Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells.

Minqian Shen,Haifei Shi

doi:10.1371/journal.pone.0151455

Abstract

Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 β-estradiol (E2), estrogen receptor-α (ER-α) selective agonist PPT, ER-β selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-β mRNA, and leptin treatment increased ER-β expression. E2 suppressed leptin-induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-β. E2 also enhanced ERK via activating ER-α and GPER and activated p38/MAPK via activating ER-β. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-β, and increasing ERK by activating ER-α and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is the most common primary carcinoma in the liver and the fourth most common cancer worldwide with high malignancy
We demonstrated that E2 attenuated leptin-induced HepG2 growth associated with suppressing proliferation and promoting apoptosis, interfering leptin-induced signal transducers and activators of transcription 3 (STAT3) and leptinsuppressed suppressor of cytokine signaling proteins 3 (SOCS3), and increasing ERK and p38/MAPK signaling
Leptin increased whereas the highest dose of E2 tested (1000 nM) decreased the numbers of HepG2 cells compared with control treatment (Fig 1A and 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary carcinoma in the liver and the fourth most common cancer worldwide with high malignancy. The incidence and mortality rate of HCC continue to increase in the USA [1]. The common risk factors of developing HCC. Antioncogenic Action of Estrogens and Estrogen Receptors include obesity, nonalcoholic fatty liver disease, chronic alcohol consumption, viral hepatitis infection, cirrhosis, and aflatoxin exposure. Among the aforementioned risk factors, the rapid increase in obesity has become the prime cause of HCC, outweighing alcohol- or virus-related etiology [2]. Epidemiological and clinical studies indicate that people with a body mass index (BMI) over 35 have greater risk for developing HCC, and obesity can precipitate other risk factors for HCC [3,4,5]

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