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Gene expression changes in 786-O cells in response to Everolimus, SGI-1027, or their combination.

ABSTRACT: Renal cell carcinoma (RCC) is one of the most common malignant tumors of urinary system. The Food and Drug Administration (FDA) has approved everolimus for the treatment of advanced RCC, but r everolimus resistance limits its application in clinic. We here reported the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 as an inducer of methuosis, a type of cell death form independent of apoptosis. Additionally, SGI-1027 and everolimus worked in concert to suppress the proliferation, migration, and invasion of renal cancer cells while also inducing apoptosis and GSDME-dependent pyroptosis. In vitro transplanted tumor mice models, everolimus combined with SGI-1027 played a significant inhibitory effect on the growth of renal cancer tumors with good tolerance. The objective of this study is to explore the mechanism of the synergistic effect of everolimus and SGI-1027. We demonstrated through analysis of transcriptome high-throughput sequencing data that lysosomes were strongly linked with the synergistic effect of everolimus and SGI-1027 at the transcriptional level, which provides a new strategy for everolimus resistance and the treatment of advanced RCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242110 | GEO | 2024/10/23

REPOSITORIES: GEO

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Project description:Background: Advanced Renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs’ migration to RCC remain unknown. Here, we comprehensively analyzed RCC secretome to identify MSCs attractants. Methods: Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T, KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. Results: When compared with normal cells, CM from advanced RCC cell lines (Caki-1, KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1, and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs’ transcriptional reprogramming, stimulating the expression of CD44, PTX3, and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs’ homing to the kidney. AREG emerged as an upregulator of MSCs’ transcription. Conclusions: advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs’ transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets. We used microarrays to determine the effect of the conditioned media (CM) collected from two RCC-derived cell lines (Caki-1, KIJ265T) and non-tumorous control cell line (RPTEC/TERT1) on the transcriptome change in mesenchymal stem/stromal cells (MSCs).

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Gene expression changes in 786-O cells in response to Everolimus, SGI-1027, or their combination.

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