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Let-7d suppresses growth, metastasis, and tumor macrophage infiltration in renal cell carcinoma by targeting COL3A1 and CCL7
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  • 作者:Boxing Su (7) (8)
    Wei Zhao (9)
    Bentao Shi (10)
    Zhongyuan Zhang (7) (8)
    Xi Yu (7) (8)
    Feng Xie (7) (8)
    Zhongqiang Guo (7) (8)
    Xiaoyu Zhang (7) (8)
    Jin Liu (7) (8)
    Qi Shen (11)
    Jinghua Wang (11)
    Xuesong Li (7) (8)
    Zhiqian Zhang (9)
    Liqun Zhou (7) (8)

    7. Department of Urology
    ; Peking University First Hospital & the Institute of Urology ; Peking University ; Beijing ; 100034 ; China
    8. National Urological Cancer Center
    ; Beijing ; 100034 ; China
    9. Department of Cell Biology
    ; Peking University School of Oncology ; Beijing Cancer Hospital and Institute ; Beijing ; 100142 ; China
    10. Department of Urology
    ; Peking University Shenzhen Hospital ; Shenzhen ; Guangdong ; 518036 ; China
    11. Department of Urological pathology
    ; Peking University First Hospital & the Institute of Urology ; Peking University ; Beijing ; 100034 ; China
  • 关键词:Renal cell carcinoma ; MicroRNA ; Let ; 7
  • 刊名:Molecular Cancer
  • 出版年:2014
  • 出版时间:December 2014
  • 年:2014
  • 卷:13
  • 期:1
  • 全文大小:5,033 KB
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  • 刊物主题:Cancer Research; Oncology;
  • 出版者:BioMed Central
  • ISSN:1476-4598
文摘
Background MicroRNAs are endogenous small noncoding RNAs that are functionally involved in numerous critical cellular processes including tumorigenesis. Data mining using a microRNA array database suggested that let-7d microRNA may be associated with renal cell carcinoma (RCC) malignant progression. Here, we performed further analyses to determine whether let-7d is functionally linked to RCC malignancy. Methods Quantitative real-time PCR was used to determine the level of mature let-7d in RCC clinical specimens and its correlation with clinicopathological data. Immunohistochemical staining was conducted to characterize the stroma of RCC. Let-7d overexpressing RCC cell lines combined with mouse models bearing cell-derived xenografts and patient-derived xenografts were used to assess the functional role of let-7d in vitro and in vivo. Results Downregulation of let-7d in clinical RCC samples was associated with advanced tumor grade and T stage and increased vascular invasion. An inverse relationship between let-7d expression and macrophage infiltration was found in clinical RCC samples. Functional studies indicated that ectopic expression of let-7d significantly inhibited RCC cell proliferation, migration, and peripheral blood monocyte (PBMC) recruitment in vitro, as well as tumor growth, metastasis, and tumor macrophage infiltration in vivo. In silico analysis and subsequent experimental validation confirmed collagen, type III, alpha 1 (COL3A1) and C-C subfamily chemokine member CCL7 as direct let-7d target genes. The addition of COL3A1 and CCL7 counteracted the inhibitory effects of let-7d on RCC cell proliferation, migration, and PBMC recruitment. The inhibition of let-7d increased cell proliferation, migration, and PBMC recruitment by the enhanced expression of COL3A1 and CCL7 genes in vitro. The mRNA levels of COL3A1 and CCL7 were inversely correlated with let-7d level in RCC clinical specimens. Conclusions These results suggest that let-7d may suppress RCC growth, metastasis, and tumor macrophage infiltration at least partially through targeting COL3A1 and CCL7.

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