Dataset Information

Tumor Cell "Slimming" Regulates Tumor Progression through PLCL1/UCP1-Mediated Lipid Browning.

ABSTRACT: Emerging evidence has highlighted the important role of abnormal lipid accumulation in cancer development and progression, but the mechanism for this phenomenon remains unclear. Here, it is demonstrated that phospholipase C-like 1/uncoupling protein 1 (PLCL1)/(UCP1)-mediated lipid browning promotes tumor cell "slimming" and represses tumor progression. By screening three independent lipid metabolism-related gene sets in clear cell renal cell carcinoma (ccRCC) and analyzing the TCGA database, it is found that PLCL1 predicted a poor prognosis and was downregulated in ccRCC. Restoration of PLCL1 expression in ccRCC cells significantly represses tumor progression and reduces abnormal lipid accumulation. Additionally, a phenomenon called tumor cell "slimming," in which tumor cell volume is reduced and lipid droplets are transformed into tiny pieces, is observed. Further studies show that PLCL1 promotes tumor cell "slimming" and represses tumor progression through UCP1-mediated lipid browning, which consumes lipids without producing ATP energy. Mechanistic investigations demonstrate that PLCL1 improves the protein stability of UCP1 by influencing the level of protein ubiquitination. Collectively, the data indicate that lipid browning mediated by PLCL1/UCP1 promotes tumor cell "slimming" and consumes abnormal lipid accumulation, which represses the progression of ccRCC. Tumor cell "slimming" offers a promising new concept and treatment modality against tumor development and progression.

SUBMITTER: Xiong Z

PROVIDER: S-EPMC6523368 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Tumor Cell "Slimming" Regulates Tumor Progression through PLCL1/UCP1-Mediated Lipid Browning.

Xiong Zhiyong Z Xiao Wen W Bao Lin L Xiong Wei W Xiao Haibing H Qu Yan Y Yuan Changfei C Ruan Hailong H Cao Qi Q Wang Keshan K Song Zhengshuai Z Wang Cheng C Hu Wenjun W Ru Zeyuan Z Tong Junwei J Cheng Gong G Xu Tianbo T Meng Xiangui X Meng Xiangui X Shi Jian J Chen Zhixian Z Yang Hongmei H Chen Ke K Zhang Xiaoping X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190325 10

Emerging evidence has highlighted the important role of abnormal lipid accumulation in cancer development and progression, but the mechanism for this phenomenon remains unclear. Here, it is demonstrated that phospholipase C-like 1/uncoupling protein 1 (PLCL1)/(UCP1)-mediated lipid browning promotes tumor cell "slimming" and represses tumor progression. By screening three independent lipid metabolism-related gene sets in clear cell renal cell carcinoma (ccRCC) and analyzing the TCGA database, it ...[more]

PMID: 31131187

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Project description:BackgroundThe VHL-HIF pathway and lipid droplet accumulation are the main characteristics of clear cell renal cell carcinoma (ccRCC). However, the connection between the two features is largely unknown.MethodsWe used transcriptional sequencing and TCGA database analysis to identify APOL1 as a novel therapeutic target for ccRCC. The oncogenic functions of APOL1 were investigated by cell proliferation, colony formation, migration and invasion assays in ccRCC cells in vitro and xenografts derived from ccRCC cells in vivo. Oil red O staining and quantification were used to detect lipid droplets. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays were carried out to identify HIF-2α bound to the promoter of APOL1 and lncRNA LINC02609. RNA-FISH and luciferase reporter assays were performed to determine that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p.FindingsRNA-seq data revealed that HIF2α can regulate APOL1 and lncRNA LINC02609 expression. We also found that HIF-2α can bind to the promoter of APOL1 and lncRNA LINC02609 and transcriptionally regulate their expression directly. We further demonstrated that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p in ccRCC. Mechanistically, APOL1-dependent lipid storage is required for endoplasmic reticulum (ER) homeostasis and cell viability and metastasis in ccRCC. We also showed that high APOL1 expression correlated with worse clinical outcomes, and knockdown of APOL1 inhibited tumor cell lipid droplet formation, proliferation, metastasis and xenograft tumor formation abilities. Together, our studies identify that HIF2α can regulate the expression of the lipid metabolism related gene APOL1 by direct and indirect means, which are essential for ccRCC tumorigenesis.InterpretationBased on the experimental data, in ccRCC, the HIF-2α/LINC02609/APOL1 axis can regulate the expression of APOL1, thus interfering with lipid storage, promoting endoplasmic reticulum homeostasis and regulating tumor progression in ccRCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future studies in ccRCC.

Project description:BackgroundThe enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC.ResultsMIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression.ConclusionsOur data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.

Dataset Information

Tumor Cell "Slimming" Regulates Tumor Progression through PLCL1/UCP1-Mediated Lipid Browning.

Publications

Tumor Cell "Slimming" Regulates Tumor Progression through PLCL1/UCP1-Mediated Lipid Browning.

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