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

doi:10.3892/or.2013.2859

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis

Authors:
- Hirohiko Suwa
- Masato Hirano
- Kouji Kawarada
- Motohiko Nagayama
- Michiko Ehara
- Tomonari Muraki
- Hayase Shisa
- Aiko Sugiyama
- Masahiro Sugimoto
- Hiroshi Hiai
- Motoo Kitano
- Jun-Ichi Tanuma
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Affiliations: Department of Oral Pathology, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Mizuho, Gifu, Japan, Department of Pathology, Saitama Cancer Center Research Institute, Ina, Saitama, Japan, Malignancy Control Research Laboratory, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Sakyo‑Ku, Kyoto, Japan, Division of Pathology, Saitama Cooperative Hospital, Kawaguchi, Saitama, Japan
Published online on: November 20, 2013 https://doi.org/10.3892/or.2013.2859
Pages: 3-12
Copyright: © Suwa et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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 Tcas3DA allele, and not the Tcas3WF allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA x WF) F1 rats, the resistant Tcas3WF 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 Ca2+ 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.

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