is associated with worse clinical outcomes.
Insights
The κB-Ras proteins, NKIRAS1 and NKIRAS2, are potential tumor suppressors. Loss of NKIRAS1 expression in human cancers lacking oncogenic RAS mutations correlates with poorer patient prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- NF-κB and Ras signaling pathways are crucial for cell proliferation, driving tumorigenesis and carcinogenesis.
- κB-Ras proteins (NKIRAS1, NKIRAS2) inhibit both NF-κB and Ras activation, suggesting a tumor suppressor role.
- Their broad relevance to human cancers necessitates further investigation into their function in tumorigenesis.
Purpose of the Study:
- To establish the relevance of κB-Ras proteins in tumorigenesis using mouse models.
- To explore the role of κB-Ras proteins in human cancers via pan-cancer bioinformatics analysis.
- To investigate the prognostic significance of NKIRAS1 and NKIRAS2 expression in human tumors.
Main Methods:
- Utilized two distinct mouse models to study tumorigenesis.
- Conducted a pan-cancer bioinformatics analysis on human tumor samples.
- Correlated gene expression levels of NKIRAS1 and NKIRAS2 with oncogenic Ras mutations and patient outcomes.
Main Results:
- NKIRAS1 and NKIRAS2 genes are seldom downregulated in tumor samples with oncogenic Ras mutations.
- Reduced expression of human NKIRAS1 is associated with worse prognosis in at least four cancer types.
- Loss of NKIRAS1 expression in human tumors without oncogenic RAS mutations correlates with adverse clinical outcomes.
Conclusions:
- NKIRAS1 loss is an independent prognostic marker for worse outcomes in specific human cancers.
- The study provides direct evidence for NKIRAS1's role as a tumor suppressor in non-RAS-mutated cancers.
- Findings highlight the complex interplay between NKIRAS genes, Ras signaling, and cancer progression.
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