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Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis
Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868494/ https://www.ncbi.nlm.nih.gov/pubmed/24253735 http://dx.doi.org/10.3892/or.2013.2859 |
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author | SUWA, HIROHIKO HIRANO, MASATO KAWARADA, KOUJI NAGAYAMA, MOTOHIKO EHARA, MICHIKO MURAKI, TOMONARI SHISA, HAYASE SUGIYAMA, AIKO SUGIMOTO, MASAHIRO HIAI, HIROSHI KITANO, MOTOO TANUMA, JUN-ICHI |
author_facet | SUWA, HIROHIKO HIRANO, MASATO KAWARADA, KOUJI NAGAYAMA, MOTOHIKO EHARA, MICHIKO MURAKI, TOMONARI SHISA, HAYASE SUGIYAMA, AIKO SUGIMOTO, MASAHIRO HIAI, HIROSHI KITANO, MOTOO TANUMA, JUN-ICHI |
author_sort | SUWA, HIROHIKO |
collection | PubMed |
description | Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3(DA) allele, and not the Tcas3(WF) allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA × WF) F1 rats, the resistant Tcas3(WF) allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca(2+) level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs. |
format | Online Article Text |
id | pubmed-3868494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-38684942013-12-20 Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis SUWA, HIROHIKO HIRANO, MASATO KAWARADA, KOUJI NAGAYAMA, MOTOHIKO EHARA, MICHIKO MURAKI, TOMONARI SHISA, HAYASE SUGIYAMA, AIKO SUGIMOTO, MASAHIRO HIAI, HIROSHI KITANO, MOTOO TANUMA, JUN-ICHI Oncol Rep Articles Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3(DA) allele, and not the Tcas3(WF) allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA × WF) F1 rats, the resistant Tcas3(WF) allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca(2+) level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs. D.A. Spandidos 2014-01 2013-11-20 /pmc/articles/PMC3868494/ /pubmed/24253735 http://dx.doi.org/10.3892/or.2013.2859 Text en Copyright © 2014, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited. |
spellingShingle | Articles SUWA, HIROHIKO HIRANO, MASATO KAWARADA, KOUJI NAGAYAMA, MOTOHIKO EHARA, MICHIKO MURAKI, TOMONARI SHISA, HAYASE SUGIYAMA, AIKO SUGIMOTO, MASAHIRO HIAI, HIROSHI KITANO, MOTOO TANUMA, JUN-ICHI Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title | Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title_full | Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title_fullStr | Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title_full_unstemmed | Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title_short | Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
title_sort | pthlh, a promising cancer modifier gene in rat tongue carcinogenesis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868494/ https://www.ncbi.nlm.nih.gov/pubmed/24253735 http://dx.doi.org/10.3892/or.2013.2859 |
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