Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization.
Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization.
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DOI：
10.1371/journal.pone.0052397
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rao MK
中科院分区：
文献类型：
--
作者：
Imam JS;Plyler JR;Bansal H;Prajapati S;Bansal S;Rebeles J;Chen HI;Chang YF;Panneerdoss S;Zoghi B;Buddavarapu KC;Broaddus R;Hornsby P;Tomlinson G;Dome J;Vadlamudi RK;Pertsemlidis A;Chen Y;Rao MK
越来越多的证据表明，含有 microRNA 的染色体区域在癌症中具有重要的功能。在这里，我们发现编码 miR-204 的基因组位点在多种癌症中经常丢失，包括卵巢癌、小儿肾肿瘤和乳腺癌。 MiR-204 在多种癌症中的表达显着降低，并作为有效的肿瘤抑制剂，在全身递送时抑制体内肿瘤转移。我们证明，miR-204 通过靶向参与肿瘤发生的基因发挥其功能，包括脑源性神经营养因子（BDNF），脑源性神经营养因子是一种神经营养蛋白家族成员，已知可促进肿瘤血管生成和侵袭。对原发性肿瘤的分析表明，BDNF 或其受体原肌球蛋白相关激酶 B (TrkB) 表达增加与 miR-204 表达显着减少同时发生。我们的结果表明，miR-204 的缺失导致 BDNF 过度表达，并随后通过 AKT/mTOR 信号通路激活小 GTPase Rac1 和肌动蛋白重组，从而导致癌细胞迁移和侵袭。这些结果表明，含有 miR-204 的基因组位点的微缺失与对肿瘤生长和转移提供关键刺激的关键致癌途径的失调直接相关。我们的研究结果为通过治疗手段控制 miR-204 水平以抑制肿瘤转移提供了强有力的理论依据。
Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.
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影响因子：
9.2
作者：
Higuchi, M;Masuyama, N;Gotoh, Y
通讯作者：
Gotoh, Y
DOI：
10.1098/rstb.1996.0035
发表时间：
1996-03-29
期刊：
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
Lewin, GR
通讯作者：
Lewin, GR
MicroRNA-204 在体外和体内调节血管平滑肌细胞钙化。
影响因子：
10.8
作者：
Cui, Rong-Rong;Li, Shi-Jun;Liao, Er-Yuan
通讯作者：
Liao, Er-Yuan
影响因子：
5
作者：
Edsjö, A;Lavenius, E;Påhlman, S
通讯作者：
Påhlman, S
影响因子：
8
作者：
Imam, J. S.;Buddavarapu, K.;Rao, M. K.
通讯作者：
Rao, M. K.