FOXC2 expression and epithelial–mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer

Abstract

Epithelial–mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E‐cadherin and increased N‐cadherin expression (EN‐switch), and increased expression of the EMT‐regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E‐cadherin and N‐cadherin in different prostatic tissues focusing on EMT, clinico‐pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986–2007) with long and complete follow‐up, 33 castration resistant prostate cancers, 33 non‐skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E‐cadherin and N‐cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial–mesenchymal phenotype, with co‐expression of E‐cadherin and N‐cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN‐switch was associated with adverse clinico‐pathological variables, such as extra‐prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN‐switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN‐switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end‐points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.

Meta-analysis of the prognostic significance of FOXC2 in various tumors

“…After applying the inclusion and exclusion criteria, 2115 patients in 15 studies were assessed. 2 – 16 A flow diagram of the study selection process is shown in Figure 1 .…”

“…A total of 2115 patients in 15 studies were recruited. 2 – 16 The following details were extracted: the first author’s last name, publication year, study country, pathology type, patient age, sex ratio, tumor stage, detection method, numbers of patients, source of HR, analysis model, follow-up and HRs with 95% confidence interval (CIs) for OS, cancer-specific survival (CSS), or disease-free survival (DFS). The HRs and corresponding 95% CIs were extracted preferentially from multivariate analyses when available.…”

RNA-seq Analysis of Wild-Type vs. FOXC2-Deficient Melanoma Cells Reveals a Role for the FOXC2 Transcription Factor in the Regulation of Multiple Oncogenic Pathways

“…First implicated as a potential oncogenic transcription factor due to its overexpression/nuclear localization in invasive breast carcinomas, particularly those of the aggressive basal-like subtype (1), FOXC2 has since been linked to the progression of a number of epithelial-derived malignancies. Indeed, FOXC2 overexpression and nuclear localization are poor prognostic indicators of survival in patients with prostate cancer (2), hepatocellular carcinoma (3), NSCLC (4), colorectal cancer (5), glioma (6), gastric cancer (7), and esophageal as well as oral tongue squamous cell carcinomas (8,9). Studies employing murine and human tumor cell lines have confirmed the oncogenic potential of the FOXC2 transcription factor, highlighting its ability to promote several hallmarks of cancer progression, including proliferation (5,9), epithelial-mesenchymal transition (EMT) (10), invasion and metastasis (11), glycolytic metabolism (12), stemness (13), and drug resistance (14,15).…”

Functional polymorphisms in FOXC2 gene and Epithelial ovarian Cancer susceptibility in Chinese population

“…It was also showed to play role in carcinogenesis. FOXC2 was identified to induce epithelial-mesenchymal transition (EMT) in prostate cancer [9],lung cancer [10]. Overexpression of FOXC2 was related to poor prognosis of hepatocellular carcinoma [11].FOXC2 activated YAP signal pathway and enhanced the glycolysis in nasopharyngeal carcinoma cells [12].…”