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

Abstract

Purpose: 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).Materials and Methods: 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 FASN 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 in vitro experiments were used to reveal the biological functions of FASN.Results: Increased FASN expression was significantly relevant to advanced T, N, and American Joint Committee on Cancer (AJCC) stages (p < 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 FASN amplification was positively correlated to VAT% (r = 0.772, p < 0.001), which significantly correlated to poor PFS (HR = 2.066, p = 0.028) and OS (HR = 2.773, p = 0.023) in the FUSCC cohort. Transient inhibition or overexpression of FASN significantly regulated A498 and 786O cell proliferation and migration by regulating epithelial–mesenchymal transition. Inhibition of FASN led to a higher apoptotic rate and decreased lipid droplet formation compared with normal control in ccRCC cells. Non-targeted metabolomics showed that decreased de novo lipogenesis might be required to sustain an elevation of glycolytic activity in 786O cells by regulating galactinol, dl-lactate, N-acetylaspartylglutamate, and sucrose, thereby participating in carcinogenesis and progression of ccRCC.Conclusion: This study demonstrated that FASN expression is positively related to aggressive cell proliferation, migration, apoptosis, and lipid droplet formation and regulates metabolic disorders of the ccRCC microenvironment. Additionally, elevated FASN mRNA expression is significantly correlated to the abdominal obesity distribution, especially VAT%, which is a significant predictor of a poor prognosis for ccRCC patients.

Network-Based Integrated Analysis of Transcriptomic Studies in Dissecting Gene Signatures for LPS-Induced Acute Lung Injury

“…Among them, the JAK/STAT pathway are critical determinants of initiating adaptive immune responses and constraining inflammatory responses eventually [ 29 ]. Janus tyrosine kinase 3 (JAK3), one of the JAK family members, is an attractive selective target for the treatment of immune-mediated disorders [ 30 ]. Inhibiting JAK3 reduces the hyperproduction of cytokine/chemokine [ 31 ].…”

Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma

“…Immunohistochemistry (IHC) was utilized to evaluate the expression level of RBCK1 (ab219955; Abcam) in 50 ccRCC and 40 adjacent normal tissues from the FUSCC Tissue Bank according to procedures previously described ( 17 ). Then, opal multispectral imaging was used to identify differential immune cell infiltration.…”

“…Cells were incubated in a humidified atmosphere incubator of 5% CO 2 at 37°C. 786-O cells have been transfected with double-stranded siRNA according to the protocol of the manufacturer using plasmid using Lipofectamine 3000 reagent (RiboBio) in a six-well plate, as previously described ( 17 ). The transfection dose for each well was 15 μl of siRNA1 (sequences: GGTGCACCTTCATCAACAA), siRNA2 (sequences: GGATTACCAGCGATTTCTA), or non-targeting siRNA (negative control) at a concentration of 10 nmol/L after incubated using RPMI-1640 for 20 min.…”

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

“…Metabolic reprogramming has a well-characterized role in cancer progression [18]. Increasing evidence suggests that tumor cells must modify their metabolism in response to their elevated energy requirements [19], and metabolic adaptations have been described in many types of cancers [20][21][22]. Of note, tumor cells undergo metabolic reprogramming that may modify the tumor microenvironment (TME) to fulfill the demands of biosynthesis and growth [23].…”