Targeting a positive regulatory loop in the tumor-macrophage interaction impairs the progression of clear cell renal cell carcinoma

Wang, Chao; Wang, Yuning; Hong, Tianyu; Ye, Jianqing; Chu, Chuanmin; Zuo, Li; Zhang, Jing; Cui, Xingang

doi:10.1038/s41418-020-00626-6

Cited by 30 publications

(27 citation statements)

References 36 publications

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“…RCC tissue microarrays (TMAs) of 407 patients from Shanghai Changhai Hospital were included in this study; they involved two series. The rst series (TMA-30) consisted of 29 patients with ccRCC (from our previous research) (15,16), who underwent surgery from 2010 to 2015. Follow-up of all patients in TMA-30 via telephone interviews con rmed either disease progression (recurrence/metastasis) or cancerrelated death.…”

Section: Patients and Specimensmentioning

confidence: 99%

“…They act through a variety of mechanisms to compromise the effects of treatment with TKIs and ICIs, including the promotion of angiogenesis (12), acceleration of tumor growth (13), and suppression of antitumor immunity (14). We have previously reported that several molecules, such as SRY-box transcription factor 17 (SOX17) (15) and gankyrin (16), can regulate the function of TAMs to facilitate the progression of ccRCC. Hence, targeting TAMs is a potential option for developing treatments against ccRCC and obtaining a synergic effect from the utilization of TKIs and ICIs (17).…”

Section: Introductionmentioning

confidence: 99%

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FCER1G Positively Relates To Macrophage Infiltration In Clear Cell Renal Cell Carcinoma And Contributes To Unfavorable Prognosis By Regulating Tumor Immunity

Dong

Chen

Pan

et al. 2021

Preprint

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Background: Tumor-associated macrophages (TAMs) are closely related to unfavorable prognosis of patients with clear cell renal cell carcinoma (ccRCC). However, the important molecules in the interaction between ccRCC and TAMs are unclear.Methods: TCGA-KIRC gene expression data of tumor tissues and normal tissues adjacent to tumor were compared to identify differentially expressed genes in ccRCC. TAMs related genes were discovered by analyzing the correlation between these differentially expressed genes and common macrophage biomarkers. Gene set enrichment analysis was performed to predict functions of TAMs related gene. The findings were further validated using RNA sequencing data obtained from the CheckMate 025 study and immunohistochemical analysis of samples from 350 patients with ccRCC. Kaplan–Meier survival curve, Cox regression analysis and Harrell’s concordance index analysis were used to determine the prognostic significance.Results: In this study, we applied bioinformatic analysis to explore TAMs related differentially expressed genes in ccRCC and identified 5 genes strongly correlated with all selected macrophage biomarkers: STAC3, LGALS9, TREM2, FCER1G, and PILRA. Among them, FCER1G was abundantly expressed in tumor tissues and showed prognostic importance in patients with ccRCC who received treatment with Nivolumab; however, it did not exhibit prognostic value in those treated with Everolimus. We also discovered that high expression levels of FCER1G are related to T cell suppression. Moreover, combination of FCER1G and macrophage biomarker CD68 can improve the prognostic stratification of patients with ccRCC from TCGA-KIRC. Based on the immunohistochemical analysis of samples from patients with ccRCC, we further validated that FCER1G and CD68 are both highly expressed in tumor tissue and correlate with each other. Higher expression of CD68 or FCER1G in ccRCC tissue indicates shorter overall survival and progression-free survival; patients with high expression of both CD68 and FCER1G have the worst outcome. Combining CD68 and FCER1G facilitates the screening of patients with a worse prognosis from the same TNM stage group.Conclusions: High expression of FCER1G in ccRCC is closely related to TAMs infiltration and suppression of T cell function. Combining the expression levels of FCER1G and macrophage biomarker CD68 may be a promising postoperative prognostic index for patients with ccRCC.

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Section: Patients and Specimensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FCER1G Positively Relates To Macrophage Infiltration In Clear Cell Renal Cell Carcinoma And Contributes To Unfavorable Prognosis By Regulating Tumor Immunity

Dong

Chen

Pan

et al. 2021

Preprint

Self Cite

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“… 35 Wang et al reported that TAMs promote metastasis and drug resistance of ccRCC through secretion of SOX17. 36 In addition, tumor-infiltrating macrophages secrete IL-23 and enhance Treg function. 37 In this study, we observed that the ratios of M2 macrophages were higher in the early stage of ccRCC, indicating that M2 macrophages play an important role in forming the immunosuppressive microenvironment in the early phase of the tumor.…”

Section: Discussionmentioning

confidence: 99%

Global Characterization of Immune Infiltration in Clear Cell Renal Cell Carcinoma

Zheng¹,

Wen²,

Cao³

et al. 2021

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Background: Immunotherapy has revolutionized the treatment of clear cell renal cell carcinoma (ccRCC). However, the therapy is constrained by drug resistance. Therefore, further characterization of immune infiltration in ccRCC is needed to improve its efficacy. Methods: Here, we adopted the CIBERSORT method to analyze the level of 22 immune cells, and analyzed the correlation of immune cells and clinical parameters in ccRCC in The Cancer Genome Atlas. We used consensus clustering to cluster ccRCC and identified differently expressed genes (DEGs) between hot and cold tumors using the "Limma" package, and then performed enrichment analysis of DEGs. Finally, we constructed and validated a Cox regression model using the "survival", "glmnet", and "survivalROC" packages, implemented in R. Results: Regulatory T cells upregulated in tumor tissue increased during tumor progression, and correlated with poor overall survival in ccRCC. Consensus clustering identified four clusters of ccRCC. To elucidate the underlying mechanisms of immune cell infiltration, we subdivided these four clusters into two major types, immune hot and cold, and identified DEGs between them. The results revealed different transcription profiles in the two tumor types, with hot tumors being enriched in immune-related signaling, whereas cold tumors were enriched in extracellular matrix remodeling and the phosphatidylinositol 3-kinase-AKT (PI3K/AKT) pathway. We further identified hub genes and prognosticrelated genes from the DEGs, and constructed a Cox regression model for predicting the overall survival of patients with ccRCC. The areas under the receiver operating characteristics curve for the risk model for the training, testing, and external Zhengzhou validation cohorts were 0.834, 0.733, and 0.812, respectively. Notably, gene sets in the prediction model could also predict the overall survival of patients receiving immunotherapy. Conclusion: These findings provide a comprehensive characterization of immune infiltration in ccRCC, while the constructed model can be used effectively to predict the overall survival of ccRCC patients.

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“…A recent study has reported that downregulation of SOX17 facilitates the targeted drug resistance and progression of clear cell renal cell carcinoma (ccRCC), which suggests SOX17 as a potential target for inhibiting targeted drug resistance and metastasis in advanced ccRCC. 31 According to these results, we proposed that restoring SOX17 expression may present a new strategy for suppressing targeted drug resistance and progression of ccRCC. Deregulation of the WNT signaling pathway, as shown in several reports, is associated with RCC carcinogenesis.…”

mentioning

confidence: 98%

“…Deregulation of the WNT signaling pathway, as shown in several reports, is associated with RCC carcinogenesis. 31 In RCC, the WNT signaling pathway is also influenced by altered epigenetic regulation. Many WNT antagonists including SFRP1, SFRP2, DKK1, DKK2 and DKK3 [32][33][34][35] are inactivated by promoter methylation, resulting in the suppression of the negative regulation of WNT signaling.…”

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confidence: 99%

SOX17 Antagonizes the WNT Signaling Pathway and is Epigenetically Inactivated in Clear-Cell Renal Cell Carcinoma

Wang

Zhu

et al. 2021

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Background: SRY-box containing gene 17 (SOX17) was reported to be a candidate tumor suppressor gene in multiple tumors. Little is known about its role in clear-cell renal cell carcinoma (ccRCC). This study aims to identify the epigenetic regulation and tumorsuppressive function of SOX17 in ccRCC. Patients and Methods: Fifty-five human ccRCC tissue samples, ten adjacent nonmalignant kidney tissue samples, 20 paired paraffin section tissues and seven RCC cell lines were obtained. Immunohistochemistry (IHC) and real-time PCR were used to examine the expression of the target genes at the mRNA and protein levels. The methylation of SOX17 was analyzed using methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) assay. The functions of SOX17 were examined by using CCK8, colony formation, wound healing assay and Matrigel invasion assays. Luciferase assay was used to analyze the function of SOX17 in the WNT signaling pathway. Results: We investigated the SOX17 expression in ccRCC tissues and adjacent non-malignant kidney tissues using PCR and IHC. The expression of SOX17 was lower in ccRCC tissues. Next, we analyzed the DNA promoter methylation of SOX17 in 55 human ccRCC tissues, 10 adjacent non-malignant kidney tissues and RCC cell lines using MSP. DNA methylation of the SOX17 promoter region occurred in 60% of ccRCC tissues and 10% of adjacent non-malignant kidney tissues. In vitro experiments showed that SOX17 suppressed the proliferation of RCC cells. Furthermore, SOX17 inhibited the migration of RCC cells as shown in the wound healing and migration assays. In addition, we found that SOX17 overexpression affected the WNT signaling pathway by downregulating c-myc and cyclinD1. Conclusion:In summary, our study showed that SOX17 is downregulated in ccRCC and the loss of SOX17 expression is regulated via epigenetic mechanisms in ccRCC. In addition, SOX17 negatively regulates the WNT signaling pathway and function as a tumor suppressor in ccRCC.

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Targeting a positive regulatory loop in the tumor-macrophage interaction impairs the progression of clear cell renal cell carcinoma

Cited by 30 publications

References 36 publications

FCER1G Positively Relates To Macrophage Infiltration In Clear Cell Renal Cell Carcinoma And Contributes To Unfavorable Prognosis By Regulating Tumor Immunity

FCER1G Positively Relates To Macrophage Infiltration In Clear Cell Renal Cell Carcinoma And Contributes To Unfavorable Prognosis By Regulating Tumor Immunity

Global Characterization of Immune Infiltration in Clear Cell Renal Cell Carcinoma

SOX17 Antagonizes the WNT Signaling Pathway and is Epigenetically Inactivated in Clear-Cell Renal Cell Carcinoma

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