SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer latency following developmental estrogenic chemical exposure
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PROVIDER: PRJNA576206 | ENA |
REPOSITORIES: ENA
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Project description:Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal (cytokeratin [CK]14+/18-) and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1d/d). Interestingly, corn oil (CO) vehicle treated Six1d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wildtype Six1 (Six1+/+) mice. Furthermore, Six1d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1+/+ mice. While DES Six1d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1+/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. We have employed whole genome microarray expression profiling as a discovery platform to identify genes associated with the phenotypic changes described above. Expression of three genes (Ihh, Krt14, and Trp63) were quantified by real-time PCR, confirming low variability between samples as well as the predicted response pattern.
2019-10-15 | GSE138501 | GEO
Project description:Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK)14+/18-] and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1 d/d). Interestingly, corn oil (CO) vehicle-treated Six1 d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wild-type Six1 (Six1 +/+) mice. Furthermore, Six1 d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1 +/+ mice. Although DES Six1 d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1 +/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14+/18+ cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14+/18+ cells. In human endometrial biopsies, 35% of malignancies showed CK14+/18+ expression, which positively correlated with tumor stage and grade and was not present in normal endometrium. IMPLICATIONS: Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14+/18+ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.
| S-EPMC6891210 | biostudies-literature
Project description:Six1-null mice display developmental defects in the inner ear associated to aberrant senescence. To understand the molecular basis of this phenotype, here we investigated gene expression profiles of otic vesicles from Six1-null and wild-type embryos at developmental stage E10.5.
2023-04-20 | GSE193334 | GEO
Project description:Investigating genomic binding of SIX1 in A673 cells transduced with shSCR or one of two shSIX1 shRNAs to deplete SIX1.
2023-05-22 | GSE215350 | GEO
Project description:Investigating genomic binding of SIX1 in EWS-502 cells transduced with shSCR or one of two shSIX1 shRNAs to deplete SIX1.
2023-05-22 | GSE233118 | GEO
Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
2023-03-10 | GSE216760 | GEO
Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
2023-03-10 | GSE216759 | GEO
Project description:The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with tumor progression and metastasis. We previously determined that the expression of Six1 mRNA increased during in vitro progression of human papillomavirus type 16 (HPV16)-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. However, if Six1 promotes HPV16-mediated transformation or not remains unknown. HKc/DR were transfected with a Six1 or control vector and RNA isolated from these cells were used in an Agilent two-color gene expression profiling experiment. The goal was to determine the effects of Six1 on global gene expression. Two-condition experiment, Six1 vs. Control HKc/DR cells. Biological replicates: 4 Six1-transfected replicates and 4 control-transfected replicates.
2013-12-24 | E-GEOD-53589 | biostudies-arrayexpress
Project description:The homeodomain transcription factor SIX1 plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical cancer. SIX1 drives the progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward malignancy: HKc/HPV16 express high levels of SIX1 mRNA and protein; overexpression of SIX1 in HKc/HPV16 produces pre-malignant, differentiation-resistant lines (HKc/DR); SIX1 overexpression in HKc/DR induces tumorigenicity. In this paper, we explore the consequences of inhibition of SIX1 expression in premalignant HKc/DR. Only partial inhibition of SIX1 expression could be obtained in HKc/DR by RNA interference. Decreased SIX1 expression (up to 80%) in HKc/DR resulted in slower proliferation, decreased HPV16-E6/E7 mRNA levels, and increased p53 protein levels. Gene expression changes induced in HKc/DR by anti-SIX1 shRNA were indicative of mesenchymal-epithelial transition (EMT) and changes in TGF-beta signaling. We conclude that HPV16-transformed cells depend on SIX1 for survival, continuous HPV16 E6/E7 gene expression and EMT.
2019-08-20 | GSE126926 | GEO