Abstract
AbstractAs a highly enriched endosomal protein within neuronal cells, NSG1 has been discovered to facilitate the process of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC). However, the precise mechanisms behind this phenomenon have yet to be elucidated. The pivotal role of transforming growth factor-β (TGF-β) in triggering the EMT and its significant contribution towards tumor metabolic reprogramming—responsible for EMT activation—has been robustly established. Nevertheless, the extent of TGF-β involvement in the NSG1-mediated EMT within ESCC and the processes through which metabolic reprogramming participates remain ambiguous. We accessed an array of extensive public genome databases to analyze NSG1 expression in ESCC. Regulation of TGF-β by NSG1 was analyzed by transcriptome sequencing, quantitative Real-Time PCR (qRT-PCR), co-immunoprecipitation (CO-IP), and immunofluorescence (IF). Additionally, cellular functional assays and western blot analyses were conducted to elucidate the effect of NSG1 on TGF-β/Smad signaling pathway, as well as its role in ESCC cell metastasis and proliferation. We validated the influence of the NSG1/TGF-β axis on metabolic reprogramming in ESCC by measuring extracellular acidification, glucose uptake, and lactate production. Our findings identify an oncogenic role for NSG1 in ESCC and show a correlation between high NSG1 expression and poor prognosis in ESCC patients. Additional research indicated TGF-β’s involvement in the NSG1-induced EMT process. From a mechanistic perspective, NSG1 upregulates TGF-β, activating the TGF-β/Smad signaling pathway and subsequently fostering the EMT process by inducing cell metabolic reprogramming—evident from elevated glycolysis levels. In conclusion, our study highlights the NSG1/TGF-β axis as a promising therapeutic target for ESCC.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Reference44 articles.
1. Tarazi M, Chidambaram S, Markar SR. Risk factors of esophageal squamous cell carcinoma beyond alcohol and smoking. Cancers. 2021;13:1009.
2. Grille VJ, Campbell S, Gibbs JF, Bauer TL. Esophageal cancer: the rise of adenocarcinoma over squamous cell carcinoma in the Asian belt. J Gastrointest Oncol. 2021;12:S339–s349.
3. Murphy G, McCormack V, Abedi-Ardekani B, Arnold M, Camargo MC, Dar NA, et al. International cancer seminars: a focus on esophageal squamous cell carcinoma. Ann Oncol: Off J Eur Soc Med Oncol. 2017;28:2086–93.
4. Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371:2499–509.
5. Ohnishi S, Futamura M, Kamino H, Nakamura Y, Kitamura N, Miyamoto Y, et al. Identification of NEEP21, encoding neuron-enriched endosomal protein of 21 kDa, as a transcriptional target of tumor suppressor p53. Int J Oncol. 2010;37:1133–41.