The miR-487b-3p/GRM3/TGFβ signaling axis is an important regulator of colon cancer tumorigenesis.
The miR-487b-3p/GRM3/TGFβ signaling axis is an important regulator of colon cancer tumorigenesis.
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DOI：
10.1038/onc.2016.499
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发表时间：
2017-06-15
期刊：
影响因子：
8
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yi H;Geng L;Black A;Talmon G;Berim L;Wang J
分子靶向治疗是治疗晚期结肠癌的重要策略。目前的研究表明，GRM 3，主要在哺乳动物中枢神经系统中表达的代谢型谷氨酸受体，在大多数测试的人结肠腺癌和结肠癌细胞系中显著上调。结肠癌细胞中GRM 3表达的敲低或GRM 3活化的抑制降低了体外细胞存活和锚定非依赖性生长，并抑制了体内肿瘤生长。在机制上，GRM 3拮抗TGFβ介导的蛋白激酶A的活化和AKT的抑制。此外，TGFβ信号传导增加了GRM 3蛋白的稳定性，并且GRM 3的敲低增强了TGFβ介导的肿瘤抑制功能。进一步的研究表明，miR-487 b-3 p直接靶向GRM 3。miR-487 b-3 p的过表达模拟GRM 3敲低的作用并抑制体内结肠癌细胞的致瘤性。miR-487 b-3 p在结肠腺癌中的表达降低，并与GRM 3表达呈负相关。总之，这些研究表明GRM 3表达的上调是结肠癌中功能重要的分子事件，并且GRM 3是结肠癌治疗的有希望的分子靶点。从治疗的观点来看，这是特别令人感兴趣和重要的，因为许多代谢型谷氨酸受体拮抗剂是可用的，其中许多已被发现不适合用于治疗神经精神障碍，原因是例如不能容易地穿透血脑屏障。由于GRM 3在结肠癌中上调，但很少在正常外周组织中表达，因此用此类试剂靶向GRM 3不太可能引起不良的神经或外周副作用，使GRM 3成为结肠癌治疗的有吸引力的特异性分子靶标。
Molecular targeting is an import strategy to treat advanced colon cancer. The current study demonstrates that expression of GRM3, a metabotropic glutamate receptor mainly expressed in mammalian central nervous system, is significantly upregulated in majority of human colonic adenocarcinomas tested and colon cancer cell lines. Knockdown of GRM3 expression or inhibition of GRM3 activation in colon cancer cells reduces cell survival and anchorage-independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, GRM3 antagonizes TGFβ-mediated activation of protein kinase A and inhibition of AKT. In addition, TGFβ signaling increases GRM3 protein stability and knockdown of GRM3 enhances TGFβ-mediated tumor suppressor function. Further studies indicate that miR-487b-3p directly targets GRM3. Overexpression of miR-487b-3p mimics the effects of GRM3 knockdown and suppresses the tumorigenicity of colon cancer cells in vivo. Expression of miR-487b-3p is decreased in colon adenocarcinomas and inversely correlates with GRM3 expression. Taken together, these studies indicate that upregulation of GRM3 expression is a functionally important molecular event in colon cancer, and that GRM3 is a promising molecular target for colon cancer treatment. This is particularly interesting and important from a therapeutic standpoint because numerous metabotropic glutamate receptor antagonists are available, many of which have been found unsuitable for treatment of neuropsychiatric disorders for reasons such as inability to readily penetrate blood brain barriers. Since GRM3 is upregulated in colon cancer, but rarely expressed in normal peripheral tissues, targeting GRM3 with such agents would not likely cause adverse neurological or peripheral side effects, making GRM3 an attractive and specific molecular target for colon cancer treatment.
影响因子：
3.8
作者：
Simms NA;Rajput A;Sharratt EA;Ongchin M;Teggart CA;Wang J;Brattain MG
通讯作者：
Brattain MG