Siglec-15 promotes progression of clear renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Yang WB
PROVIDER: S-EPMC8577683 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Siglec-15 promotes progression of clear renal cell carcinoma.
Yang Wen-Bo WB Qin Cai-Peng CP Du Yi-Qing YQ Han Song-Chen SC Xu Tao T
Chinese medical journal 20210922 21
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Project description:BackgroundAccumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown.MethodsThe expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays.ResultscircAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo.ConclusionOur results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC.
| S-EPMC7901094 | biostudies-literature
Project description:In recent decades, substantial advancements in epigenetics have unveiled a profound understanding of its mechanisms in tumorigenesis and have offered promising strategies for epigenetic therapy in cancer patients. In our study, through bioinformatics analysis, we discovered a significant downregulation and hypermethylation of FOXI2 in clear cell renal cell carcinoma (ccRCC), while the expression in chromophobe cell carcinoma (chRCC) exhibited the opposite trend. Moreover, we established a strong correlation between FOXI2 expression levels and the prognosis of ccRCC. Gene enrichment analysis and cell function experiments unequivocally demonstrate that FOXI2 possesses the capability to induce cell cycle arrest and inhibit cell proliferation. Our research findings demonstrate that the expression of FOXI2 in ccRCC is under the regulation of promoter hypermethylation. Furthermore, in vitro experiments have conclusively shown that the overexpression of FOXI2 induces cell cycle arrest and inhibits cell proliferation.
| S-EPMC11016964 | biostudies-literature
Project description:The pioneering work from Lieping Chen's laboratory identified Siglec-15 as a novel tumor immune suppressor, while the regulatory mechanisms underlying the broad upregulation of Siglec-15 in human cancers remain obscure. Here we found that long non-coding RNA (lncRNA) LINC00973 was higher in Siglec-15-positive clear-cell renal cell carcinoma (ccRCC), and LINC00973 positively regulated Siglec-15 expression at transcriptional level. This effect was evidently dependent on miR-7109-3p (designated as miR-7109 hereafter), and we provided evidence that Siglec-15 is a direct target of miR-7109. Through sponging miR-7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec-15, and, consequently, was involved in cancer immune suppression. We further demonstrated that LINC00973 and miR-7109 expression in ccRCC antagonistically influenced immune activation of co-cultured Jurkat cells. Our study highlighted the importance of LINC00973-miR-7109-Siglec-15 in immune evasion in ccRCC, which offers significant opportunity for both therapeutic intervention and diagnostic/prognostic exploitations.
| S-EPMC7541001 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. While the localized form of this disease can be treated surgically, advanced and metastatic stages are resistant to chemotherapies. Although more innovative treatments, such as targeted or immune-based therapies, exist, the need for new therapeutic options remains. ccRCC presents unique metabolic signatures and multiple studies have reported a significant increase in levels of reduced glutathione (GSH) and its precursors in ccRCC tumor samples compared with normal kidney tissues. These observations led us to investigate the effects of blocking the GSH pathway, particularly the gamma-glutamyltransferase 1 (GGT1) enzyme, in multiple ccRCC cell lines. In this study, we provide in vitro and in vivo evidence that GGT1/GSH pathway inhibition impacts ccRCC cell growth, through increased cell-cycle arrest. Of note, GGT1 inhibition also impairs ccRCC cell migration. Finally, pharmacologic GSH pathway inhibition decreases ccRCC cell proliferation and increases sensitivity to standard chemotherapy. Our results suggest that GGT1/GSH pathway inhibition represents a new strategy to overcome ccRCC chemoresistance. IMPLICATIONS: GGT1/GSH pathway inhibition represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.
| S-EPMC6726546 | biostudies-literature
Project description:OBJECTIVE:The most common kidney cancer, clear cell renal cell carcinoma (ccRCC), is closely associated with obesity. The "clear cell" variant of RCC gets its name from the large lipid droplets that accumulate in the tumor cells. Although renal lipid metabolism is altered in ccRCC, the mechanisms and lipids driving this are not well understood. METHODS:We used shotgun lipidomics in human ccRCC tumors and matched normal adjacent renal tissue. To assess MBOAT7s gene expression across tumor severity, we examined histologically graded human ccRCC samples. We then utilized genome editing in ccRCC cell lines to understand the role of MBOAT7 in ccRCC progression. RESULTS:We identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7-/- cells fail to form tumors in vivo. RNAseq of MBOAT7-/- cells identified alterations in cell migration and extracellular matrix organization that were functionally validated in migration assays. CONCLUSIONS:This study highlights the accumulation of AA-PI in ccRCC and demonstrates a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism and identify MBOAT7 as a novel target in advanced ccRCC.
| S-EPMC7033598 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is one of the most common urological malignancies. Identifying novel biomarkers and investigating the underlying mechanism of ccRCC development will be crucial to the management and treatment of ccRCC in patients. Thymosin b10 (TMSB10), a member of the thymosin family, is involved in various physiological processes, including tissue regeneration and inflammatory regulation. Moreover, it has been found to be upregulated in many types of carcinoma. However, its roles in ccRCC remain to be elucidated. The present study aimed to explore the expression of TMSB10 in ccRCC through mining The Cancer Genome Atlas (TCGA) and Oncomine databases, and to investigate the association between TMSB10 expression and clinicopathological factors. Furthermore, immunohistochemistry assays and western blotting were conducted to verify TMSB10 expression levels in human ccRCC tissues and cell lines. Functional analyses were also performed to identify the roles of TMSB10 in vitro. The results revealed that TMSB10 was significantly upregulated in RCC tissues and cell lines. The expression of TMSB10 was closely associated with various clinicopathological parameters. In addition, high expression of TMSB10 predicted poor clinical outcome. The receiver operating characteristic curve revealed that TMSB10 could sufficiently distinguish the tumor from normal kidney (area under the curve = 0.9543, P<0.0001). Furthermore, knockdown of TMSB10 impaired the proliferation of ccRCC cells, and attenuated cell and invasion in vitro. In addition, TMSB10 knockdown downregulated reduced the phosphorylation of PI3K and the expression of vascular endothelial growth factor. In conclusion, the present study demonstrated that high expression of TMSB10 could serve as a useful diagnostic and prognostic biomarker and a potential therapeutic target for ccRCC.
| S-EPMC7115359 | biostudies-literature
Project description:The carcinogenesis and progression of renal cell carcinoma (RCC), a heterogeneous cancer derived from renal tubular epithelial cells, is closely related to oxidative stress responses (OSRs). Oxidative stress responses participate in various biological processes related to the metabolism and metastatic potential of cancer such as inflammation, epithelial-mesenchymal transition (EMT), and angiogenesis. In this study, we investigated the role of broad complex-tramtrack-bric-a-brac and cap 'n' collar homology 1 (BACH1), a key transcription factor for OSRs, in clear cell RCC (ccRCC) development and prognosis. The poor prognosis and elevation of serum inflammation markers in nephrectomized ccRCC patients were correlated with the intratumor expression of BACH1 accompanied by a downregulation of heme oxygenase-1. BACH1 contributes to the invasion and migration abilities of RCC cell lines without affecting their proliferation in vitro. In contrast, BACH1 contributes to tumor progression in vivo, in relation to OSRs with the activation of EMT-related pathways. BACH1 involvement in other OSR-linked pathways, including inflammatory responses, angiogenesis, and mTOR signaling, was further revealed by RNA sequencing analysis of BACH1-knockdown cells. In conclusion, the crucial role of BACH1 in the pathogenesis and poor prognosis of ccRCC through the promotion of OSRs is suggested.
| S-EPMC9899607 | biostudies-literature
Project description:Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients' clinical information have revealed leptin's prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.
| S-EPMC7999177 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma and exhibits a high risk of invasion and metastasis. It is urgent to uncover a novel biomarker and clarify the underlying mechanism for ccRCC progression and metastasis. Although accumulating research has demonstrated that long non-coding RNAs (lncRNAs) play crucial roles in tumor progression, numerous lncRNAs in ccRCC are largely unknown. Therefore, we screened the differentially expressed lncRNAs among several GEO datasets and chose LNC00160 for further investigation. LNC00160 was significantly upregulated in ccRCC and high expression predicted poor prognosis; higher expression of LNC00160 was associated with advanced clinic pathological parameters in TCGA_KIRC Cohort. Knockdown of LNC00160 suppressed malignancy of ccRCC in vitro and in vivo. Correlation analysis and gene set enrichment analysis (GSEA) revealed that LNC00160 might be associated with Wnt signaling pathway, mTOR signaling pathway, fatty acid metabolism and cell cycle. In conclusion, our results demonstrated that LNC00160 acted as an oncogenic gene and a specific prognostic indicator for patients with ccRCC, and that LNC00160 might be a targeted intervention for ccRCC patients in the future.
| S-EPMC7202521 | biostudies-literature
Project description:ObjectivesClear cell renal cell carcinoma (ccRCC) is characterized histologically by accumulation of cholesterol esters, cholesterol and other neutral lipids. Lysosomal acid lipase (LAL) is a critical enzyme involved in the cholesterol ester metabolism. Here, we sought to determine whether LAL could orchestrate metabolism of cholesterol esters in order to promote ccRCC progression.Materials and methodsQuantitative reverse-transcription PCR and western blots were conducted to assess the expression of LAL in human ccRCC tissues. We analysed the relationship between LAL levels and patient survival using tissue microarrays. We used cell proliferation assays, colony formation assays, cell death assays, metabolic assays and xenograft tumour models to evaluate the biological function and underlying mechanisms.ResultsLAL was up-regulated in ccRCC tissue. Tissue microarray analysis revealed higher levels of LAL in advanced grades of ccRCC, and high LAL expression indicated lower patient survival. Suppressing LAL expression not only blocked the utilization of cholesterol esters but also impaired proliferation and cellular survival. Furthermore, immunohistochemistry staining showed that LAL expression was correlated with Akt phosphorylation. Suppressing LAL expression decreased the phosphorylation level of Akt and Src and reduced the level of 14,15-epoxyeicosatrienoic acids in ccRCC cells. Supplement of 14,15-epoxyeicosatrienoic acids rescued proliferation in vitro and in vivo.ConclusionsLAL promoted cell proliferation and survival via metabolism of epoxyeicosatrienoic acids and activation of the Src/Akt pathway.
| S-EPMC6528899 | biostudies-literature