Estrogen may mediate low incidence of HCC in women

By Ingrid Grasmo

Study findings suggest that estrogen may have a suppressive effect on hepatocellular carcinoma (HCC), potentially explaining its lower incidence in women.

HCC is the fifth most common malignancy worldwide and occurs predominantly in men, who are more likely to develop the condition and have a worse prognosis than women.

"Our results provide direct evidence of the important role of oestrogen in live tumour growth and its contribution to the gender disparity in HCC progression," say Pingping Shen (Nanjing University, China) and colleagues.

To investigate the role of estrogen in HCC progression, the team developed an orthotopic homograft tumor model by implanting H22 cells into the livers of mice. In addition, male and female mice were castrated and estrogen treatment was administered.

Pathologic analysis of mice after H22 implantation showed that males exhibited a shorter lifespan, larger tumor volume, and lower serum alpha-fetoprotein (AFP) compared with females.

Castration of male mice had no significant impact on tumor growth, whereas ovariectomy in female mice significantly increased tumor volume.

Administration of estrogen in H22-implanted mice models significantly reduced tumor weight in both castrated and noncastrated male mice and ovariectomized females.

"These results suggest that oestrogen, rather than androgen, may potentially play an important role in gender disparity during HCC progression," say the researchers.

Since tumor malignancy is closely related to tumor cell proliferation, invasion, and apoptosis, the team then used immunohistochemical analyses to measure levels of related proteins. They found decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, proliferating cell nuclear antigen, cyclin A, cyclin D1, and Bcl-2, in addition to increased expression of cleaved caspase 3.

Analysis of results from two cell lines confirmed the observed changes in expression of these proteins and indicated that the estrogen receptor α-mediated inhibition of nuclear factor kappa-B (NF-κB) binding activity was a crucial event in the process.

Indeed, estrogen treatment decreased the DNA-binding activity of NF-κB. The researchers suggest that estrogen begins the signaling cascade by activating estrogen receptor α, which downregulates NF-κB activity, and in turn affects the expression of downstream targets and ultimately results in inhibition of tumor growth, invasion, and induction of apoptosis.

"Taken together, our data demonstrate that estrogen plays a dominant role in gender disparity during HCC progression," conclude the researchers in the Journal of Pathology.

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