BACKGROUND AND AIM: While gender differences in @entity157 ( @entity157 ) are profound, the mechanism is unclear. Using castration and hormone replacement strategies, we tested whether these gender differences are attributable to @entity251 or @entity53 / @entity1420 (E/P) effects on cell cycle regulators and @entity899 . METHODS: We studied dysplastic liver and HCCs in intact and castrated @entity107 ( @entity108 )-injected C57BL/6J male and female @entity19 , with or without hormonal replacement. Effects of sex @entity230 on proliferation and survival of primary hepatocytes and primary @entity157 cells were also characterized. RESULTS: @entity108 -injected females displayed fewer @entity7905 and slower onset of @entity157 than males, with smaller/more differentiated @entity5 and fewer @entity3 . Castration of @entity108 -injected males reduced cyclin E kinase and augmented hepatocyte apoptosis compared with intact males; E/P enhanced these effects. In intact females, cyclin E kinase activity was less than in males; @entity251 administered to ovariectomized females up-regulated cyclin E, increased cyclin E kinase and accelerated hepatocarcinogenesis. In vitro, @entity251 increased expression of cell cycle regulators ( @entity1896 , cyclin E and @entity17068 ) and reduced @entity899 and @entity5207 , which enhanced hepatocyte viability. In contrast, @entity53 both suppressed hepatocyte cell cycle markers, up-regulated @entity899 and reduced viability of hepatocytes and @entity157 cells. CONCLUSIONS: @entity251 is the positive regulator of hepatocyte cell cycle via cyclin E, while @entity53 plays a negative role by effects of @entity899 and @entity5207 . Together, both sex hormones determine the male predominance of gender differences in hepatocarcinogenesis.

XXXX regulation of cyclin E kinase is a key factor determining gender differences in hepatocarcinogenesis.

@entity1896 :: ('12443(Tax:10090)', 'Gene') :: ['cyclin D1'] @entity251 :: ('MESH:D013739', 'Chemical') :: ['testosterone', 'Testosterone'] @entity108 :: ('CHEBI:34873', 'Chemical') :: ['DEN'] @entity1420 :: ('MESH:D011374', 'Chemical') :: ['progesterone'] @entity899 :: ('22060(Tax:10090)', 'Gene') :: ['p53'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity107 :: ('MESH:D004052', 'Chemical') :: ['diethylnitrosamine'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumors'] @entity7905 :: ('MESH:C565785', 'Disease') :: ['dysplastic foci'] @entity53 :: ('MESH:D004958', 'Chemical') :: ['estradiol'] @entity5207 :: ('12575(Tax:10090)', 'Gene') :: ['p21'] @entity3 :: ('MESH:D009362', 'Disease') :: ['metastases'] @entity230 :: ('MESH:D013256', 'Chemical') :: ['steroids'] @entity157 :: ('MESH:D006528', 'Disease') :: ['HCC', 'hepatocellular carcinoma'] @entity17068 :: ('12566(Tax:10090)', 'Gene') :: ['cyclin-dependent kinase 2']
@entity251 :: (MESH:D013739,Chemical) :: ['Testosterone']
