Helka Parviainen

FOG-2 and GATA-4 Are Coexpressed in the Mouse Ovary and Can Modulate Müllerian-Inhibiting Substance Expression

Abstract Transcription factor GATA-4 has been suggested to have a role in mammalian gonadogenesis, e.g., through activation of the Müllerian-inhibiting substance (MIS) gene expression. Although the expression of GATA-4 during gonadogenesis has been elucidated in detail, very little is known about FOG-2, an essential cofactor for GATA-4, in ovarian development. We explored in detail the expression of FOG-2 and GATA-4 in the fetal and postnatal mouse ovary and in the fetal testis using Northern blotting, RNA in situ hybridization, and immunohistochemistry. GATA-4 and FOG-2 are evident in the bipotential urogenital ridge, and their expression persists in the fetal mouse ovary; this result is different from earlier reports of GATA-4 downregulation in the fetal ovary. In contrast to ovary, FOG-2 expression is lost in the fetal Sertoli cells along with the formation of the testicular cords, leading to the hypothesis that FOG-2 has a specific role in the fetal ovaries counteracting the transactivation of the MIS gene by GATA-4. In vitro transfection assays verified that FOG-2 is able to repress the effect of GATA-4 on MIS transactivation in granulosa cells. In postnatal ovary, granulosa cells of growing follicles express FOG-2, partially overlapping with the expression of MIS. These data suggest an important role for FOG-2 and the GATA transcription factors in the developing ovary.

WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival

WNT4 plays an important role in female sexual development and ovarian function. WNT4-deficiency leads disturbed development of the internal genitalia in mouse and human, and to a dramatic reduction of mouse oocytes. However, the expression and role of WNT4 in human ovaries is yet unknown. The expression of WNT4 mRNA and protein was studied in human adult and fetal ovaries (gestational ages 12-41 weeks), and the role of WNT4 in oocyte apoptosis was investigated in WNT4-deficient mice. WNT4 mRNA and protein were present in human ovaries throughout fetal development and in different follicular stages in adult ovaries. Compared with wild-type mice, WNT4-deficient mice had a markedly enhanced rate of oocyte apoptosis, with the highest values at gestational ages of 14.5 and 16.5 days post-coitum. The current results support a view that WNT4 may have a role in oocyte selection and follicle formation and maturation in human ovaries.

GATA-4:FOG Interactions Regulate Gastric Epithelial Development in the Mouse

Transcription factor GATA‐4 is a key participant in cytodifferentiation of the mouse hindstomach. Here we show that GATA‐4 cooperates with a Friend‐of‐GATA (FOG) cofactor to direct gene expression in this segment of gut. Immunohistochemical staining revealed that GATA‐4 and FOG‐1 are co‐expressed in hindstomach epithelial cells from embryonic days (E) 11.5 to 18.5. The other member of the mammalian FOG family, FOG‐2, was not detected in gastric epithelium. To show that GATA‐4:FOG interactions influence stomach development, we analyzed Gata4ki/ki mice, which express a mutant GATA‐4 that cannot bind FOG cofactors. Sonic Hedgehog, an endoderm‐derived signaling molecule normally down‐regulated in the distal stomach, was over‐expressed in hindstomach epithelium of E11.5 Gata4ki/ki mice, and there was a concomitant decrease in fibroblast growth factor‐10 in adjacent mesenchyme. We conclude that functional interaction between GATA‐4 and a member of the FOG family, presumably FOG‐1, is required for proper epithelial‐mesenchymal signaling in the developing stomach. Developmental Dynamics 234:355–362, 2005.

GATA transcription factors in adrenal development and tumors

Of the six GATA transcription factors, GATA-4 and GATA-6 are expressed in the mouse and human adrenal with distinct developmental profiles. GATA-4 is confined to the fetal cortex, i.e. to the less differentiated proliferating cells, while GATA-6 is expressed both in the fetal and adult adrenal. In vitro, GATA-4 regulates inhibin-alpha and steroidogenic factor-1 implicated in normal adrenal function. GATA-6 probably has roles in the development and differentiation of adrenocortical cells, and in the regulation of steroidogenesis. GATA-4 expression is dramatically upregulated and GATA-6 downregulated in gonadotropin dependent mouse adrenocortical tumors. This is accompanied by the appearance of luteinizing hormone receptor (LHR). In vitro, GATA-4 transactivates LHR promoter, and gonadotropins upregulate GATA-4 levels. Human adrenal tumors occasionally express GATA-4, whereas GATA-6 levels are usually lower than normal.

Nude Mice as a Model for Gonadotropin‐Induced Adrenocortical Neoplasia

Certain inbred mice (e.g., DBA/2J, CE) develop sex steroid producing adrenocortical tumors following gonadectomy. This adrenal response is thought to result from an unopposed increase in circulating gonadotropins and/or a decrease in factor(s) of gonadal origin. To differentiate between these two possibilities, we utilized the NU/J strain of nude mice, which are immunologically compromised and therefore permissive to xenografts. One group of female nude mice was gonadectomized, while another group of females received xenografts of CHO cells stably transfected with human chorionic gonadotropin (hCG). After 1–2 months, subcapsular adrenocortical neoplasms containing sex steroid‐producing cells were observed in both groups. We conclude that high levels of circulating gonadotropins are sufficient to induce adrenocortical tumorigenesis, even in the presence of intact gonads.

Biliary Anomalies in Patients With HNF1B Diabetes

Context The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s) Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.

Neoadjuvant therapy offers longer survival than upfront surgery for poorly differentiated and higher stage pancreatic cancer

Abstract Background: Neoadjuvant therapy for pancreatic cancer remains controversial. Our aim was to assess differences in survival, disease recurrence and histopathological tumor characteristics between patients treated with neoadjuvant therapy followed by subsequent surgery and patients undergoing upfront surgery. Material and methods: Out of 399 consecutive pancreatic ductal adenocarcinoma (PDAC) patients operated at Helsinki University Hospital in 2000–2015, 75 borderline resectable patients were treated with neoadjuvant therapy. Resectable propensity scored patients (n = 150) underwent upfront surgery. Neoadjuvant therapy consisted of folfirinox, single gemcitabine or combined with cisplatin, nab-paclitaxel or capecitabine with or without radiation. Survival was calculated with Kaplan–Meier and compared with the Breslow test. Survival was determined from the start of treatment, being the first day of treatment for patients treated with neoadjuvant therapy and the date of surgery for others. Results: Between 2000 and 2015 median disease-specific survival (DSS) [34 vs. 26 months, p = .016] and disease-free survival (DFS) [22 vs. 13 months, p = .001] were longer in patients treated with neoadjuvant therapy than in those undergoing upfront surgery. Survival differences were not significant in the 2000s but were, in turn, among patients treated in the 2010s with better survival for patients treated with neoadjuvant therapy [DSS 35 vs. 26 months, p = .008 and DFS 25 vs. 13 months, p = .001]. Especially patients with poorly differentiated G3 tumors [DSS 30 vs. 11 months, p = .004 and DFS 21 vs. 7 months, p = .001] and higher stage IIB–III [DSS 34 vs. 20 months, p = .006 and DFS 21 vs. 10 months, p = .001] had longer survival when treated with neoadjuvant therapy. Conclusions: PDAC patients treated with neoadjuvant therapy had longer DSS and DFS than those undergoing upfront surgery. Neoadjuvant therapy benefits especially borderline resectable patients with higher stage and poorly differentiated tumors.