Upregulation of FOXP1 is a new independent unfavorable prognosticator and a specific predictor of lymphatic dissemination in cutaneous melanoma patients

Abstract

BackgroundFOXP1 is a pleiotropic protein that plays important roles in immune responses (B-cell development regulation and differentiation of monocyte), organ development (cardiac valves, lung, and esophagus), and neuronal development. Besides being the primary regulator of normal human tissue development, FOXP1 also plays a role in tumorigenesis. However, the potential value of FOXP1 expression in tumor prognosis remains controversial. FOXP1 expression was assessed in tumor cells (TCs) and stromal cells (SCs) of cutaneous melanomas with the aim of analyzing the associations between FOXP1 expression and clinicopathological characteristics. We believe this article to be the first report analyzing the correlations between FOXP1 expression and clinicopathological, as well as histological, characteristics in melanoma.Materials and methodsIn total, 96 formalin-fixed, paraffin-embedded primary cutaneous melanoma tissue specimens were subjected to immunohistochemical analysis for FOXP1, and the results were correlated with classical clinicopathological features and patient survival.ResultsFOXP1 overexpression in TCs was strongly associated with the presence of metastases in sentinel lymph nodes (p=0.0003, OR=11.66) and positive status of regional lymph nodes (p=0.0006, OR=22.15). In 96% (52 of 54) of patients presenting with low FOXP1 expression, no clinical or histopathological features of lymphatic dissemination were observed. However, thinner and nonulcerated tumors were reported to have increased numbers of FOXP1-positive SCs. In addition, a strong association was observed between FOXP1 upregulation in SCs and the absence of regional lymph node metastases. There was a significant correlation between FOXP1 upregulation in TCs and shorter cancer-specific overall survival (log-rank test, p=0.0040) and disease-free survival (log-rank test, p=0.0021). FOXP1 expression was confirmed in multivariate analysis as a factor that significantly unfavorably impacts prognosis in melanoma patients (HR=3.14, p=0.0299, adjusted for age, Breslow thickness, and sex).ConclusionThe findings from this study indicate that FOXP1 has a major role in melanoma progression, which makes it a candidate for molecular target-based cancer therapy.

miR-149-3p reverses CD8 + T-cell exhaustion by reducing inhibitory receptors and promoting cytokine secretion in breast cancer cells

“…Exhaustion is characterized by elevated levels of inhibitory receptors (IRs) such as programmed death-1 (PD1), cytotoxic T-lymphocyte antigen 4 (CTLA4), T-cell immunoglobulin domain and mucin domain 3 (TIM3), B-and T-lymphocyte attenuator (BTLA), and lymphocyte activation gene 3 (LAG3), CD244 (2B4) [4][5][6][7][8][9]; diminished levels of effector cytokines, such as interlekin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); and impaired CD8 + T-cell cytotoxicity [10]. Foxp1, a member of subfamily P of the forkhead box (FOX) transcription factor family, plays a pivotal role in modulating early B-cell development, T-cell quiescence and monocyte differentiation, and in mediating effective antitumour immune response [11][12][13][14]. Foxp1 is highly expressed in oestrogen receptor-positive human breast cancer cells and can inhibit the migration of tumour-infiltrating T cells [15].…”

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

“…This is consistent with our experiments, where only the ALDH low and not the ALDH high fraction was able to initiate tumor growth after transplantation of 10 cells ( Figure 6 b). Such an effect might be related to the decreased expression of several CSC genes such as Lats1 , Stat3 , and Foxp1 in the ALDH high cells (data not shown) reported to be associated with melanoma aggressiveness [ 82 , 83 , 84 ]. However, the significance of these genes in the potentially reduced tumorigenicity of ALDH high B16-F10 cells requires experimental verification.…”

Impact of FOXP1 rs2687201 genetic variant on the susceptibility to HCV‐related hepatocellular carcinoma in Egyptians

“…[38] Many studies have reported that FOXP1 is abnormally expressed in various types of cancers and its expression also has a significant correlation with aggressive malignant phenotypes of tumors and poor prognosis in patients. [25,26,28] FOXP1 polymorphisms have been associated with cancer [39] where FOXP1 genetic variants were found to be associated with an increased risk of esophageal adenocarcinoma development. [40] Other FOXP1 SNPs have been reported to be significantly associated with cutaneous squamous cell carcinoma [41] and basal cell carcinoma reaching genome-wide significance.…”

“…[23] On the other hand, FOXP1 has been recognized as a potential oncogene. High expression levels of FOXP1 were reported in ovarian cancer, [24] cutaneous melanoma [25] and in many types of B-cell lymphomas such as diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma exhibiting correlation with worse outcome. [26] Expression of FOXP1 was higher in human primary HCC samples when compared to corresponding normal liver tissues indicating its potential role in tumorigenesis.…”