Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Mol Cancer. 2011 May 19;10:59. doi: 10.1186/1476-4598-10-59.
Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.
We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.
These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.
星形细胞瘤是最常见和最具侵袭性的脑肿瘤，其特征为高度浸润性生长。染色体 7 获得，其热点位于 7q32，似乎是星形细胞瘤中最突出的异常。以前的报告表明，位于染色体 7q32 的 microRNA-335（miR-335）在许多癌症中失调；然而，miR-335 在星形细胞瘤中的生物学功能尚未阐明。
我们报告 miR-335 作为一种肿瘤促进因子，赋予恶性星形细胞瘤肿瘤发生特征，如生长和侵袭。C6 星形细胞瘤细胞和人恶性星形细胞瘤中 miR-335 水平高度升高。C6 细胞中 miR-335 的异位表达显著增强细胞活力、集落形成能力和侵袭能力。相反，向 C6 细胞递送针对 miR-335 的拮抗剂（antagomir-335）导致生长停滞、细胞凋亡、侵袭抑制和星形细胞瘤异种移植物的明显消退。进一步的研究表明，miR-335 在转录后水平靶向形态发生相关的卷曲蛋白激活物 1（Daam1）。此外，内源性 Daam1 的沉默（siDaam1）可以模拟 miR-335 的致癌作用，并逆转 antagomir-335 诱导的生长停滞、促凋亡和侵袭抑制作用。值得注意的是，miR-335 的致癌作用和 siDAAM1 以及 antagomir-335 的抗肿瘤作用在人星形细胞瘤 U87-MG 细胞中也得到了证实。
这些发现表明 miR-335 具有致癌作用，并为通过靶向 miR-335 治疗恶性星形细胞瘤提供了新的思路。
