Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis.
Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0280560 |
| _version_ | 1797942980347166720 |
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| author | Takafumi Nakayama Masaaki Sunaoshi Yi Shang Mizuki Takahashi Takato Saito Benjamin J Blyth Yoshiko Amasaki Kazuhiro Daino Yoshiya Shimada Akira Tachibana Shizuko Kakinuma |
| author_facet | Takafumi Nakayama Masaaki Sunaoshi Yi Shang Mizuki Takahashi Takato Saito Benjamin J Blyth Yoshiko Amasaki Kazuhiro Daino Yoshiya Shimada Akira Tachibana Shizuko Kakinuma |
| author_sort | Takafumi Nakayama |
| collection | DOAJ |
| description | Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division-associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division-related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis. |
| first_indexed | 2024-04-10T20:16:04Z |
| format | Article |
| id | doaj.art-d593dc7b262f475e8791f1b1924e1242 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-10T20:16:04Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d593dc7b262f475e8791f1b1924e12422023-01-26T05:32:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01181e028056010.1371/journal.pone.0280560Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis.Takafumi NakayamaMasaaki SunaoshiYi ShangMizuki TakahashiTakato SaitoBenjamin J BlythYoshiko AmasakiKazuhiro DainoYoshiya ShimadaAkira TachibanaShizuko KakinumaCalorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division-associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division-related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis.https://doi.org/10.1371/journal.pone.0280560 |
| spellingShingle | Takafumi Nakayama Masaaki Sunaoshi Yi Shang Mizuki Takahashi Takato Saito Benjamin J Blyth Yoshiko Amasaki Kazuhiro Daino Yoshiya Shimada Akira Tachibana Shizuko Kakinuma Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. PLoS ONE |
| title | Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. |
| title_full | Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. |
| title_fullStr | Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. |
| title_full_unstemmed | Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. |
| title_short | Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis. |
| title_sort | calorie restriction alters the mechanisms of radiation induced mouse thymic lymphomagenesis |
| url | https://doi.org/10.1371/journal.pone.0280560 |
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