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Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis.

ABSTRACT: Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is difficult to diagnose as it can be confounded with other cystic lung disorders, such as congenital pulmonary airway malformation (CPAM). PPB is associated with mutations in DICER1 that perturb the microRNA (miRNA) profile in lung. How DICER1 and miRNAs act during PPB pathogenesis remains unsolved. Lung epithelial deletion of the Yin Yang1 (Yy1) gene in mice causes a phenotype mimicking the cystic form of PPB and affects the expression of key regulators of lung development. Similar changes in expression were observed in PPB but not in CPAM lung biopsies, revealing a distinctive PPB molecular signature. Deregulation of molecules promoting epithelial-mesenchymal transition (EMT) was detected in PPB specimens, suggesting that EMT might participate in tumor progression. Changes in miRNA expression also occurred in PPB lung biopsies. miR-125a-3p, a candidate to regulate YY1 expression and lung branching, was abnormally highly expressed in PPB samples. Together, these findings support the concept that reduced expression of YY1, due to the abnormal miRNA profile resulting from DICER1 mutations, contributes to PPB development via its impact on the expression of key lung developmental genes.This article has an associated First Person interview with the joint first authors of the paper.

SUBMITTER: Landry-Truchon K

PROVIDER: S-EPMC7790197 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis.

Landry-Truchon Kim K Houde Nicolas N Lhuillier Mickaël M Charron Louis L Hadchouel Alice A Delacourt Christophe C Foulkes William D WD Galmiche-Rolland Louise L Jeannotte Lucie L

Disease models & mechanisms 20201106 12

Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is difficult to diagnose as it can be confounded with other cystic lung disorders, such as congenital pulmonary airway malformation (CPAM). PPB is associated with mutations in DICER1 that perturb the microRNA (miRNA) profile in lung. How DICER1 and miRNAs act during PPB pathogenesis remains unsolved. Lung epithelial de ...[more]

PMID: 33158935

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Project description:DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

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Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis.

Publications

Deletion of <i>Yy1</i> in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis.

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