TFE3 fusion proteins promote the progression of TFE3 rearranged renal cell carcinoma via enhancing chaperone-mediated lipophagy.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2025-03-06 DOI:10.1186/s12964-025-02117-y

Wenliang Ma, Yi Chen, Guijuan Chen, Lei Yang, Yanwen Lu, Xiang Dong, Dongmei Li, Weidong Gan

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引用次数: 0

Abstract

Background: TFE3 rearranged renal cell carcinoma (TFE3 rRCC), classified as a distinct entity of RCCs, exhibits aggressive biological behavior and possesses unique metabolic characteristics. In the present study, TFE3 rRCC with high expression of TFE3 fusion proteins was employed to investigate the features of lipid metabolism and its underlying mechanism in cancer progression.

Methods: Fluorescence microscope and flow cytometry were employed to detect lipid droplets (LDs). GPO-PAP method and Oil Red O staining were used to quantify triacylglycerol levels. The data for bioinformatics analysis were sourced from GEO and iProX. The biological roles of TFE3 and LAMP2A were investigated by CCK8 assay, EdU staining, seahorse, transwell assay, colony, and sphere formation assay. The regulatory mechanisms involving TFE3, LAMP2A and Hsc70 were investigated using western blotting, immunohistochemistry, qRT-PCR, luciferase assays, Co-IP techniques, and ChIP analyses.

Results: The level of LDs accumulation in TFE3 rRCC was relatively low, and the knockdown of TFE3 led to an increase in LDs accumulation while inhibiting tumor progression. The underlying mechanism revealed that TFE3 fusion proteins inhibited the biosynthesis of LDs within the endoplasmic reticulum by promoting the degradation of DGAT1 and DGAT2 via autophagy. Furthermore, TFE3 fusion proteins upregulated LAMP2A, thereby enhancing chaperone-mediated autophagy pathways. The process facilitated the degradation of LDs and promoted oxidative metabolism of long-chain fatty acids in mitochondria.

Conclusions: TFE3 fusion proteins facilitated the progression of TFE3 rRCC through enhancing the degradation of LDs via chaperone-mediated lipophagy. LAMP2A could serve as a novel potential prognostic biomarker and therapeutic targets.

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.