The transcription factor FOXE1 is a key player in thyroid development and function and 19 has been identified by genome-‐‑wide association studies as susceptibility gene for papillary thyroid 20 cancer. Several cancer-‐‑associated polymorphisms fall into gene regulatory regions and are likely to 21 affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression 22 modulate thyroid cancer development has not been investigated. Here we describe the effects of 23 Foxe1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for Foxe1 null allele 24 (Foxe+/-‐‑) were crossed with a BrafV600E-‐‑inducible cancer model to develop thyroid cancer in either 25 Foxe1+/+ or Foxe1+/-‐‑ genetic background. In Foxe1+/+ mice cancer histological features are quite similar 26 to that of human high-‐‑grade papillary thyroid carcinomas, while cancers developed with reduced 27 Foxe1 gene dosage maintain morphological features resembling less malignant thyroid cancers, 28 showing reduced proliferation index and increased apoptosis as well. Such cancers, however, 29 appear severely undifferentiated, indicating that Foxe1 levels affect thyroid differentiation during 30 neoplastic transformation. These results show that Foxe1 dosage exerts pleiotropic effects on 31 thyroid cancer phenotype, by affecting histology and regulating key markers of tumor 32 differentiation and progression, thus suggesting the possibility that FOXE1 could behave as 33 lineage-‐‑specific oncogene in follicular cell-‐‑derived thyroid cancer.
Foxe1 gene dosage affects thyroid cancer histology and differentiation in vivo
Credendino S. C.;Amendola E.;De Felice M.;
2020
Abstract
The transcription factor FOXE1 is a key player in thyroid development and function and 19 has been identified by genome-‐‑wide association studies as susceptibility gene for papillary thyroid 20 cancer. Several cancer-‐‑associated polymorphisms fall into gene regulatory regions and are likely to 21 affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression 22 modulate thyroid cancer development has not been investigated. Here we describe the effects of 23 Foxe1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for Foxe1 null allele 24 (Foxe+/-‐‑) were crossed with a BrafV600E-‐‑inducible cancer model to develop thyroid cancer in either 25 Foxe1+/+ or Foxe1+/-‐‑ genetic background. In Foxe1+/+ mice cancer histological features are quite similar 26 to that of human high-‐‑grade papillary thyroid carcinomas, while cancers developed with reduced 27 Foxe1 gene dosage maintain morphological features resembling less malignant thyroid cancers, 28 showing reduced proliferation index and increased apoptosis as well. Such cancers, however, 29 appear severely undifferentiated, indicating that Foxe1 levels affect thyroid differentiation during 30 neoplastic transformation. These results show that Foxe1 dosage exerts pleiotropic effects on 31 thyroid cancer phenotype, by affecting histology and regulating key markers of tumor 32 differentiation and progression, thus suggesting the possibility that FOXE1 could behave as 33 lineage-‐‑specific oncogene in follicular cell-‐‑derived thyroid cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
