ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway

Chen, Junru; Ding, Chaofeng; Chen, Yunhao; Hu, Wendi; Yu, Chengkuan; Peng, Chuanhui; Feng, Xiaode; Cheng, Qiyang; Wu, Wenxuan; Lu, Yuejie; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

doi:10.1016/j.canlet.2020.12.019

Cited by 118 publications

(95 citation statements)

References 33 publications

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“…Present studies have demonstrated that the ACSL4 dysregulation is associated with the progression of many malignant tumors, including gastric cancer, prostate cancer, and colorectal cancer ( 57 – 59 ). What’s more, ACSL4 could regulate lipogenesis by affecting the expression of FASN and ACC1 ( 60 , 61 ). Therefore, we speculated that lncRNATSPEAR-AS2 could affect fatty acid metabolism of CRC through the targeted regulation of ACSL4, which still needs further experiments to prove.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer

Peng

Wen

et al. 2021

Front. Oncol.

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Abnormal metabolism, including abnormal fatty acid metabolism, is an emerging hallmark of cancer. The current study sought to investigate the potential prognostic value of fatty acid metabolism-related long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). To this end, we obtained the gene expression data and clinical data of patients with CRC from The Cancer Genome Atlas (TCGA) database. Through gene set variation analysis (GSVA), we found that the fatty acid metabolism pathway was related to the clinical stage and prognosis of patients with CRC. After screening differentially expressed RNAs, we constructed a fatty acid metabolism-related competing endogenous RNA (ceRNA) network based on the miRTarBase, miRDB, TargetScan, and StarBase databases. Next, eight fatty acid metabolism-related lncRNAs included in the ceRNA network were identified to build a prognostic signature with Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, and a nomogram was established based on the lncRNA signature and clinical variables. The signature and nomogram were further validated by Kaplan–Meier survival analysis, Cox regression analysis, calibration plots, receiver operating characteristic (ROC) curves, decision curve analysis (DCA). Besides, the TCGA internal and the quantitative real-time polymerase chain reaction (qRT-PCR) external cohorts were applied to successfully validate the robustness of the signature and nomogram. Finally, in vitro assays showed that knockdown of prognostic lncRNA TSPEAR-AS2 decreased the triglyceride (TG) content and the expressions of fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in CRC cells, which indicated the important role of lncRNA TSPEAR-AS2 in modulating fatty acid metabolism of CRC. The result of Oil Red O staining showed that the lipid content in lncRNA TSPEAR-AS2 high expression group was higher than that in lncRNA TSPEAR-AS2 low expression group. Our study may provide helpful information for fatty acid metabolism targeting therapies in CRC.

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Section: Discussionmentioning

confidence: 99%

Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer

Peng

Wen

et al. 2021

Front. Oncol.

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“…CPT1A is a rate-limiting enzyme in the transport of long-chain fatty acids for β -oxidation [ 31 ], PPAR- α is known to have an important role in fatty liver, and the mechanism of carcinogenesis has been clarified [ 32 ]. SREBP1 is crucial for lipogenesis as well as HCC cell proliferation and metastasis [ 33 ]; in the current study, it was found that the expressions of these three proteins above were increased in HCC cells transfected by miR-603 mimic; the results indicated that miR-603 can promote the lipid accumulation and then accelerate the HCC progression.…”

Section: Discussionmentioning

confidence: 53%

Mechanistic Investigation on the Regulation of FABP1 by the IL-6/miR-603 Signaling in the Pathogenesis of Hepatocellular Carcinoma

Lin

Zheng

et al. 2021

BioMed Research International

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Background. Abnormal lipid metabolism is closely associated with the invasiveness and metastasis of cancer. Fatty acid-binding proteins (FABPs) play essential roles in lipid metabolism, and miRNAs can affect lipid metabolism by targeting FABPs. However, the exact mechanism is unknown. Methods. FABP1 expression in HCC tissues was analyzed by immunochemistry with tissue microarrays. The lipid content was detected by Oil Red O staining, and the interaction between FABP1 and free fatty acid (FFA) was studied by a labeling and tracking method. miRNA arrays were used to detect the expression of miRNAs in IL-6-stimulated HCC cells. miR-603 expression was verified by qPCR. The proteins were checked by Western blot analysis. Gain and loss function evaluation was assessed by lentivirus and miRNA mimic transfection in Huh-7 cells, while reactive oxygen species (ROS) were detected by fluorescence. Results. FABP1 expression was significantly decreased in approximately 90% (81/90) of HCC patients. FABP1 expression in adjacent tissues was closely associated with overall survival. Meanwhile, lipid was abundant in the adjacent tissues, yet significantly reduced in HCC tissues. FABP1 and FFA can promote each other for being uptaken by Huh-7 cells. FABP1 overexpression induced apoptosis and inhibited the proliferation, migration, invasion, and metastasis of Huh-7 cells. IL-6 treatment affected the expression of miRNAs, and miR-603 was overexpressed in HCC tissues. Also, miR-603 overexpression promoted the proliferation, migration, invasion, and metastasis of Huh-7 cells. Bioinformatic analysis predicted that miR-603 targets the 3 ′ -UTR region of FABP1. However, miR-603 overexpression inhibited the expression of the FABP1 but increased the CPT1A, PPAR-α, and SREBP1 expressions. FABP1 overexpression reduced ROS in HCC cells, while miR-603 can reverse these effects. Conclusion. Our results indicate that in the pathogenesis of HCC, IL-6 induces miR-603 expression, which subsequently inhibits FABP1 expression, promotes the lipid metabolism- and synthesis-related proteins, and finally increases the cellular oxidative stress level and leads to the metastasis of HCC.

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“…SREBP-1 is a transcriptional factor and plays a pivotal role in the proliferation and metastasis of liver cancer cells by regulating fatty acid synthesis and [81] and suppressing liver inflammation [82]. Other factors, such as long-chain acyl CoA synthetase 4 (ACSL4) [83], caveolin-1 (Cav1) [84], and zinc fingers and homeoboxes 2 (ZHX2) [85], can regulate lipid metabolism via the SREBP1 signaling pathway. Lipid metabolism is correlated tightly with glucose metabolism in HCC.…”

Section: Srebp-1mentioning

confidence: 99%

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Zhang

Yang

2021

Cancers

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

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ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway

Cited by 118 publications

References 33 publications

Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer

Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer

Mechanistic Investigation on the Regulation of FABP1 by the IL-6/miR-603 Signaling in the Pathogenesis of Hepatocellular Carcinoma

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

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