Let-7d suppresses growth, metastasis, and tumor macrophage infiltration in renal cell carcinoma by targeting COL3A1 and CCL7.
Let-7d suppresses growth, metastasis, and tumor macrophage infiltration in renal cell carcinoma by targeting COL3A1 and CCL7.
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Let-7d 通过靶向 COL3A1 和 CCL7 抑制肾细胞癌的生长、转移和肿瘤巨噬细胞浸润
DOI：
10.1186/1476-4598-13-206
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发表时间：
2014-09-06
期刊：
影响因子：
37.3
通讯作者：
Zhou L
中科院分区：
文献类型：
--
作者：
Su B;Zhao W;Shi B;Zhang Z;Yu X;Xie F;Guo Z;Zhang X;Liu J;Shen Q;Wang J;Li X;Zhang Z;Zhou L
micrornas是内源性小的非编码rna，在功能上参与了包括肿瘤发生在内的许多关键细胞过程。使用microRNA阵列数据库的数据挖掘表明let-7d microRNA可能与肾细胞癌（RCC）恶性进展有关。在这里，我们进行了进一步的分析，以确定let-7d是否在功能上与RCC恶性肿瘤相关。方法采用实时荧光定量PCR法测定肾小细胞癌临床标本中成熟let-7d的水平及其与临床病理资料的相关性。采用免疫组化染色对RCC间质进行表征。利用过表达Let-7d的RCC细胞系与细胞源异种移植物和患者源异种移植物小鼠模型结合，评估Let-7d在体外和体内的功能作用。结果在临床RCC样本中，let-7d的下调与肿瘤分级、T分期和血管侵袭增加有关。在临床RCC样本中发现let-7d表达与巨噬细胞浸润呈负相关。功能研究表明，let-7d的异位表达可显著抑制体外RCC细胞的增殖、迁移和外周血单核细胞（PBMC）的募集，以及体内肿瘤的生长、转移和肿瘤巨噬细胞的浸润。在硅分析和随后的实验验证中证实胶原蛋白，III型，α 1 （COL3A1）和C-C亚家族趋化因子成员CCL7是直接let-7d靶基因。COL3A1和CCL7的加入抵消了let-7d对RCC细胞增殖、迁移和PBMC募集的抑制作用。在体外，let-7d的抑制通过增强COL3A1和CCL7基因的表达，增加了细胞增殖、迁移和PBMC募集。在RCC临床标本中，COL3A1和CCL7 mRNA水平与let-7d水平呈负相关。结论let-7d至少部分通过靶向COL3A1和CCL7抑制RCC生长、转移和肿瘤巨噬细胞浸润。
BackgroundMicroRNAs 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.MethodsQuantitative 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-7din vitroandin vivo.ResultsDownregulation 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) recruitmentin vitro, as well as tumor growth, metastasis, and tumor macrophage infiltrationin vivo. In silicoanalysis 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 genesin vitro. The mRNA levels of COL3A1 and CCL7 were inversely correlated with let-7d level in RCC clinical specimens.ConclusionsThese 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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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
DOI：
10.1016/j.bbrc.2011.11.119
发表时间：
2012-01-06
影响因子：
3.1
作者：
Liu, Yongchao;Yin, Bingde;Fan, Jie
通讯作者：
Fan, Jie
影响因子：
8
作者：
Provenzano, P. P.;Inman, D. R.;Eliceiri, K. W.;Keely, P. J.
通讯作者：
Keely, P. J.
影响因子：
6.4
作者：
Jung, Da-Woon;Che, Zhong Min;Kim, Jin
通讯作者：
Kim, Jin
静脉注射HMSC改善了小鼠的心肌梗塞，因为栓塞在肺中的细胞被激活以分泌抗炎蛋白TSG-6。
影响因子：
23.9
作者：
Lee RH;Pulin AA;Seo MJ;Kota DJ;Ylostalo J;Larson BL;Semprun-Prieto L;Delafontaine P;Prockop DJ
通讯作者：
Prockop DJ