Fig 1: Regulation of NR5A2 activity by LGR4 mediated canonical WNT/CTNNB1 signaling pathway. (A) The mRNA levels of Cyp11a1 and Hsd3b1 in the WT and LGR4 mutant oviducts at the estrus stage. (B) Diagram of conserved NR5A1/2 binding sites in the Cyp11a1 and Hsd3b1 promoters predicted in silico. (C) IHC assays to detect the NR5A2 protein location in the WT or Lgr4-deficient oviducts. (D) IHC assays to detect the CTNNB1 protein level in the WT or Lgr4-deficient oviducts. (E) The mRNA levels of WNT target genes in WT and LGR4 mutant oviducts at estrus stage. (F) The chromatin of primary oviductal epithelial cells from WT or Lgr4 mutant mice was immunoprecipitated with a NR5A2 antibody. Immunoprecipitated DNA was amplified with the sets of specific primers for the indicated NR5A2 binding sites in Cyp11a1 and Hsd3b1 promoters (upper panel). The relative fold change of Cyp11a1 and Hsd3b1 genes of the primary oviductal epithelial cells after the treatment of WNT4/RSPO2 or CT99201 (lower panel) are presented. *p = 0.05; **p = 0.01; ***p = 0.001. Scale bar, 50 µm in (C,D). IHC, immunohistochemistry.
Fig 2: Histopathological and immunohistochemical features of the case report (see text for details). HE: 10× (left) and 20× (right) magnification; IHC: 20× magnification. HE, haematoxylin-eosin; a-SMA, a-smooth muscle actin; SF1, steroidogenic factor-1; OCT-4, octamer-binding transcription factor 4; SALL-4, Sal-like protein 4.
Fig 3: Diagram of the tumor origin and differentiation status of PitNETThe top yellow box, middle green box, and bottom brown box represent TPIT, PIT1, and SF1 lineage, respectively. The left panel represents the self-renewal trajectory of adult APG. The middle and right panels represent PitNETs in well and poorly differentiation status, respectively. The solid line represents the development process of endocrine cells in adult APG. The dashed line represents the potential tumorigenesis process of PitNET. The markers were annotated below each APG or PitNET subtype. Characteristics of each tumor subtype are listed below the diagram, with higher recurrence subtypes emphasized in bold red font. The speculated Pre.TPIT and Pre.SF1 are labeled with gray dashed line circles since they were not detected in our study.
Fig 4: The recurrence prediction capability of Ki-67 index for PitNET was stratified by the new differentiation classification(A) Cox regression survival analyses reveal the recurrence predictive values of multiple factors in three lineages. HR, hazard ratios; N, number of patients; *p < 0.05, **p < 0.01, ***p < 0.001.(B–D) Kaplan-Meier PFS curves for PIT1 lineage tumors (B), silent TPIT tumors (C), and SF1 lineage tumors (D) stratified by Ki-67 index. The p value was calculated by the log rank test.(E–G) Kaplan-Meier PFS curves for patients with PIT1 lineage tumors (E), silent TPIT tumors (F), and SF1 lineage tumors (G) stratified by differentiation status and Ki-67 index. The p value was calculated by the log rank test.(H) Recurrence prediction value of differentiation status and Ki-67 index in each lineage. n.s., not significant.
Fig 5: The differentiation status was related to long-term recurrence in an independent cohort of 800 patients(A) Heatmap showing IHC staining intensities in an independent cohort of 800 PitNETs.(B–D) Scatterplot showing the NTS H score (x axis) versus the PRL H score (y axis) (B), serum PRL concentration (ng/mL) (y axis) (C), and DRD2 H score(y axis) (D) in 115 pathologically PRL-positive tumors, respectively. The p value was calculated by Spearman’s correlation analysis.(E and F) Kaplan-Meier PFS curves for 220 patients with PIT1 lineage tumors (E) and 61 patients with silent TPIT tumors (F) stratified by differentiation marker expression. The p value was calculated by the log rank test.(G) The bar plot shows the gender proportion between well and poorly differentiated silent TPIT tumors. The p value was calculated by Fisher exact test.(H) Kaplan-Meier PFS curves for 83 patients with silent TPIT tumors stratified by gender. The p value was calculated by the log rank test.(I) Kaplan-Meier PFS curves for 281 patients with SF1 lineage tumors stratified by differentiation marker expression. The p value was calculated by the log rank test. See also Figure S11.
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