Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

FSH, acting through multiple signaling pathways, regulates the proliferation and growth of granulosa cells, which are critical for ovulation. The present study investigated whether AMP-activated protein kinase (AMPK), which controls the energy balance of the cell, plays a role in FSH-mediated increase in granulosa cell proliferation. Cells isolated from immature rat ovaries were grown in serum-free, phenol red free DMEM-F12 and were treated with FSH (50 ng/ml) for 0, 5, and 15 min. Western blot analysis showed a significant reduction in AMPK activation as observed by a reduction of phosphorylation at thr 172 in response to FSH treatment at all time points tested. FSH also reduced AMPK phosphorylation in a dose-dependent manner with maximum inhibition at 100 ng/ml. The chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, 0.5 mm) increased the cell cycle inhibitor p27 kip expression significantly, whereas the AMPK inhibitor (compound C, 20 μm) and FSH reduced p27kip expression significantly compared with control. FSH treatment resulted in an increase in the phosphorylation of AMPK at ser 485/491 and a reduction in thr 172 phosphorylation. Inhibition of Akt phosphorylation using Akt inhibitor VIII reversed the inhibitory effect of FSH on thr 172 phosphorylation of AMPK, whereas ERK inhibitor U0126 had no effect. These results show that FSH, through an Akt-dependent pathway, phosphorylates AMPK at ser 481/495 and inhibits its activation by reducing thr 172 phosphorylation. AMPK activation by 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment resulted in a reduction of cell cycle regulatory protein cyclin D2 mRNA expression, whereas FSH increased the expression by 2-fold. These results suggest that FSH promotes granulosa cell proliferation by increasing cyclin D2 mRNA expression and by reducing p27 kip expression by inhibiting AMPK activation through an Akt-dependent pathway. FSH stimulates granulosa cell proliferation by reducing cell cycle inhibitor p27 kip through AMP kinase inhibition.

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FOXL2 and TERT promoter mutation detection in circulating tumor DNA of adult granulosa cell tumors as biomarker for disease monitoring

Gynecologic Oncology ◽

10.1016/j.ygyno.2021.05.027 ◽

2021 ◽

Author(s):

Jolijn W. Groeneweg ◽

Joline F. Roze ◽

Edith D.J. Peters ◽

Ferdinando Sereno ◽

Anna G.J. Brink ◽

...

Keyword(s):

Granulosa Cell ◽

Mutation Detection ◽

Circulating Tumor Dna ◽

Disease Monitoring ◽

Tert Promoter Mutation ◽

Promoter Mutation ◽

Granulosa Cell Tumors ◽

Tert Promoter ◽

Tumor Dna

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Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22042047 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2047

Author(s):

Nina Schmid ◽

Kim-Gwendolyn Dietrich ◽

Ignasi Forne ◽

Alexander Burges ◽

Magdalena Szymanska ◽

...

Keyword(s):

Cell Proliferation ◽

Granulosa Cell ◽

Granulosa Cells ◽

Drug Targets ◽

Growth Regulation ◽

Sirtuin 1 ◽

Ki 67 ◽

Granulosa Cell Tumors ◽

Novel Drug

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

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In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Cancers ◽

10.3390/cancers13030368 ◽

2021 ◽

Vol 13 (3) ◽

pp. 368

Author(s):

Joline Roze ◽

Elena Sendino Garví ◽

Ellen Stelloo ◽

Christina Stangl ◽

Ferdinando Sereno ◽

...

Keyword(s):

Granulosa Cell ◽

Cell Lines ◽

Combination Treatment ◽

Drug Testing ◽

Drug Application ◽

Hormonal Treatment ◽

Patient Specific ◽

Granulosa Cell Tumors ◽

Potential Synergy

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.

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Diagnostic and Prognostic Significance of Keap1 mRNA Expression for Lung Cancer Based on Microarray and Clinical Information from Oncomine Database

Current Medical Science ◽

10.1007/s11596-021-2378-2 ◽

2021 ◽

Author(s):

Guang-ya Liu ◽

Wei Zhang ◽

Xu-chi Chen ◽

Wen-juan Wu ◽

Shi-qian Wan

Keyword(s):

Lung Cancer ◽

Mrna Expression ◽

Prognostic Significance ◽

Clinical Information ◽

Oncomine Database

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Multiple recurrence of granulosa cell tumor of the ovary: A case report and literature review

10.1055/s-0039-1685319 ◽

2016 ◽

Author(s):

Varkha Chandra ◽

Sandhya Jain ◽

Neerja Goel ◽

Bindia Gupta ◽

Shalini Rajaram

Keyword(s):

Case Report ◽

Granulosa Cell ◽

Adnexal Mass ◽

Malignant Tumors ◽

Abdominal Mass ◽

Pelvic Mass ◽

Granulosa Cell Tumor ◽

Cell Tumor ◽

Surgical Staging ◽

Granulosa Cell Tumors

Introduction: Granulosa cell tumors comprise approximately 5% of all ovarian malignancy and account for 70% of malignant sex cord stromal tumors. Granulosa cell tumors have been diagnosed from infancy, the peak incidence being perimenopausal age. The potential of malignancy of these tumors is low, recurrences are often late and found in 10-33% of cases. Case Report: A 32-year-old P1L1 presented with large abdominal mass for which she underwent staging laparotomy with debulking surgery. She was a known case of granulosa cell tumor in the past and had undergone three laparotomies, along with chemotherapy. At the age of 13 yrs, she was diagnosed with a stage IA granulosa cell tumor (GCT) of the ovary first time. She underwent surgical staging and removal of left sided adnexal mass, after which she was asymptomatic for 7 years. In 2003 she again presented with lump abdomen for which she underwent resection of adnexal mass, histopathology was consistent with recurrent GCT. After second surgery she also received two cycles of chemotherapy. Despite adjuvant chemotherapy, patient presented again after three years in 2006 with adnexal mass and was found to have a third recurrence. At that time, she received 6 cycles of chemotherapy and the mass regressed. Meanwhile she got married and had one child. After four year in 2010 she again presented with lump abdomen and she underwent surgical staging, total abdominal hysterectomy with right salphingo ophorectomy along with removal of mass. After five year in 2015 she again presented with lump abdomen; there was a large pelvic mass which was removed and patient referred for chemotherapy. Discussion: GCTS which a rare malignant tumors of ovary tend to be associated with late recurrences. Although most recurrences occurs within 10 years after initial diagnosis, there are occasional reports of recurrences after10 years. We experienced the rare case of a patient who relapsed multiple times over 20 years, despite surgical and targeted treatment. Conclusion: The long history of granulosa cell tumor highlights the importance of extended follow up of the patient.

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Bilateral juvenile granulosa cell tumors in a 4-month-old dysmorphic infant

The American Journal of Surgical Pathology ◽

10.1097/00000478-198112000-00008 ◽

1981 ◽

Vol 5 (8) ◽

pp. 789-795 ◽

Cited By ~ 20

Author(s):

Theodore J. Pysher ◽

David C. Hitch ◽

Henry F. Krous

Keyword(s):

Granulosa Cell ◽

Granulosa Cell Tumors

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