Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors.
Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors.
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DOI：
10.1053/j.gastro.2011.07.038
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发表时间：
2011-11
期刊：
影响因子：
29.4
通讯作者：
Pothoulakis C
中科院分区：
文献类型：
--
作者：
Bakirtzi K;Hatziapostolou M;Karagiannides I;Polytarchou C;Jaeger S;Iliopoulos D;Pothoulakis C
神经降压素（NT）通过NT受体-1（NTR 1）促进结肠癌和炎症。microRNA通过靶向mRNA来调节蛋白质合成。我们确定了NTR 1刺激人结肠（NCM 460）上皮细胞的microRNA特征。来自NT刺激的过表达NTR 1的NCM 460细胞的RNA用于微阵列表达分析。通过序列同源性、ChIP-分析和qPCR鉴定NF-κB结合位点。通过软琼脂试验和SCID小鼠中的HCT-116肿瘤异种移植物评估肿瘤发生。通过生物信息学、真实的时间PCR和Western blot鉴定NT调控的microRNA的下游靶点。NT刺激了38种microRNA的差异表达。我们鉴定了miR-21和miR-155上的NF-κB结合位点，这些位点先前与肿瘤生长有关。NT增加了HCT-116细胞的集落数量，而针对miR-21和/或miR-155的反义microRNA抑制了这种反应（p<0.001）。NT给药（i. p.）增加了异种移植肿瘤中的肿瘤生长速率，而miR-21和/或miR-155反义减弱了这种应答。由于miR-21和miR-155的潜在下游靶点分别是PTEN和SOCS 1，并且两者都在Akt的上游，因此我们研究了NT对Akt活化的影响。NT激活HCT-116细胞中的Akt，这一作用被miR-21和/或miR-155反义抑制（p<0.001）。我们首次报道PPP 2CA磷酸酶作为miR-155靶点发挥NT对Akt的作用。NT通过Akt和NF-κB刺激结肠细胞中miR-21和miR-155的表达，并且这两种microRNA响应于NT介导结肠肿瘤生长。重要的是，发现这种NT-microRNA回路在人类结肠癌中受到干扰，并与肿瘤阶段相关，表明其与人类结肠癌发生相关。
Neurotensin (NT) promotes colon cancer and inflammation via NT receptor-1 (NTR1). MicroRNAs regulate protein synthesis by targeting mRNAs. We determined the microRNA signature of NTR1 stimulation on human colonic (NCM460) epithelial cells. RNA from NT-stimulated NCM460 cells overexpressing NTR1 was used for microarray expression analysis. NF-κB binding sites were identified by sequence homology, ChIP-assay and qPCR. Tumorigenesis was assessed by the soft agar assay and HCT-116 tumor xenografts in SCID mice. Down-stream targets of NT-regulated microRNAs were identified via bioinformatics, real time PCR and Western blot. NT stimulated differential expression of 38 microRNAs. We identified NF-κB binding sites on miR-21 and miR-155, previously implicated in tumor growth. NT increased the number of colonies of HCT-116 cells and antisense-microRNAs against miR-21 and/or miR-155 inhibited this response (p<0.001). NT administration (i.p.) increased the rate of tumor growth in xenograft tumors while miR-21 and/or miR-155 antisense attenuated this response. Since potential downstream targets of miR-21 and miR-155 are PTEN and SOCS1, respectively, and both are upstream of Akt, we investigated the effect of NT on Akt activation. NT activated Akt in HCT-116 cells, an effect inhibited by miR-21 and/or miR-155 antisense (p<0.001). We report for the first time PPP2CA phosphatase as a miR-155 target exerting the effects of NT on Akt. NT stimulates miR-21 and miR-155 expression in colonocytes via Akt and NF-κB, and both microRNAs mediate colon tumor growth in response to NT. Importantly, this NT-microRNA circuit is found perturbated in human colon cancers and correlates with tumor stage, suggesting its relevance to human colon carcinogenesis.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
29.4
作者：
McKenna LB;Schug J;Vourekas A;McKenna JB;Bramswig NC;Friedman JR;Kaestner KH
通讯作者：
Kaestner KH
DOI：
10.1073/pnas.93.22.12611
发表时间：
1996-10-29
影响因子：
11.1
作者：
Castagliuolo, I;Leeman, SE;Pothoulakis, C
通讯作者：
Pothoulakis, C
DOI：
10.1073/pnas.93.21.11382
发表时间：
1996-10-15
影响因子：
11.1
作者：
Naldini, L;Blomer, U;Verma, IM
通讯作者：
Verma, IM