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Published on: October 27, 2015
Evaluation of Rint1 as a modifier of intestinal tumorigenesis and cancer risk
Karla L Otterpohl1, Karen A Gould1
1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
The Rad50 Interacting Protein 1 (Rint1) influences cellular homeostasis through maintenance of endoplasmic reticulum, Golgi and centrosome integrity and regulation of vesicle transport, autophagy and the G2/M checkpoint. Rint1 has been postulated to function as a tumor suppressor as well as an oncogene, with its role depending perhaps upon the precise cellular and/or experimental context. In humans, heterozygosity for germline missense variants in RINT1 have, in some studies, been associated with increased risk of both breast and Lynch syndrome type cancers. However, it is not known if these germline variants represent loss of function alleles or gain of function alleles. Based upon these findings, as well as our initial consideration of Rint1 as a potential candidate for Mom5, a genetic modifier of intestinal tumorigenesis in ApcMin/+ mice, we sought to explicitly examine the impact of Rint1 on tumorigenesis in ApcMin/+ mice. However, heterozygosity for a knockout of Rint1 had no impact on tumorigenesis in Rint1+/-; ApcMin/+ mice. Likewise, we found no evidence to suggest that the remaining Rint1 allele was lost somatically in intestinal tumors in ApcMin/+ mice. Interestingly, in contrast to what has been observed in Rint1+/- mice on a mixed genetic background, Rint1+/- mice on a pure C57BL/6J background did not show spontaneous tumor development. We also evaluated colorectal cancer data available in the COSMIC and ONCOMINE databases and found that RINT1 overexpression, as well as the presence of somatic missense mutations in RINT1 were associated with colorectal cancer development. In vitro evaluation of two missense variants in RINT1 suggested that such variants do have the potential to impact RINT1 function.
Insights
Rad50 Interacting Protein 1 (Rint1) plays a role in cellular homeostasis. Studies show Rint1 variants are linked to cancer risk, but its role in tumorigenesis remains unclear.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Rad50 Interacting Protein 1 (Rint1) is crucial for cellular homeostasis, affecting organelle integrity and cell cycle regulation.
- Rint1's role in cancer is debated, potentially acting as a tumor suppressor or oncogene depending on context.
- Germline RINT1 variants are associated with increased breast and Lynch syndrome cancer risks, but their functional impact is unknown.
Purpose of the Study:
- To investigate the impact of Rint1 on intestinal tumorigenesis in ApcMin/+ mice.
- To determine if Rint1 acts as a tumor suppressor in the context of intestinal cancer.
- To analyze the association of RINT1 alterations with colorectal cancer development.
Main Methods:
- Generated Rint1+/-; ApcMin/+ mice to assess tumorigenesis.
- Analyzed somatic Rint1 allele loss in intestinal tumors.
- Examined RINT1 expression and mutation data in human colorectal cancer databases (COSMIC, ONCOMINE).
- Performed in vitro studies on RINT1 missense variants.
Main Results:
- Heterozygosity for Rint1 knockout did not affect intestinal tumorigenesis in ApcMin/+ mice.
- No somatic loss of the remaining Rint1 allele was observed in tumors.
- Rint1+/- mice on a pure C57BL/6J background showed no spontaneous tumor development.
- RINT1 overexpression and somatic missense mutations correlated with colorectal cancer development.
- In vitro analysis indicated potential functional impact of RINT1 missense variants.
Conclusions:
- Rint1 does not appear to function as a tumor suppressor in the context of ApcMin/+ driven intestinal tumorigenesis.
- RINT1 alterations, including overexpression and somatic mutations, are associated with colorectal cancer.
- Further research is needed to elucidate the precise role of Rint1 variants in cancer etiology.
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