Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival
Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival
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DOI：
10.1038/onc.2014.40
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发表时间：
2015-02-26
期刊：
影响因子：
8
通讯作者：
Blaeker, H.
中科院分区：
文献类型：
--
作者：
Bickeboeller, M.;Tagscherer, K. E.;Blaeker, H.
富含豆蔻酰丙氨酸的C-激酶底物（MARCKS）在多种人类肿瘤中起肿瘤抑制剂的作用。在结直肠癌（CRC）中，MARCKS已被证明是肿瘤中微卫星不稳定性（MSI-H）途径的突变失活的优先靶点，但关于其对肠道癌发生的影响知之甚少。为了更详细地研究MARCKS失活的相关性，我们通过免疫组化分析了926个MSI型CRC的MARCKS表达，并研究了结直肠癌细胞系中MARCKS缺失的功能后果。我们发现MARCKS表达的缺失并不局限于MSI-H癌症，也发生在微卫星稳定（MSS）肿瘤中，在这些肿瘤中，MARCKS表达的缺失与总生存期、癌症特异性生存期和无病生存期的不良结局相关（分别为P = 0.002、P = 0.0018、P = 0.0001;单变量分析）。在MARCKS阳性MSS结肠癌细胞系（SW 480和SW 707）中，小干扰RNA（siRNA）介导的MARCKS敲低可抵抗肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞凋亡。这伴随着细胞表面的TRAIL受体DR 4和DR 5的下调以及AKT信号传导的激活。抑制AKT信号传导和野生型MARCKS的瞬时过表达，而不是缺乏效应结构域（艾德）的MARCKS，消除了抗凋亡作用。总之，我们的数据表明MARCKS失活在CRC中很常见，并且与MSS癌症的不良结局相关。MARCKS在MSS CRC细胞中作为细胞凋亡的介质的发现为迄今为止建立的MARCKS在细胞运动和增殖中的作用增加了新的肿瘤抑制功能，并且可以解释MARCKS耗尽在MSS CRC中的预后作用。
The myristoylated alanine-rich C-kinase substrate (MARCKS) acts as a tumor suppressor in a variety of human neoplasms. In colorectal cancers (CRCs), MARCKS has been shown to be a preferential target of mutational inactivation in tumors following the microsatellite instability (MSI-H) pathway but little is known about its impact on intestinal carcinogenesis. To investigate the relevance of MARCKS inactivation in more detail, we analyzed 926 MSI-typed CRCs for MARCKS expression by immunohistochemistry and studied the functional consequences of MARCKS depletion in colorectal cancer cell lines. We found that loss of MARCKS expression was not restricted to MSI-H cancers but also occurred in microsatellite stable (MSS) tumors, where it was associated with an adverse outcome regarding overall survival, cancer-specific and disease-free survival (P = 0.002, P = 0.0018, P = 0.0001, respectively; univariate analysis). In MARCKS-positive MSS colon cancer cell lines (SW480 and SW707) small interfering RNA (siRNA)-mediated knockdown of MARCKS conferred resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. This was accompanied by the downregulation of the TRAIL receptors DR4 and DR5 at the cell surface and activation of AKT signaling. Inhibition of AKT signaling and transient overexpression of wild-type MARCKS, but not of MARCKS lacking the effector domain (ED), abolished the anti-apoptotic effect. In conclusion, our data show that inactivation of MARCKS is common in CRCs and is associated with adverse outcome in MSS cancers. The finding that MARCKS acts as a mediator of apoptosis in MSS CRC cells adds a novel tumor-suppressing function to the so far established roles of MARCKS in cell motility and proliferation and can explain the prognostic effect of MARCKS depletion in MSS CRC.