title: Sustained proliferation and resistance to apoptosis after a cytotoxic insult are early alterations in rat colon carcinogenesis.
abstract: To study the early alterations in carcinogenesis, we determined apoptosis and proliferation in rat mucin depleted foci (MDF), precancerous lesions in the colon under basal conditions and 24 h after treatment with 1,2-dimethylhydrazine (DMH), which induces apoptosis in the colon. Spontaneous apoptosis in MDF was higher than in normal mucosa (Apoptotic Index was 1.61 ± 0.30 and 0.21 ± 0.02 in MDF and normal mucosa, respectively, mean ± SE, p < 0.05). DMH (30 and 75 mg/kg) increased apoptosis in both normal mucosa and MDF (up to 20 times higher compared to basal levels in normal mucosa, but only two times in MDF). MDF had a higher and deregulated pattern of proliferation along the crypt compared to normal mucosa. After DMH, proliferation in normal mucosa was significantly depressed, but it did not vary in MDF. Survivin-Birc5 regulating apoptosis and proliferation was significantly over-expressed (RT-qPCR and immunohistochemistry experiments) in MDF vs. normal mucosa, but did not vary in response to DMH. The expression of the pro-apoptotic protein Bak did not vary in normal mucosa and MDF. Since inflammation is present in MDF, which may hamper apoptosis, we studied the effect of pre-treatment with aspirin (600 ppm in the diet for 10 days). No significant effects of aspirin were observed. In conclusion, MDF had a higher spontaneous apoptosis and proliferation coupled with a reduced response to apoptotic stimuli from cytotoxic compounds. Survivin over-expression in MDF indicates that this is an early event in colon carcinogenesis and suggests that down-regulation of Survivin may represent a strategy for cancer prevention.
authors: Department of Pharmacology, University of Florence, Florence, Italy.
authors: Angelo Pietro
authors: AP
authors: Femia
authors: Francesca
authors: F
authors: Salvianti
authors: Cristina
authors: C
authors: Luceri
authors: Piero
authors: P
authors: Dolara
authors: Maddalena
authors: M
authors: Salvadori
authors: Pamela
authors: P
authors: Pinzani
authors: Giovanna
authors: G
authors: Caderni
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D014408:Biomarkers, Tumor; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015232:Dinoprostone / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D000077022:Survivin; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494774:Bak1 protein, rat; D014408:Biomarkers, Tumor; C516989:Birc5 protein, rat; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; D009077:Mucins; D000077022:Survivin; D050998:bcl-2 Homologous Antagonist-Killer Protein; D053148:Caspase 3; D019813:1,2-Dimethylhydrazine; D015232:Dinoprostone; D001241:Aspirin