RESUMO
OBJECTIVE: To identify the transcriptomic changes of ectopic lesions and eutopic endometrial tissues during the progression of endometriosis, we performed transcriptomic analysis in the eutopic endometrium and ectopic lesions. DESIGN: Laboratory study. SETTING: Academic medical center. ANIMALS: Four fertile and 4 subfertile Pgrcre/+Rosa26mTmG/+ mice with endometriosis, and 4 sham mice for each group of endometriosis mice as control. These mice underwent either surgery to induce endometriosis or sham surgery. Fertile sham and mice with endometriosis were used 1 month after surgery, whereas subfertile ones were used 3 months after surgery. INTERVENTIONS: Early and chronic effects of endometriosis on transcriptomics of ectopic lesions and eutopic endometrium. MAIN OUTCOME MEASURES: RNA-sequencing analysis and identification of differentially expressed genes and pathways in the ectopic lesions and eutopic uteri from mice with endometriosis and sham mice at day 3.5 of pregnancy. RESULTS: Our mouse model recapitulates the transcriptomic changes of ectopic lesions in humans. RNA-sequencing analysis was performed in ectopic lesions and eutopic uteri from mice with or without endometriosis during the progression of the disease. Estrogen activity, inflammation, angiogenesis, and fibrosis pathways were consistently elevated in all the ectopic lesions compared with eutopic endometrium. Cholesterol/glucose synthesis and stem cell pluripotency pathways were more enhanced in ectopic lesions from subfertile mice compared with their eutopic endometrium. Dysregulation of infiltration of macrophage, dendritic, T and B cells was validated with the use of immunohistochemistry in ectopic lesions. Multiple ligand-receptor pairs between the ectopic and eutopic endometrium were altered compared with the sham endometrium. Suppressed WNT and EGF pathways were only found in the eutopic endometrium from subfertile not fertile mice compared with sham. CONCLUSIONS: Our mouse endometriosis model recapitulates the transcriptomics of ectopic lesions in humans. Our transcriptomic analysis during endometriosis progression in our mouse model will help us understand the pathophysiology of endometriosis.
Assuntos
Modelos Animais de Doenças , Progressão da Doença , Endometriose , Endométrio , Transcriptoma , Animais , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Feminino , Camundongos , Endométrio/metabolismo , Endométrio/patologiaRESUMO
Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgrcre/+Erbb2f/fPtenf/f (Erbb2d/d Ptend/d) was developed to evaluate the effect of ERBB2 targeted therapy in endometrial cancer with PTEN deficiency. Histopathological and molecular analysis was performed for Ptend/d and Erbb2d/dPtend/d mice. Histopathological analysis revealed that Erbb2d/dPtend/d mice significantly reduced development and progression of endometrial cancer compared to Ptend/d mice. Furthermore, percentage of proliferative cells in Erbb2d/dPtend/d mice revealed anti-tumorigenic effect of Erbb2 ablation compared to Ptend/d mice. Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Ptend/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Ptend/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.
Assuntos
Carcinogênese , Neoplasias do Endométrio , Mutação , PTEN Fosfo-Hidrolase , Receptor ErbB-2 , Feminino , Animais , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Camundongos , Carcinogênese/genética , Modelos Animais de Doenças , Proliferação de CélulasRESUMO
Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.