AUTHOR=Xu Wenhao , Hu Xiaoxin , Anwaier Aihetaimujiang , Wang Jun , Liu Wangrui , Tian Xi , Zhu Wenkai , Ma Chunguang , Wan Fangning , Shi Guohai , Qu Yuan-Yuan , Zhang Hailiang , Ye Dingwei 

TITLE=Fatty Acid Synthase Correlates With Prognosis-Related Abdominal Adipose Distribution and Metabolic Disorders of Clear Cell Renal Cell Carcinoma

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=7

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2020.610229

DOI=10.3389/fmolb.2020.610229

ISSN=2296-889X

ABSTRACT=<p><bold>Purpose:</bold> Lipid metabolism reprogramming is a major pathway in tumor evolution. This study investigated fatty acid synthase (FASN) mRNA expression in anthropometric adipose tissue and elucidated the prognostic value and potential mechanism of clear cell renal cell carcinoma (ccRCC).</p><p><bold>Materials and Methods:</bold> Transcription profiles were obtained from 533 ccRCC samples in The Cancer Genome Atlas (TCGA) cohorts. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry were performed to detect <italic>FASN</italic> expression in 380 paired ccRCC and normal tissues from the Fudan University Shanghai Cancer Center (FUSCC). Visceral adipose tissue (VAT) and subcutaneous adipose tissue were at the level of the umbilicus as measured by magnetic resonance imaging (MRI). Non-targeted metabolomics and <italic>in vitro</italic> experiments were used to reveal the biological functions of FASN.</p><p><bold>Results:</bold> Increased <italic>FASN</italic> expression was significantly relevant to advanced T, N, and American Joint Committee on Cancer (AJCC) stages (<italic>p</italic> &lt; 0.01) and significantly correlated to poor progression-free survival (PFS) and overall survival (OS) of 913 ccRCC patients in FUSCC and TCGA cohorts. Pearson's correlation coefficient indicated that <italic>FASN</italic> amplification was positively correlated to VAT% (<italic>r</italic> = 0.772, <italic>p</italic> &lt; 0.001), which significantly correlated to poor PFS (HR = 2.066, <italic>p</italic> = 0.028) and OS (HR = 2.773, <italic>p</italic> = 0.023) in the FUSCC cohort. Transient inhibition or overexpression of <italic>FASN</italic> significantly regulated A498 and 786O cell proliferation and migration by regulating epithelial–mesenchymal transition. Inhibition of <italic>FASN</italic> led to a higher apoptotic rate and decreased lipid droplet formation compared with normal control in ccRCC cells. Non-targeted metabolomics showed that decreased <italic>de novo</italic> lipogenesis might be required to sustain an elevation of glycolytic activity in 786O cells by regulating galactinol, <sc>dl</sc>-lactate, N-acetylaspartylglutamate, and sucrose, thereby participating in carcinogenesis and progression of ccRCC.</p><p><bold>Conclusion:</bold> This study demonstrated that <italic>FASN</italic> expression is positively related to aggressive cell proliferation, migration, apoptosis, and lipid droplet formation and regulates metabolic disorders of the ccRCC microenvironment. Additionally, elevated <italic>FASN</italic> mRNA expression is significantly correlated to the abdominal obesity distribution, especially VAT%, which is a significant predictor of a poor prognosis for ccRCC patients.</p>