Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, PR China.
Mol Cancer Res. 2013 Mar;11(3):230-9. doi: 10.1158/1541-7786.MCR-12-0632. Epub 2013 Jan 15.
Tiam1 is a rac1-specific guanine nucleotide exchange factor, and Tiam1-rac1 is involved in a number of cellular processes. Rac1 and RhoA act as molecular switches that cycle between GTP- and GDP-bound states to balance the activities of rac1 and RhoA. The downregulation of rac1 activity leads to upregulation of RhoA activity, which promotes invasion and migration of pancreatic cancers cells. At present, however, the role of Tiam1-rac1 and RhoA in pancreatic cancers is not fully understood. We found that Tiam1 was upregulated in pancreatic cancers and was significantly expressed in tumors without lymph node involvement or distant metastasis compared with cancers where there was involvement. Although Tiam1-rac1 signaling promoted pancreatic cancer cell proliferation and tumor growth via the Wnt signaling pathway in vitro and in vivo, inhibiting Tiam1-rac1 signaling did not prolong the overall survival time in vivo. This provided evidence that there was a balance between rac1 and RhoA activities in pancreatic cancers. Furthermore, only the combined inhibition of Tiam1-rac1 and RhoA had a beneficial effect on the growth of pancreatic cancers in vivo. Taken together, these results suggest that the progression of pancreatic tumors is partially controlled by the balance between Tiam1-rac1 and RhoA.
Tiam1 是 Rac1 特异性鸟嘌呤核苷酸交换因子，Tiam1-Rac1 参与许多细胞过程。Rac1 和 RhoA 作为分子开关，在 GTP 和 GDP 结合状态之间循环，以平衡 Rac1 和 RhoA 的活性。Rac1 活性的下调导致 RhoA 活性的上调，从而促进胰腺癌细胞的侵袭和迁移。然而，目前 Tiam1-Rac1 和 RhoA 在胰腺癌中的作用尚不完全清楚。我们发现 Tiam1 在胰腺癌中上调，并且在无淋巴结受累或无远处转移的肿瘤中与有受累的肿瘤相比显著表达。尽管 Tiam1-Rac1 信号通路在体外和体内通过 Wnt 信号通路促进胰腺癌细胞增殖和肿瘤生长，但抑制 Tiam1-Rac1 信号通路并没有延长体内的总生存时间。这提供了证据表明 Rac1 和 RhoA 活性在胰腺癌中存在平衡。此外，只有 Tiam1-Rac1 和 RhoA 的联合抑制对体内胰腺癌的生长有有益的影响。总之，这些结果表明胰腺肿瘤的进展部分受到 Tiam1-Rac1 和 RhoA 之间平衡的控制。
