https://www.cell.com/cell/pdf/0092-8674(93)90484-8.pdf

Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse.

Carcinogenesis may result from the action of any one or a combination of chemical, physical, biologic, and/or genetic insults to cells The process of carcinogenesis may be divided into at least three stages: initiation, promotion, and progression The first stage of carcinogenesis, initiation, results from an irreversible genetic alteration, most likely one or more simple mutations, transversions, transitions, and/or small deletions in DNA The reversible stage of promotion does not involve changes in the structure of DNA but rather in the expression of the genome mediated through promoter-receptor interactions The final irreversible stage of progression is characterized by karyotypic instability and malignant growth Critical molecular targets during the stages of carcinogenesis include proto-oncogenes, cellular oncogenes, and tumor suppressor genes, alterations in both alleles of the latter being found only in the stage of progression Although many of these critical target genes have been identified, the ultimate number and characteristics of molecular alterations that define neoplasia have not been elucidated

The molecular biology of carcinogenesis.

ContextHepatocellular carcinoma (HCC) has a male predominance and is closely
related to hepatitis B virus (HBV) infection. Hepatitis B virus vaccination
was launched in 1984 in Taiwan for neonates of mothers carrying hepatitis
B e antigen, resulting in a decreased incidence of HCC in children. The effect
on boys vs girls is not known.ObjectiveTo evaluate the association between a HBV vaccination program with incidence
of childhood HCC by sex.Design and SettingAnalysis of data collected from Taiwan's National Cancer Registry System
and the Taiwan Childhood Hepatoma Study Group between 1981 and 1996.ParticipantsChildren aged 6 to 14 years who were diagnosed as having HCC (201 boys
and 70 girls).Main Outcome MeasureIncidence of HCC in boys and girls before and after implementation of
the vaccination program.ResultsThe boy-girl incidence ratio decreased steadily from 4.5 in 1981-1984
(before the program's introduction) to 1.9 in 1990-1996 (6-12 years after
the vaccination program was launched). The incidence of HCC in boys born after
1984 was significantly reduced in comparison with those born before 1978 (relative
risk [RR], 0.72; P = .002). No significant decrease
in HCC incidence was observed in girls born in the same periods (RR, 0.77; P = .20). The incidence of HCC in boys remained stable
with increasing age, while an increase of HCC incidence with age in girls
was observed. These age and sex effects remained the same regardless of birth
before or after the vaccination program.ConclusionOur results suggest that boys may benefit more from HBV vaccination
than girls in the prevention of HCC.

https://jamanetwork.com/journals/jama/articlepdf/193365/jbr00227.pdf

Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls.

To study the molecular mechanisms of circadian gene expression, we have sought to identify genes whose expression in mouse liver is regulated by the transcription factor DBP (albumin D-site-binding protein). This PAR basic leucine zipper protein accumulates according to a robust circadian rhythm in nuclei of hepatocytes and other cell types. Here, we report that the Cyp2a4 gene, encoding the cytochrome P450 steroid 15alpha-hydroxylase, is a novel circadian expression gene. This enzyme catalyzes one of the hydroxylation reactions leading to further metabolism of the sex hormones testosterone and estradiol in the liver. Accumulation of CYP2A4 mRNA in mouse liver displays circadian kinetics indistinguishable from those of the highly related CYP2A5 gene. Proteins encoded by both the Cyp2a4 and Cyp2a5 genes also display daily variation in accumulation, though this is more dramatic for CYP2A4 than for CYP2A5. Biochemical evidence, including in vitro DNase I footprinting on the Cyp2a4 and Cyp2a5 promoters and cotransfection experiments with the human hepatoma cell line HepG2, suggests that the Cyp2a4 and Cyp2a5 genes are indeed regulated by DBP. These conclusions are corroborated by genetic studies, in which the circadian amplitude of CYP2A4 and CYP2A5 mRNAs and protein expression in the liver was significantly impaired in a mutant mouse strain homozygous for a dbp null allele. These experiments strongly suggest that DBP is a major factor controlling circadian expression of the Cyp2a4 and Cyp2a5 genes in the mouse liver.

/pdf/circadian-expression-of-the-steroid-15-a-hydroxylase-cyp2a4-3xqms4fv3j.pdf

Circadian Expression of the Steroid 15 α-Hydroxylase (Cyp2a4) and Coumarin 7-Hydroxylase (Cyp2a5) Genes in Mouse Liver Is Regulated by the PAR Leucine Zipper Transcription Factor DBP

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver.

Tfm (testicular feminization) mutant mice lack functional androgen receptors. By studying liver tumor development in Tfm mice, we have shown that the greater susceptibility of male mice relative to female mice for liver tumor induction by N,N-diethylnitrosamine is androgen receptor-dependent. C57BL/6J normal and Tfm mutant mice were injected at 12 days of age with N,N-diethylnitrosamine (0.2 mumol/g, i.p.), and liver tumors were enumerated in 50-week-old animals. Normal males averaged 20 liver tumors per animal; Tfm males, 0.7; normal females, 0.6; and Tfm/+ heterozygous females, 1.5. The androgen receptor gene and the Tfm mutation are X chromosome linked. Because of random X chromosome inactivation, hepatocytes from Tfm/+ heterozygous female mice are mosaic with respect to the expression of mutant or wild-type receptors. To determine if testosterone acts directly as a liver tumor promoter, through the androgen receptor in preneoplastic hepatocytes, or by an indirect mechanism, we chronically treated these mosaic female mice with testosterone and measured the androgen receptor content of the resulting tumors. B6C3F1 Tfm/+ mosaic and +/+ wild-type female mice were injected i.p. at 12 days of age with N,N-diethylnitrosamine (0.1 mumol/g) and ovariectomized at 8 weeks of age. Half of the mice of each group subsequently received biweekly s.c. injections of testosterone (0.15 mg per mouse) for 30 weeks. Tumor multiplicity was the same for wild-type and Tfm/+ mosaic females treated with testosterone (31-32 tumors per animal at 38 weeks of age) and was increased relative to females not treated with testosterone (13-17 tumors per animal at 50 weeks of age). Testosterone treatment did not significantly increase the percentage of androgen receptor-positive tumors in Tfm/+ mosaic females: 58% of the tumors from Tfm/+ mosaic females treated with testosterone were receptor positive compared to 48% in Tfm/+ females not treated with testosterone and 92% in wild-type females treated with testosterone. Finally, the number of androgen receptors in the majority of liver tumors examined was greatly decreased relative to the surrounding normal liver tissue. We conclude that liver tumor promotion by testosterone requires a functional androgen receptor in the intact animal. However, this promotion is not cell autonomous; that is, the response of the preneoplastic hepatocyte is not dependent on the expression of functional receptor in the target cell.

Cynthia N. Leary

Papers

Promotion of murine hepatocarcinogenesis by testosterone is androgen receptor-dependent but not cell autonomous