PubMed · 4834904
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T J Foley. 1974. Ectopic hyperparathyroidism.. https://doi.org/10.1016/0002-9610(74)90247-5
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The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the HMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis.
This study was designed to assess the diagnostic value of an immunochemical fecal occult blood test for small colorectal adenomas. In a screening program based comparative study, 60 colorectal adenomas under 1 cm (small polyp group), 60 colorectal adenomas 1 cm or larger (large polyp group) and 60 colorectal cancers (cancer group) detected by occult blood screening, and 120 healthy controls (control group), served as subjects. Moreover, 50 small adenomas, 50 large adenomas and 50 cancers detected in out-patient clinics, and 100 controls, served as subjects of a hospital based comparative study. Each of these subjects was tested by an immunochemical occult blood with 3 consecutive days, after removal of these colorectal neoplasms in a screening program based study and before as well as after removal in a hospital based study, and the positivity rate of this test was evaluated among these four groups in the two comparative studies. The positivity rate in a screening program based study was 23% for small polyp group, 8% for large polyp group, 5% for cancer group and 6% for control group, respectively. Significant difference was noted between small polyp and cancer as well as control groups (p <0.01), and between small polyp and large polyp groups (p <0.05). In a hospital based study, however, there was no significant difference in the positivity rate among four groups. These results suggest that high proportion of small polyps detected by fecal occult blood test screening may not be associated with bleeding from adenomas but probably from another gastrointestinal pathology.
Aberrant crypt foci (ACF) are microscopic lesions which can be detected, after methylene blue staining, in the overtly normal looking colonic mucosa of cancer patients. ACF have been postulated to be precursor lesions which develop into colorectal cancer. Mutations of K-ras and p53 are two important genetic events implicated in colon carcinogenesis. Mutations in K-ras are detectable at earlier stages, while mutations in p53 are detectable at later stages of colon carcinogenesis. Our objective was to compare the nature of genetic alterations in K-ras (codon 12 and 13) and in p53 (exon 4-9) between ACF and corresponding colonic tumors from cancer patients. ACF with > or =20 crypts/focus were harvested from overtly normal looking colonic mucosa of cancer patients at a distance of (approx.) 5 cm from the site of colonic tumors. The colonic tumors and ACF samples were compared for K-ras codon 12 and 13 base pair sequence, using DNA sequencing and for p53 (exon 5-9) allelic types, using PCR-SSCP and DNA sequencing. The results demonstrated a perfect correlation in terms of the type of K-ras allele (wild or mutated) between the ACF (> or =20 crypts/focus) and corresponding colonic tumors in 11/13 cancer patients. Analyses of p53 mutations demonstrated the presence of p53 mutations in colonic carcinomas from 10/13 patients. However, p53 mutations could be detected in an ACF from only 1/13 patient. The results provides further evidence to the role of ACF as precursor to colon cancer. The presence of an identical K-ras as well as p53 mutation in an ACF and the corresponding colonic carcinoma in a patient suggests the possibility of existence of ACF that may be at a more advanced stage in the sequence of colonic tumorigenesis than others. In conclusion, the results suggest that a subset of ACF with higher multiplicity might be considered more likely to progress to more advanced lesions and should be explored as markers of colon cancer risk.