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CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

ABSTRACT: We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.

SUBMITTER: Arakaki R

PROVIDER: S-EPMC5083746 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

Arakaki Ryuichiro R Yamasaki Toshinari T Kanno Toru T Shibasaki Noboru N Sakamoto Hiromasa H Utsunomiya Noriaki N Sumiyoshi Takayuki T Shibuya Shinsuke S Tsuruyama Tatsuaki T Nakamura Eijiro E Ogawa Osamu O Kamba Tomomi T

Cancer medicine 20160926 10

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expre ...[more]

PMID: 27666332

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Project description:Gasdermin (GSDM) family members are involved in numerous biological processes, including pyroptosis, as well as in the initiation and progression of various types of cancer. However, the specific role of GSDM genes in clear cell renal cell carcinoma (ccRCC) has yet to be fully clarified. The present study investigated the differential expression and genetic alterations GSDM genes, their effects on prognosis and immune modulation, and their functional enrichment in ccRCC. Several bioinformatics databases were used, including UALCAN, The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Metascape, Tumor Immune Estimation Resource, GSCALite and cBioPortal. The results revealed that the expression levels of GSDMA, GSDMB, GSDMC and GSDMD were significantly upregulated in cancer tissues compared with those in paracancerous tissues in patients with ccRCC, whereas the expression of DFNB59 exhibited the opposite trend. The results were experimentally validated in patients with ccRCC, and it was confirmed that the expression levels of GSDMA, GSDMB, GSDMC, GSDMD and GSDME (DFNA5) were significantly enhanced, whereas (PJVK, DFNB59) expression was reduced. In addition, elevated GSDMB, GSDMD and DFNA5 expression levels were clearly associated with worse pathological characteristics of ccRCC, including a high pathological stage and high tumor grade. Furthermore, the high expression levels of GSDMB, GSDMC, GSDMD, DFNA5 and PJVK were shown to be associated with worse overall survival (OS) and progression-free interval in patients with ccRCC. Both univariate and multivariate analyses indicated that the expression of GSDMB was independently associated with the OS of patients with ccRCC. Additionally, a high mutation rate of GSDM genes (33%) was observed in patients with ccRCC, and GSDM gene mutations were also significantly associated with a poor OS in patients with ccRCC. Significant associations between GSDM genes and ccRCC immunoprofiling and drug sensitivity were also determined. In conclusion, the findings of the present study indicated that GSDMB, GSDMD and DFNA5 may be considered promising therapeutic agents and potential biomarkers for patients with ccRCC. Furthermore, GSDMB could act as an independent predictor for the OS of patients with ccRCC.

Project description:Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.

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CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

Publications

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

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