PROMOTION OF MURINE HEPATOCARCINOGENESIS BY TESTOSTERONE IS ANDROGEN RECEPTOR-DEPENDENT BUT NOT CELL AUTONOMOUS
PROMOTION OF MURINE HEPATOCARCINOGENESIS BY TESTOSTERONE IS ANDROGEN RECEPTOR-DEPENDENT BUT NOT CELL AUTONOMOUS
复制标题
DOI：
10.1073/pnas.86.19.7505
复制
发表时间：
1989-10-01
影响因子：
11.1
通讯作者：
DRINKWATER, NR
中科院分区：
文献类型：
--
作者：
KEMP, CJ;LEARY, CN;DRINKWATER, NR
睾丸雌性化突变小鼠缺乏功能性雄激素受体。通过对Tfm小鼠肝脏肿瘤发展的研究，我们发现雄性小鼠对N，N-二乙基亚硝胺诱导肝脏肿瘤的易感性高于雌性小鼠，这是雄激素受体依赖性的。C57BL/6J正常小鼠和Tfm突变小鼠在12日龄时注射N，N-二乙基亚硝胺（0.2 .mu）。Mol /g, i.p.)，并对50周龄动物的肝脏肿瘤进行计数。正常雄性平均每只动物20个肝脏肿瘤；男性：0.7；正常女性，0.6；杂合雌性Tfm/+， 1.5。雄激素受体基因和Tfm突变是X染色体相连的。由于随机X染色体失活，来自Tfm/+杂合雌性小鼠的肝细胞在突变型或野生型受体的表达方面是嵌合的。为了确定睾丸激素是通过肿瘤前肝细胞中的雄激素受体，还是通过间接机制直接作为肝肿瘤的促进剂，我们用睾丸激素长期治疗这些马赛克雌性小鼠，并测量所产生肿瘤的雄激素受体含量。B6C3F1Tfm/+马赛克型和+/+野生型雌性小鼠在12日龄时腹腔注射N，N-二乙基亚硝胺（0.1 .mu）。Mol /g)， 8周龄切除卵巢。随后，每组一半的小鼠接受双周s.c.注射睾酮（每只0.15 mg），持续30周。睾丸激素治疗的野生型和Tfm/+马赛克雌性小鼠的肿瘤多样性相同（38周龄时每只动物有31-32个肿瘤），相对于未接受睾丸激素治疗的雌性小鼠（50周龄时每只动物有13-17个肿瘤），肿瘤多样性有所增加。睾酮治疗并没有显著增加Tfm/+马赛克雌性中雄激素受体阳性肿瘤的百分比：接受睾酮治疗的Tfm/+马赛克雌性中有58%的肿瘤受体阳性，而未接受睾酮治疗的Tfm/+雌性为48%，接受睾酮治疗的野生型雌性为92%。最后，与周围正常肝组织相比，大多数肝脏肿瘤中雄激素受体的数量大大减少。我们得出结论，睾酮促进肝脏肿瘤的发生需要在完整的动物中有一个功能性的雄激素受体。然而，这种提升不是细胞自主的；也就是说，肿瘤前肝细胞的反应不依赖于靶细胞中功能受体的表达。
Tfm (testicular feminization) mutant mice lack functional androgen receptors. By studing 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 .mu.mol/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 mechanim, we chronically treated these mosaic female mice with testosterone and measured the androgen receptor content of the resulting tumors. B6C3F1Tfm/+ mosaic and +/+ wild-type female mice were injected i.p. at 12 days of age with N,N-diethylnitrosamine (0.1 .mu.mol/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.