Abstract
Granulosa cell tumors (GCTs) are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs.
Highlights
Granulosa cell tumors (GCTs) account for 5–8% of all ovarian cancers [1]
Western blot results showed that the KGN cells and human granulosa cells had similar patterns of expression of the ErbB family members, with EGF receptor (EGFR) as the predominant receptor in these cells
In another proven GCT cell line, COV434 cells [46], the expression of ErbB3 and ErbB4 was dominant compared to EGFR and ErbB2 (Figure 1B)
Summary
Granulosa cell tumors (GCTs) account for 5–8% of all ovarian cancers [1]. GCTs present many features typical of normal granulosa cells. They express the FSH receptor gene, secret inhibins and produce estrogen [2,3]. GCTs are often slow to develop and have a propensity for late recurrence [5,6]. These tumors have malignant potential and about 50% of cases are diagnosed with metastases [7,8]. The mechanisms underlying GCT initiation, progression, recurrence and metastasis are unknown
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