Background: Foxm1 is up-regulated in prostate adenocarcinomas and its expression correlates with the poor prognosis. Results: Conditional depletion of Foxm1 in prostate epithelial cells inhibits tumor cell proliferation, angiogenesis, and metastasis. Conclusion: Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis in mouse models. Significance: Foxm1 may play a key role in the pathogenesis of prostate cancer in human patients.
BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide and mortality mostly results from loco-regional recurrence and metastasis. Despite its significance, our knowledge on molecular, cellular and environmental mechanisms that drive disease pathogenesis remains largely elusive, and there are limited therapeutic options, with only negligible clinical benefit.MethodsWe applied global gene expression profiling with samples derived from a recently established mouse model for oral cancer recurrence and identified a list of genes with differential expression between primary and recurrent tumors.ResultsOne differentially expressed gene codes for Myb-binding protein 1a (MYBBP1A), which is known as a transcriptional co-regulator that physically interacts with nuclear transcription factors, such as NFκB and p53. We confirmed significantly reduced MYBBP1A protein levels on tissue sections of recurrent mouse tumors compared to primary tumors by immunohistochemistry, and found aberrant MYBBP1A protein levels also in tumor samples of HNSCC patients. Interestingly, silencing of MYBBP1A expression in murine SCC7 and in human HNSCC cell lines elicited increased migration but decreased cell growth.ConclusionWe provide experimental evidence that MYBBP1A is an important molecular switch in the regulation of tumor cell proliferation versus migration in HNSCC and it will be a major challenge for the future to proof the concept whether regulation MYBBP1A expression and/or function could serve as a novel option for anti-cancer therapy.
Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three-dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated-like phenotype, indicating a context-dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC.No conflicts of interest were declared. heterogeneous expression of keratins [10][11][12].Despite a large body of evidence that FOXM1 has a role in HNSCC [13][14][15][16], its oncogenic functions in this type of cancer are not yet sufficiently understood. In Figure 3. shRNA-mediated FOXM1 knockdown decreases the number of proliferating cells and facilitates progression towards a more differentiated-like phenotype. (A) H&E staining of CAL27 organotypic cultures demonstrating a squamous-like phenotype after 16 days of culture. Scale bar = 100 μm. (B) Representative pictures of immunostaining for a series of indicated differentiation markers in CAL27 organotypic cultures at day 16. Scale bar = 100 μm. (C) RT-qPCR analysis of organotypes showing a gradual decrease in FOXM1 and its targets CCNF and GTSE1 upon FOXM1 knockdown, while differentiation-related genes such as JUND and IVL were upregulated both by FOXM1 knockdown and by increased time of culture. The data shown are from one experiment. (D) RT-qPCR analysis of FOXM1 and IVL expression levels in a large series of CAL27 shCtr or shFOXM1 organotypic cultures showing a trend for IVL upregulation following FOXM1 knockdown. Each dot represents one organotype. (E) FOXM1 expression was reduced by culturing cells in 3D organotypes as demonstrated by the reduction of FOXM1 transcript level measured by RT-qPCR. Each data point represents one sample under one condition or the other. (F) Computer-assisted quantification of the number of Ki-67-positive cells detected by immunohistochemistry in shCtr and FOXM1-depleted organotypes. Each data point represents one analyzed field of the organotype. (G) Examples for the Ki-67 immunohistochemistry data quantified in panel F. Ki-67-positive cells were detected in the basal layer for both conditions at day 8. In the control, cycling cells were present throughout the organotype at day 16, while they were restricted to the basal layer upon FOXM1 downregu...
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