Pioneer of prostate cancer: past, present and the future of FOXA1

Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.

Expression of miR-760 in cervical squamous cell carcinoma tissues and cells and its effect on malignant biological behaviors of SiHa cells / 中国肿瘤生物治疗杂志

@#Objective: To investigate the expression of microRNA(miR) -760 in human cervical squamous cell carcinoma (CSCC) tissues and cells, and it’s effects on the proliferation, apoptosis, invasion, migration and epithelial-mesenchymal transition (EMT) of SiHa cells, as well as its molecular mechanism. Methods: Eighty pairs of CSCC cancerous and corresponding para-cancerous tissue specimens which were pathologically confirmed and 40 cases of normal cervical tissue specimens obtained by myomectomy in Liaocheng Maternal and Child Health Hospital of Shandong Province from April 2015 to August 2018 were selected. The expression of miR-760 in CSCC tissues, para-cancerous tissues and normal cervical tissues, human CSCC cell lines (SiHa, HCC94) and human cervical squamous epithelial immortalized H8 cells were detected by qPCR, and the relationship between miR-760 and clinicopathological characteristics of CSCC patients was analyzed. miR-760 mimics and NC-mimics plasmids were transfected into SiHa cells by liposome transfection. The expression of miR-760 in SiHa cells was detected by qPCR, the proliferation activity and apoptosis rate were detected by CCK-8 test and flow cytometry, respectively. The invasion and migration of SiHa cells were detected by Transwell assay. The expressions of EMT-related proteins, such as E-cadherin, vimentin and N-cadherin, in SiHa cells were detected by WB. Bioinformatics was used to predict the targeting relationship between FOXA1 and miR-760, and double luciferase reporter gene assay was used to verify the direct regulation of miR-760 on FOXA1. Results: The expression of miR-760 in CSCC tissues was significantly lower than that in para-cancerous tissues and normal cervical tissues (all P<0.01), and the expression of miR-760 was closely related to lymphnode metastasis and clinical stage (all P<0.01). The expression of miR-760 in SiHa and HCC94 cells was significantly lower than that in H8 cells (all P<0.01). Up-regulation of the expression of miR-760 could significantly inhibit the proliferation, invasion and migration of SiHa cells (all P<0.01), promote apoptosis (P<0.01), up-regulate the expression of E-cadherin protein (P<0.01), and down-regulate the protein expressions of vimentin and N-cadherin (all P<0.01).FOXA1 was a direct target gene of miR-760 (P<0.01). Up-regulation of miR760 significantly inhibited the mRNA and protein expressions of FOXA1 in SiHa cells (all P<0.05). Conclusion: The expression of miR-760 is down-regulated in CSCC tissues and cells, and it can regulate the proliferation, invasion, migration and apoptosis of CSCC cells by targeting FOXA1. ··

Relationship between Helicobacter pylori Infection and Expression of FOXA1 in Gastric Mucosa / 胃肠病学

Background:Helicobacter pylori( Hp)is listed as Group 1 human carcinogen. Transcription factor FOX family plays important role in the development of tumor,and FOXA1 is a key target transcription factor of some microRNAs( miRNAs). Aims:To investigate the relationship of Hp infection with expression of FOXA1 in gastric mucosal tissues. Methods:Eighty patients undergone gastroscopy from Jan. 2014 Sept. 2014 were enrolled. Hp infection was detected by 14 C-urease breath test( 14 C-UBT),modified Giemsa staining and bacterial culture. Expression of FOXA1 in gastric mucosal tissues was determined by immunohistochemical SP method. Results:FOXA1 expression in Hp positive tissues was significantly higher than that in Hp negative tissues(73. 8% vs. 47. 4%;χ2 =4. 81,P<0. 05). Conclusions:High expression of FOXA1 in gastric mucosal tissues suggests that miRNAs pathway may be one of the molecular mechanisms of Hp infection leading to gastric intraepithelial neoplasia even gastric cancer.

The expression and relationship between FOXA1 and ERβin triple negative breast cancer / 中国癌症杂志

Background and purpose:The expression of ERβin triple negative breast cancer(TNBC) might be associated with good prognosis in TNBC patients. ERβand ERαhave considerable homology. FOXA1 plays an important role in ERαexpression and function. The aim of this study was to analyze the expression of FOXA1 and ERβin TNBC and the relationship between them and the clinicopathologic characteristics and prognosis. Methods:The breast cancer samples in Peking Union Medical College Hospital were collected from Nov. in 2011 to Dec. in 2013, and TNBC were screened out based on the expression of ERα, PR and HER-2. Thirty ERβ-negative samples and 30 ERβ-positive samples were selected randomly according to the ERβexpression. We used immunohistochemical method to detect the expression of FOXA1. Finally, 48 TNBC samples were obtained to analyze the results. Results:The total positive rate of FOXA1 was 35.4%(17/48). In the ERβ-positive group, the positive rate of FOXA1 was 35.7%(10/28),and in the ERβ-negative group, the positive rate of FOXA1 was 35% (7/20). The expression of FOXA1 in these 2 groups had no signiifcant difference (P=0.83), which indicated that there was no relation between ERβand FOXA1. The FOXA1 positive group and FOXA1 negative group also showed no signiifcant difference in age, tumor size, and lymphatic metastasis number in axilla, tumor grade, tumor stage, NPI and DFS. However, Ki-67 showed negative correlation with FOXA1 expression (P<0.01). Conclusion:FOXA1 expression had no relationship with ERβexpression in TNBC. Ki-67 showed negative correlation with FOXA1 expression, which might hint that the proliferation of tumor cell was lower in FOXA1 positive TNBC.