APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression
Abstract Background Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pat...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-019-5867-y |
| _version_ | 1818217818357760000 |
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| author | Noha-Ehssan Mohamed Trevor Hay Karen R. Reed Matthew J. Smalley Alan R. Clarke |
| author_facet | Noha-Ehssan Mohamed Trevor Hay Karen R. Reed Matthew J. Smalley Alan R. Clarke |
| author_sort | Noha-Ehssan Mohamed |
| collection | DOAJ |
| description | Abstract Background Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. Methods A detailed analysis of ovarian histology, gene expression, ovulation and hormone levels was carried out in 10 week old and in aged constitutive APC2-knockout (Apc2 −/−) mice (mixed background). Statistical significance for qRT-PCR data was determined from 95% confidence intervals. Significance testing was performed using 2-tailed Student’s t-test, when 2 experimental cohorts were compared. When more were compared, ANOVA test was used, followed by a post-hoc test (LSD or Games-Howell). P-values of < 0.05 were considered statistically significant. Results APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. Conclusions Our work adds APC2 to the growing list of WNT-signalling members that regulate ovarian homeostasis, fertility and suppress GCT formation. Importantly, given that the APC2-deficient mouse develops tumours that recapitulate the molecular signature and histological features of human adult GCTs, this mouse has excellent potential as a pre-clinical model to study ovarian subfertility and transitioning to GCT, tumour biology and for therapeutic testing. |
| first_indexed | 2024-12-12T07:13:54Z |
| format | Article |
| id | doaj.art-a3dbe4dd62544d03a2a0e349a57e5ed3 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-12T07:13:54Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-a3dbe4dd62544d03a2a0e349a57e5ed32022-12-22T00:33:33ZengBMCBMC Cancer1471-24072019-07-0119111610.1186/s12885-019-5867-yAPC2 is critical for ovarian WNT signalling control, fertility and tumour suppressionNoha-Ehssan Mohamed0Trevor Hay1Karen R. Reed2Matthew J. Smalley3Alan R. Clarke4European Cancer Stem Cell Research Institute, Cardiff University School of BiosciencesEuropean Cancer Stem Cell Research Institute, Cardiff University School of BiosciencesEuropean Cancer Stem Cell Research Institute, Cardiff University School of BiosciencesEuropean Cancer Stem Cell Research Institute, Cardiff University School of BiosciencesEuropean Cancer Stem Cell Research Institute, Cardiff University School of BiosciencesAbstract Background Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. Methods A detailed analysis of ovarian histology, gene expression, ovulation and hormone levels was carried out in 10 week old and in aged constitutive APC2-knockout (Apc2 −/−) mice (mixed background). Statistical significance for qRT-PCR data was determined from 95% confidence intervals. Significance testing was performed using 2-tailed Student’s t-test, when 2 experimental cohorts were compared. When more were compared, ANOVA test was used, followed by a post-hoc test (LSD or Games-Howell). P-values of < 0.05 were considered statistically significant. Results APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. Conclusions Our work adds APC2 to the growing list of WNT-signalling members that regulate ovarian homeostasis, fertility and suppress GCT formation. Importantly, given that the APC2-deficient mouse develops tumours that recapitulate the molecular signature and histological features of human adult GCTs, this mouse has excellent potential as a pre-clinical model to study ovarian subfertility and transitioning to GCT, tumour biology and for therapeutic testing.http://link.springer.com/article/10.1186/s12885-019-5867-yAPC2APC hypomorphWNT signallingOvarian fertilityOvarian cancerGranulosa cell tumour |
| spellingShingle | Noha-Ehssan Mohamed Trevor Hay Karen R. Reed Matthew J. Smalley Alan R. Clarke APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression BMC Cancer APC2 APC hypomorph WNT signalling Ovarian fertility Ovarian cancer Granulosa cell tumour |
| title | APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression |
| title_full | APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression |
| title_fullStr | APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression |
| title_full_unstemmed | APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression |
| title_short | APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression |
| title_sort | apc2 is critical for ovarian wnt signalling control fertility and tumour suppression |
| topic | APC2 APC hypomorph WNT signalling Ovarian fertility Ovarian cancer Granulosa cell tumour |
| url | http://link.springer.com/article/10.1186/s12885-019-5867-y |
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