Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells.
Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells.
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DOI：
10.1371/journal.pone.0066439
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mulder KM
中科院分区：
文献类型：
--
作者：
Jin Q;Liu G;Domeier PP;Ding W;Mulder KM
我们以前已经描述了一种新的肌动蛋白细胞骨架调节剂，它也调节TGFβ敏感上皮细胞中Ras和丝裂原活化蛋白激酶的活性。在这里，我们研究了这种信号调节蛋白（km 23 -1）在介导人类结直肠癌（CRC）细胞的迁移，侵袭和肿瘤生长的功能作用。我们发现，人CRC细胞中km 23 -1的小干扰RNA（siRNA）缺失抑制了组成性细胞外信号调节激酶（ERK）激活，以及促侵袭性ERK效应子功能，包括Elk-1的磷酸化、c-Fos-DNA结合的组成性调节、TGFβ1启动子反式激活和TGFβ1分泌。此外，km 23 -1的敲低降低了条件培养基和成纤维细胞共培养物中CRC细胞分泌因子的旁分泌作用。此外，人CRC细胞中的km 23 -1缺失减少了细胞迁移和侵袭，以及ERK调节的转移相关支架蛋白Ezrin的表达。最后，km 23 -1抑制显著抑制体内肿瘤形成。因此，我们的研究结果表明，km 23 -1作为一种新的抗转移靶点的人结肠癌细胞，能够减少肿瘤的生长和侵袭，通过一种机制，涉及抑制各种前迁移的CRC功能。这些包括ERK信号传导减少、TGFβ1产生减少、质膜-细胞骨架连接体Ezrin表达减少，以及结肠癌分泌因子对成纤维细胞迁移和有丝分裂发生的旁分泌作用减弱。因此，km 23 -1抑制剂可能代表了一种可行的治疗策略，用于干扰结肠癌的进展和侵袭。
We have previously described a novel modulator of the actin cytoskeleton that also regulates Ras and mitogen-activated protein kinase activities in TGFβ-sensitive epithelial cells. Here we examined the functional role of this signaling regulatory protein (km23-1) in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells. We show that small interfering RNA (siRNA) depletion of km23-1 in human CRC cells inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as pro-invasive ERK effector functions that include phosphorylation of Elk-1, constitutive regulation of c-Fos-DNA binding, TGFβ1 promoter transactivation, and TGFβ1 secretion. In addition, knockdown of km23-1 reduced the paracrine effects of CRC cell-secreted factors in conditioned medium and in fibroblast co-cultures. Moreover, km23-1 depletion in human CRC cells reduced cell migration and invasion, as well as expression of the ERK-regulated, metastasis-associated scaffold protein Ezrin. Finally, km23-1 inhibition significantly suppressed tumor formation in vivo. Thus, our results implicate km23-1 as a novel anti-metastasis target for human colon carcinoma cells, capable of decreasing tumor growth and invasion via a mechanism involving suppression of various pro-migratory features of CRC. These include a reduction in ERK signaling, diminished TGFβ1 production, decreased expression of the plasma membrane-cytoskeletal linker Ezrin, as well as attenuation of the paracrine effects of colon carcinoma-secreted factors on fibroblast migration and mitogenesis. As such, km23-1 inhibitors may represent a viable therapeutic strategy for interfering with colon cancer progression and invasion.
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DOI：
10.1016/j.bbrc.2012.10.047
发表时间：
2012-11-23
影响因子：
3.1
作者：
Jin, Qunyan;Pulipati, Nageswara R.;Zhou, Weidong;Staub, Cory M.;Liotta, Lance A.;Mulder, Kathleen M.
通讯作者：
Mulder, Kathleen M.
影响因子：
4.8
作者：
Jin, Qunyan;Ding, Wei;Mulder, Kathleen M.
通讯作者：
Mulder, Kathleen M.
影响因子：
11.2
作者：
Chen H;Zhu G;Li Y;Padia RN;Dong Z;Pan ZK;Liu K;Huang S
通讯作者：
Huang S
影响因子：
4.8
作者：
Briggs, Joseph W.;Ren, Ling;Khanna, Chand
通讯作者：
Khanna, Chand
影响因子：
4.8
作者：
Gao, Shu-Ying;Li, En-Min;Xu, Li-Yan
通讯作者：
Xu, Li-Yan