Maintenance of the bladder cancer precursor urothelial hyperplasia requires FOXA1 and persistent expression of oncogenic HRAS

Abstract

Tumorigenesis requires accumulation of genetic and epigenetic alterations, some of which drive tumor initiation. “Oncogene addiction” describes the phenomenon that (1) well-established cancers are dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype and that (2) withdrawal of the single oncogenic event leads to growth arrest and/or cancer regression. While oncogene addiction has been experimentally validated in advanced tumor models, its role in tumor precursors has not been investigated. We utilized the requirement of Forkhead box A1 (Foxa1) for transcriptional activation of the Upk2-promoter to temporally control the expression of Upk2-HRAS* oncogene, an inducer of urothelial hyperplasia in transgenic mice. Inducible homozygous knockout of Foxa1 in Upk2-HRAS*/UBC-CreERT2/Foxa1loxp/loxp mice results in reduced HRAS* levels. This led to a marked reduction of urothelial proliferation as evidenced by urothelial thinning, degenerative changes such as intracellular vacuole formation, and reduced Ki67 expression. Reduced proliferation did not affect basal, Krt14-positive cells, supporting the fact that Foxa1-regulated Upk2-HRAS* expression occurs primarily in supra-basal cells. Our results indicate that maintenance of urothelial hyperplasia in Upk2-HRAS* mice depends on continuous expression of Foxa1 and activated HRAS, and that mutated receptor tyrosine kinases, FOXA1 and/or other downstream effectors may mediate oncogene addiction in urothelial hyperplasia.

Proposing Specific Neuronal Epithelial-to-Mesenchymal Transition Genes as an Ancillary Tool for Differential Diagnosis among Pulmonary Neuroendocrine Neoplasms

“…In the present study, we also found high levels of KRT14 EMT gene expression in LCNEC compared to AC, as well as high levels of MAP1B in SCLC. These EMT genes are involved in phenotypic changes related to the dimension and stability of the cytoskeleton during tumorigenesis [ 43 ]. Their expression may minimize the known difficulty to separate LCNEC from SCLC, as well as AC from LCNEC and AC from SCLC in terms of cell dimension [ 44 ], with significant interobserver variation and biological similarities contributing to this aspect [ 45 ].…”

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

“…Several studies have reported that FOXA1 is a luminal marker and prognostic biomarker in BCa [ 50 , 51 ], and a lack of nuclear expression for FOXA1 could be regarded as basal-like MIBC [ 52 ]. Continuous expression of FOXA1 can lead to a marked reduction in urothelial proliferation [ 53 ]. However, the detailed mechanisms of FOXA1 in regulating BCa metastasis are still not fully understood.…”

Activation of PPARγ and inhibition of cell proliferation reduces key proteins associated with the basal subtype of bladder cancer in As3+-transformed UROtsa cells

“…In BC cell lines, studies by others have shown that have shown that GATA3 and FOXA1 cooperate with PPARγ activation to drive the differentiation of a basal bladder cancer subtype to a more differentiated luminal subtype [ 23 ]. Other studies have also linked the expression of FOXA1 to the development of the luminal subtype of urothelial cancer [ 42 – 44 ]. In our studies, treatment with TG did result in the differentiation of the As 3+ -transformed cells based upon morphological changes and induced the expression of PPARγ as well as FOXA1 both of which are factors known to drive luminal differentiation of bladder cancer cell lines.…”