MicroRNA-192 suppresses liver metastasis of colon cancer.
MicroRNA-192 suppresses liver metastasis of colon cancer.
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转移导致大多数结肠癌死亡，但机制的理解和治疗选择仍然有限。在这里，我们发现microRNA（miR）-192的表达与结肠癌细胞的转移潜力呈负相关。miR-192的异位表达使结肠癌细胞对生长因子剥夺应激（GFDS）诱导的凋亡敏感，而miR-192的抑制赋予抗性。miR-192的过表达抑制结肠癌原位小鼠模型中向肝脏的转移定植。与原发性肿瘤中的转移表型相关的改变包括细胞凋亡增加、增殖减少和血管生成。进一步的研究表明，miR-192在体内外下调Bcl-2、Zeb 2和VEGFA的表达，分别导致细胞凋亡增加、E-cadherin表达增加和血管生成减少。最后，对人类结肠腺癌进行的研究表明，与正常结肠上皮相比，肿瘤细胞中miR-192的表达显着降低。重要的是，与I期或II期病变相比，IV期肿瘤中的miR-192表达显著降低。这些发现表明miR-192在结肠癌的发生和发展中起着重要作用。我们的研究强调了miR-192表达在结肠癌中的临床相关性和预后意义。因此，我们的研究的一个主要意义是，miR-192表达的恢复或其靶基因（Bcl-2，Zeb 2或VEGFA）的拮抗作用可能对结肠癌患者的抗转移治疗具有相当大的治疗潜力。
Metastasis causes most deaths from colon cancer yet mechanistic understanding and therapeutic options remain limited. Here we show that expression of microRNA (miR)-192 is inversely correlated with metastatic potential of colon cancer cells. Ectopic expression of miR-192 sensitizes colon cancer cells to growth factor deprivation stress (GFDS)-induced apoptosis whereas inhibition of miR-192 confers resistance. Overexpression of miR-192 inhibits metastatic colonization to the liver in an orthotopic mouse model of colon cancer. Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis. Further studies indicate that miR-192 down-regulates expression of Bcl-2, Zeb2 and VEGFA in vitro and in vivo, which is responsible for enhanced apoptosis, increased expression of E-cadherin and decreased angiogenesis in vivo respectively. Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared to normal colonic epithelium. Importantly, there is a significant decrease of miR-192 expression in stage IV tumors when compared to stage I or II lesions. These findings indicate that miR-192 plays an important role in colon cancer development and progression. Our studies underscore the clinical relevance and prognostic significance of miR-192 expression in colon cancer. Therefore, a major implication of our studies is that restoration of miR-192 expression or antagonism of its target genes (Bcl-2, Zeb2 or VEGFA) may have considerable therapeutic potential for anti-metastatic therapy in patients with colon cancer.
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影响因子：
4.3
作者：
Fang, Ling;Du, William W.;Yang, Burton B.
通讯作者：
Yang, Burton B.
影响因子：
2.7
作者：
Chiang, Yeunpo;Song, Yongxi;Xu, Huimian
通讯作者：
Xu, Huimian
影响因子：
3.7
作者：
Klinger, Markus;Tamandl, Dietmar;Gruenberger, Thomas
通讯作者：
Gruenberger, Thomas
影响因子：
11.2
作者：
Forrester, E;Chytil, A;Moses, HL
通讯作者：
Moses, HL
DOI：
10.1073/pnas.0404432101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Calin, GA;Liu, CG;Croce, CM
通讯作者：
Croce, CM