FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers

Abstract

The forkhead box (FOXA) family of transcription factors regulates gene expression and chromatin structure during tumorigenesis and embryonic development. Until now, the relationship between FOXA1 and the nasopharyngeal carcinoma (NPC) has not yet been reported. Therefore, our purpose is to analyze the expression of FOXA1 in 56 NPC patients compared to 10 normal nasopharyngeal mucosae and to correlate the expression with the clinicopathological features. Besides, we investigated the association between FOXA1 and LMP1 gene expression, as well as the EMT markers namely the E-cadherin and Twist1. Among 56 NPC tissues, 34 (60.7%) cases were positive for FOXA1. Furthermore, we noticed that FOXA1 expression correlated with TNM (p=0.037), and age at diagnosis (p=0.05). Moreover, positive expression of FOXA1 is likely to be associated with prolonged disease-free survival and overall survival rates. On the other hand, we observed a positive association between the expression of E-cadherin and FOXA1 (p=0.0051) whereas Twist1 correlated negatively with FOXA1 (p=0.004). Furthermore, knowing that LMP1 plays a key role in the pathogenesis of NPC, we explored the association of FOXA1 with the LMP1 gene expression in both NPC cell lines and tissues. We found that, in the C666-1 which displays low levels of LMP1, the expression of FOXA1 is high, and inversely in the C15 cell line that expresses a high level of LMP1, the level of FOXA1 is low. Besides, in accordance to our results, we found that in NPC tissues there is a negative association between LMP1 and FOXA1. In conclusion, our results suggest that the overexpression of FOXA1 is associated with a nonaggressive behavior and favorable prognosis in NPC patients. FOXA1 could contribute in the EMT process through key factors as E-cadherin, Twist1, and LMP1.

High FOXA1 immunohistochemical expression level associates with mucinous histology, favorable clinico-pathological prognostic parameters and survival advantage in epithelial ovarian cancer

“…Moreover, FOXA1-over-expressing cholangiocarcinoma cells exhibit a significant reduction in proliferative, invasive and spheroid formation abilities, and its down-regulation subsequently reduces microRNA (miR)-122 expression and induces epithelial-mesenchymal transition (EMT) and disease progression 19 . In nasopharyngeal carcinoma, FOXA1 overexpression associates with a non-aggressive behavior and favorable prognosis in early TNM stages 16 , and suppresses growth, migration and invasion of the carcinoma cells via downregulation of miR-100-5p or miR-125b-5p 17 . As a tumor suppressor, FOXA1 was found to inhibit PI3K/Akt signaling pathway in hepatocellular carcinoma 14 .…”

“…Over the past decade, the biologic role of FOXA1 has been investigated in various human cancers including the mammary 6 , 12 , 13 , prostatic 8 , 10 , hepatocellular 14 , cervical 15 , nasopharyngeal 16 , 17 and colorectal 18 carcinomas, cholangiocarcinoma 19 and ductal carcinoma in situ of the breast 20 using different methodologies, although contradictory data were obtained concerning its prognostic implications and as whether it acts as an oncogene or a tumor-suppressor gene 5 , 18 .…”

Adrenergic-Angiogenic Crosstalk in Head and Neck Cancer: Mechanisms and Therapeutic Implications

“…While the direct effects of EBV oncoproteins including LMP1 on adrenergic signaling is unclear, the study showed that both clones of the NPC cell line expressed ADRB2 and were inhibited by PRO through downregulation of MMP-2/9 expression [17]. Similarly, the forkhead box (FOXA) family of transcription factors have been implicated in the biology of NPC [53,54]. Overexpression of FOXA1 has been shown to suppress proliferation, migration, and invasion of NPC cells in culture [53].…”

“…Overexpression of FOXA1 has been shown to suppress proliferation, migration, and invasion of NPC cells in culture [53]. In NPC patients, FOXA1 expression has been correlated with prolonged disease-free survival and overall survival [54]. However, the effects of PRO on FOXA1 signaling has not been previously reported.…”

Epithelial–Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review

“…( Figure 1 f) FOXA1 is highly expressed in normal nasopharyngeal tissue and is downregulated in NPCs, and its overexpression can inhibit cell proliferation and invasion. This possibly occurs due to its ability to disrupt processes related to EMT, such as the inhibition of Twist1 [ 85 , 86 ].…”