SLC52A3 expression is activated by NF-κB p65/Rel-B and serves as a prognostic biomarker in esophageal cancer

• Published in: Cellular and molecular life sciences : CMLS Vol. 75; no. 14; pp. 2643 - 2661
• Main Authors: Long, Lin, Pang, Xiao-Xiao, Lei, Fei, Zhang, Jia-Sheng, Wang, Wei, Liao, Lian-Di, Xu, Xiu-E, He, Jian-Zhong, Wu, Jian-Yi, Wu, Zhi-Yong, Wang, Li-Dong, Lin, De-Chen, Li, En-Min, Xu, Li-Yan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2018; Springer Nature B.V
• Subjects: 5' Flanking Region - genetics; Aberration; absorption; Adult; Aged; Base Sequence; Binding sites; Binding Sites - genetics; Biochemistry; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Biology; Cell Line, Tumor; Cell proliferation; Chromatin; Coding; Electrophoretic mobility; Esophageal cancer; Esophageal carcinoma; esophageal neoplasms; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Female; gel electrophoresis; Gene Expression Regulation, Neoplastic; Humans; Immunoprecipitation; Life Sciences; Male; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Middle Aged; Molecular modelling; NF-κB protein; Original; Original Article; patients; precipitin tests; Prognosis; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Riboflavin; Signaling; Squamous cell carcinoma; Survival; Survival Analysis; survival rate; Transcription; transcription (genetics); transcription factor NF-kappa B; Transcription Factor RelA - metabolism; Transcription Factor RelB - metabolism; tumor necrosis factor-alpha; Tumor necrosis factor-α; Riboflavin; NF-κB; TNFα; Rel-B; Esophageal cancer; SLC52A3
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-018-2757-4

The human riboflavin transporter-3 (encoded by SLC52A3 ) plays a prominent role in riboflavin absorption. Interestingly, abnormal expression patterns of SLC52A3 in multiple types of human cancers have been recently noted. However, the molecular mechanisms underlying its dysregulation remain unclear. In this study, we find that SLC52A3 has two transcript variants that differ in the transcriptional start site, and encode different proteins: SLC52A3a and SLC52A3b. Importantly, aberrant expressions of SLC52A3 are associated with stepwise development of esophageal squamous cell carcinoma (ESCC) as well as the survival rates of ESCC patients. Functionally, SLC52A3a, but not SLC52A3b, strongly promotes the proliferation and colony formation of ESCC cells. Furthermore, SLC52A3 5′-flanking regions contain NF-κB p65/Rel-B-binding sites, which are crucial for mediating SLC52A3 transcriptional activity in ESCC cells. Chromatin immunoprecipitation and electrophoretic mobility shift assay reveal that p65/Rel-B bind to 5′-flanking regions of SLC52A3 . Accordingly, NF-κB signaling upregulates SLC52A3 transcription upon TNFα stimulation. Taken together, these results elucidate the mechanisms underlying SLC52A3 overexpression in ESCC. More importantly, our findings identify SLC52A3 as both a predictive and prognostic biomarker for this deadly cancer.