title: Luteinizing hormone receptor deficiency increases the susceptibility to alkylating agent-induced lymphomagenesis in mice.
abstract: Previous studies have revealed a close link between luteinizing hormone (LH)/human chorionic gonadotropin (hCG) signaling and oncogenesis in gonadal and nongonadal tissues. To investigate whether genetic ablation of LH receptor (Lhr) affects the animal's oncogenic susceptibility, adult female wild-type (wt), heterozygous, and homozygous Lhr knockout (LhrKO) mice were intraperitoneally injected with an alkylating agent, N-methyl-N-nitrosourea (MNU, 50 mg/kg of body weight). The mice were sacrificed when they were short of breath or 10 months after the injection. The results showed that MNU induced non-Hodgkin's thymic and lymphonodus lymphomas in 70.6% and 100% of heterozygous and homozygous animals, respectively, compared with 35.7% in wt siblings. The tumor development was rapid; they were more aggressive and metastasized to the spleen, liver, and kidney in Lhr-deficient mice compared to wt siblings. All tumors were immunostained-positive for a T-cell specific marker, CD3, but not for a B-cell marker, CD22, suggesting that all the lymphomas arose from T-cells, which are known to be LH/hCG receptor-positive. There was no rearrangement of the Lhr gene locus or differences in thymic cell proliferation among the genotypes. However, apoptosis was lower in the Lhr-deficient thymuses. The thymic Bcl-2 levels were elevated and caspase-3 activation was reduced in Lhr heterozygous and homozygous animals. In conclusion, MNU induced a higher incidence and an earlier onset of aggressive lymphomas in LhrKO animals, which may be associated with a reduction in apoptosis of thymocytes.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Louisville School of Medicine, MDR Building Room 438, Health Sciences Center, Louisville, KY 40292, USA.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Yu
authors.forename: Fangping
authors.initials: F
authors.lastname: Yuan
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.forename: Dexin
authors.initials: D
authors.lastname: Lin
authors.forename: Zijian
authors.initials: Z
authors.lastname: Lan
authors.forename: C V
authors.initials: CV
authors.lastname: Rao
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Lei
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016399:Lymphoma, T-Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011974:Receptors, LH / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000477:Alkylating Agents; D011974:Receptors, LH; D008770:Methylnitrosourea