FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis.
FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis.
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FBW7通过抑制HIF1α/CEACAM5功能轴抑制结直肠癌转移
DOI：
10.7150/ijbs.24505
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发表时间：
2018
影响因子：
9.2
通讯作者：
Cai S
中科院分区：
文献类型：
--
作者：
Li Q;Li Y;Li J;Ma Y;Dai W;Mo S;Xu Y;Li X;Cai S
F-box和WD repeat domain containing 7（FBW 7）通过靶向癌蛋白降解而作为主要的肿瘤抑制因子发挥作用。FBW 7是大肠癌中最常见的突变基因之一。然而，其在《儿童权利公约》发展中的作用和可能的机制仍不清楚。在本研究中，我们采用组织芯片（TMA）中的免疫组织化学染色，包括276例I-IV期CRC患者的样本，并分析FBW 7表达与临床病理参数以及总生存期（OS）和无病生存期（DFS）的相关性。进一步在体外验证了FBW 7对迁移的影响。然后分析全基因组表达微阵列（GEO，登录号GSE 76443）以找到FBW 7的可能靶标。体外功能实验和TMA免疫组化染色证实了上述结果。最后，荧光素酶和染色质免疫沉淀（ChIP）试验进行了鉴定可能的机制。TMA中FBW 7的表达水平与血清CEA水平、静脉浸润、N分期和M分期呈负相关，与大肠癌患者的生存期呈正相关（P<0.05）。异位FBW 7表达在体外显著抑制结肠癌细胞的迁移。GEO分析显示，FBW 7的降低与编码CEA的CEACAM 5水平的升高显著相关。通过TMA的IHC验证了相关性，并且沉默CEACAM 5抑制体外迁移。从机制上讲，我们证明CEACAM 5是HIF 1 α靶基因，FBW 7以HIF 1 α依赖性方式调节CEACAM 5。总之，我们的研究结果表明，FBW 7通过调节结肠直肠癌中的HIF 1 α/CEACAM 5轴来抑制迁移。因此，我们的研究揭示了FBW 7对HIF 1 α/CEACAM 5信号传导轴的影响，并构成了CRC的潜在预后预测因子和治疗靶点。
F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated in vitro. Whole-genome expression microarray (GEO,accession numbers GSE76443), was then analyzed to find the possible target of FBW7. The results were verified by functional experiments in vitro and IHC staining of TMA. Finally, luciferase and chromatin immunoprecipitation (ChIP) assays were carried out to identify the possible mechanisms. The expression level of FBW7 in TMA was negatively correlated with serum CEA level, venous invasion, N stage and M stage, and positively associated with the survival of CRC patients(P<0.05). Ectopic FBW7 expression significantly suppressed migration of colon cancer cells in vitro. GEO analysis revealed that decreased FBW7 significantly correlated with increased level of CEACAM5, which encoded CEA. The correlation was verified by IHC of TMA and silencing CEACAM5 inhibited migration in vitro. Mechanistically, we demonstrated that CEACAM5 was a HIF1α target gene and that FBW7 regulated CEACAM5 in a HIF1α-dependent manner. In conclusion, our results revealed that FBW7 suppressed migration through regulation of the HIF1α/CEACAM5 axis in colorectal cancer. Therefore, our study sheds novel lights on the impact of FBW7 on HIF1α/CEACAM5 signaling axis and constitutes potential prognostic predictors and therapeutic targets for CRC.
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影响因子：
37.3
作者：
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影响因子：
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作者：
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影响因子：
3.7
作者：
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通讯作者：
Fleming, Fergal J.
影响因子：
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作者：
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影响因子：
15.3
作者：
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Freedman, S O