FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.

Download Full-text

Activation-Induced Cytidine Deaminase Expression Facilitates the Malignant Phenotype and Epithelial-to-Mesenchymal Transition in Clear Cell Renal Cell Carcinoma

DNA and Cell Biology ◽

10.1089/dna.2019.5119 ◽

2020 ◽

Vol 39 (7) ◽

pp. 1299-1312

Author(s):

Zhifei Che ◽

Jinfeng Fan ◽

Zhiyan Zhou ◽

Qi Li ◽

Zhe Ma ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epithelial To Mesenchymal Transition ◽

Clear Cell ◽

Cytidine Deaminase ◽

Malignant Phenotype ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition ◽

Activation Induced Cytidine Deaminase

Download Full-text

Overexpression of CIP2A in clear cell renal cell carcinoma promotes cellular epithelial-mesenchymal transition and is associated with poor prognosis

Oncology Reports ◽

10.3892/or.2015.4217 ◽

2015 ◽

Vol 34 (5) ◽

pp. 2515-2522 ◽

Cited By ~ 7

Author(s):

QIZHEN TANG ◽

QIFEI WANG ◽

GUANG ZENG ◽

QUANLIN LI ◽

TAO JIANG ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Poor Prognosis ◽

Clear Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

Download Full-text

Clear Cell Renal Cell Carcinoma is linked to Epithelial-to-Mesenchymal Transition and to Fibrosis

Physiological Reports ◽

10.14814/phy2.13305 ◽

2017 ◽

Vol 5 (11) ◽

pp. e13305 ◽

Cited By ~ 10

Author(s):

Lea Landolt ◽

Øystein Eikrem ◽

Philipp Strauss ◽

Andreas Scherer ◽

David H. Lovett ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epithelial To Mesenchymal Transition ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

Download Full-text

Downregulation of SNX5 By KLF9 Leads to Clear Cell Renal Cell Carcinoma Progression By Inducing CD44 Internalization and Suppressing Epithelial-to-Mesenchymal Transition

10.21203/rs.3.rs-500950/v1 ◽

2021 ◽

Author(s):

Qingqing Zhou ◽

Jiajun Li ◽

Chao Ge ◽

Jinsi Chen ◽

Wei Tian ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Western Blot ◽

Cell Carcinoma ◽

Renal Cell ◽

Poor Prognosis ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition ◽

E Cadherin

Abstract Background: Aberrant expression of SNX5 can contribute to tumourigenesis, invasion, and metastasis of several human cancers. However, the clinicopathological and biological significance of SNX5 in clear cell renal cell carcinoma (ccRCC) remain unclear. The aim of this study was to examine the role of SNX5 in the progression of ccRCC.Methods: Immunohistochemical (IHC), Western blot, qRT-PCR, western blot, flow cytometry and immunofluorescence were used to detect the expression of indicated molecules. The biological role of SNX5 in ccRCC cells was evaluated by CCK8, colony formation, transwell assay, subcutaneous tumor formation as well as veil tail injection. ChIP assay and luciferase reporter assay were used to determine the direct binding of KLF9 to the promoter of the SNX5 gene.Results: SNX5 expression was downregulated in human ccRCC tissues. SNX5 expression was negatively correlated with tumor size, AJCC stage, tumor thrombus of inferior vena cava (IVC) and poor prognosis of ccRCC. Ectopic expression of SNX5 inhibited ccRCC cell proliferation and metastasis whereas knockdown of SNX5 increase these activities both in vitro and in vivo. Mechanistically, overexpression of SNX5 blocked internalization and intracellular trafficking of CD44 in ccRCC cells. Exogenous expression of CD44 partially rescued the inhibitory effects of SNX5 on the proliferation and invasion activity of ccRCC cells. Knockdown of SNX5 in ccRCC cells was associated with epithelial mesenchymal transition (EMT), including the down-regulation of E-cadherin, ZO-1 and Claudin-1 and the concomitant up-regulation of Snail and N-cadherin. In addition, SNX5 inhibited TGF-β-induced migration, invasion and EMT in ccRCC cells. Moreover, we observed a significant correlation between SNX5 expression and E-cadherin levels in ccRCC patients. In addition, KLF9 directly bound to the SNX5 promoter and increased SNX5 transcription. SNX5 expression was closely correlated with KLF9 expression in ccRCC. Moreover, we found that the combination of SNX5 and CD44 or E-cadherin or KLF9 was a more powerful predictor of poor prognosis than either parameter alone.Conclusion: Collectively, our data reveal a mechanism that KLF9-mediated SNX5 expression was associated with poor prognosis via trafficking of CD44 and promoting EMT in ccRCC. SNX5 may be a potential prognostic biomarker and therapeutic target for patients with ccRCC.

Download Full-text