J Cancer 2020; 11(9):2485-2495. doi:10.7150/jca.40709 This issue
1. Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South University, Changsha 410013, Hunan, China
2. The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China
3. The Key Laboratory of Carcinogenesis of the National Health Commission, Xiangya Hospital, Central South University, Changsha 410078, Hunan, China
4. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
5. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
6. Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
7. Department of Dermatology, Second Xiangya Hospital, The Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, 410011, Hunan, China
8. Department of Dermatology, Xiangya Hospital of Central South University, Changsha, 410008, China
# These authors contributed equally.
Background: Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck cancer, within highest incidence in South China and southeastern Asia but rare in other regions worldwide. FOXA1 is a pioneer factor implicated in various human malignancies. Downregulation of FOXA1 promotes NPC cells proliferation, invasiveness in vitro and tumorigenicity in vivo. However, it is remain elusive to determine whether microRNAs (miRNAs) regulated by FOXA1 contribute to NPC progression.
Methods: In this study, differentially expressed miRNAs and mRNAs induced by FOXA1 expression were determined by microarray. Integrative miRNA-mRNA regulatory networks mediated by FOXA1 in NPC were established. The expressions of differentially expressed miRNAs in NPC cells were measured by quantitative reverse-transcription PCR. Cell viability was determined by CCK-8 assays. Cell migration and invasiveness were measured by Transwell assays. The correlation between miRNAs and its target mRNAs was analyzed.
Results: FOXA1 suppressed the expression of miR-100-5p and miR-125b-5p in NPC cells. Silencing either miR-100-5p or miR-125b-5p inhibited the malignant behaviors of NPC cells, whereas re-expression of miR-100-5p or miR-125b-5p restored the malignancy of NPC cells repressed by FOXA1. Mechanistically, miR-100-5p or miR-125b-5p suppressed RASGRP3 or FOXN3 expression respectively via direct binding to its 3'-UTR. Furthermore, we demonstrated that FOXA1 induced RASGRP3 or FOXN3 expression via inhibiting miR-100-5p or miR-125b-5p. Upregulation of RASGRP3 or FOXN3 contributed to inhibition of NPC by FOXA1. We also demonstrated that the mRNA levels of RASGRP3 and FOXN3 are positively correlated with FOXA1.
Conclusion: Our study provided evidence the first time that FOXA1 suppresses NPC cells via downregulation of miR-100-5p or miR-125b-5p.
Keywords: nasopharyngeal carcinoma, FOXA1, microRNA, miR-100, miR-125b