LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance
LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance
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DOI：
10.1007/s00428-018-2298-0
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发表时间：
2018-05-01
期刊：
影响因子：
3.5
通讯作者：
Bravou, Vasiliki
中科院分区：
文献类型：
--
作者：
Aggelou, Helen;Chadla, Panagiota;Bravou, Vasiliki
Cofilin磷酸化调节对于肌动蛋白丝周转是重要的，并且与癌症有关。Cofilin的磷酸化由LIM激酶（LIMKs）介导，而去磷酸化由弹弓磷酸酶（SSH）介导。LIMK和SSH促进癌细胞的侵袭和转移，并代表新的抗癌靶点。然而，关于LIMK/cofilin和SSH在人结直肠癌（CRC）中的作用知之甚少。在这项研究中，我们的目的是解决他们的表达和意义，在人类CRC。我们通过免疫组织化学方法评估了143例结直肠癌患者非磷酸化（活性）和磷酸化cofilin、LIMK 1、LIMK 2和SSH 1的表达与临床病理参数、转移性疾病对化疗的反应以及上皮-间质转化（EMT）标志物β-连环蛋白、E-cadherin和ZEB的关系。我们发现，活性cofilin，LIMK 1，LIMK 2和SSH 1在人CRC中过表达，并与肿瘤进展参数相关。SSH 1是淋巴结转移的独立预测因子。LIMK 1和SSH 1表达在化疗无应答者中也较高，多变量分析显示SSH 1可独立预测转移性疾病对化疗的应答。活性cofilin，LIMK 1，LIMK 2和SSH 1也与EMT标志物相关。此外，免疫荧光分析显示，与亲本HT 29细胞相比，在对5-氟尿嘧啶耐药的HT 29结肠癌细胞中，活性cofilin、LIMK 1、LIMK 2和SSH 1的表达增加。我们的研究结果表明，F-actin调节剂LIMK/cofilin途径和SSH 1与CRC进展和化疗耐药性相关，代表了CRC中有前途的肿瘤生物标志物和治疗靶点。
Cofilin phospho-regulation is important for actin filament turnover and is implicated in cancer. Phosphorylation of cofilin is mediated by LIM kinases (LIMKs) and dephosphorylation by Slingshot phosphatases (SSH). LIMKs and SSH promote cancer cell invasion and metastasis and represent novel anti-cancer targets. However, little is known regarding LIMK/cofilin and SSH in human colorectal cancer (CRC). In this study, we aimed to address their expression and significance in human CRC. We evaluated expression of non-phosphorylated (active) and phosphorylated cofilin, LIMK1, LIMK2, and SSH1 by immunohistochemistry in 143 human CRC samples in relation to clinicopathologic parameters, response of metastatic disease to chemotherapy, and epithelial-mesenchymal transition (EMT) markers beta-catenin, E-cadherin, and ZEB. We show that active cofilin, LIMK1, LIMK2, and SSH1 are overexpressed in human CRC and are associated with tumor progression parameters. SSH1 is an independent predictor of lymph node metastasis by multivariate analysis. LIMK1 and SSH1 expression is also higher in non-responders to chemotherapy, and SSH1 is shown by multivariate analysis to independently predict response of metastatic disease to chemotherapy. Active cofilin, LIMK1, LIMK2, and SSH1 also correlated with the EMT markers examined. In addition, immunofluorescence analysis showed increased expression of active cofilin, LIMK1, LIMK2, and SSH1 in HT29 colon cancer cells resistant to 5-fluorouracil compared to parental HT29 cells. Our results suggest that F-actin regulators LIMK/cofilin pathway and SSH1 are associated with CRC progression and chemoresistance representing promising tumor biomarkers and therapeutic targets in CRC.