CD147 增强单羧酸转运蛋白-1/4 的表达通过调节 Akt-FoxO3-NF-κB 通路促进胆管癌迁移和侵袭。
CD147 augmented monocarboxylate transporter-1/4 expression through modulation of the Akt-FoxO3-NF-κB pathway promotes cholangiocarcinoma migration and invasion.
机构信息
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40005, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
出版信息
Cell Oncol (Dordr). 2020 Apr;43(2):211-222. doi: 10.1007/s13402-019-00479-3. Epub 2019 Nov 15.
PURPOSE
Cholangiocarcinoma (CCA) is an aggressive type of cancer. The major obstacles for treatment are its late presentation and the occurrence metastases. Targeting the metastatic process may serve as a treatment option. CD147 is a membrane protein that promotes CCA metastasis. High lactate levels in CCA are predicted to result from lactate dehydrogenase A expression and sensitivity to monocarboxylate transporter (MCT) inhibitors. An involvement of CD147 in MCT maturation has been reported, but the exact role of MCT in CCA is not clear. Here, we aimed to assess the mechanism of CD147-promoted CCA progression through MCT regulation.
METHODS
The expression levels of CD147 and MCT-1/4 in human CCA tissues were determined by immunohistochemistry. Two CD147 knockout (CD147 KO) CCA cell (KKU-213) clones were established using the CRISPR/Cas9 system. Cell migration and invasion were determined using a Boyden chamber assay. Temporal protein levels were modified by siRNA, specific inhibitors and/or activators. The expression of target proteins was determined using Western blot analyses.
RESULTS
CD147 and MCT-1/4 were found to be overexpressed in CCA tissues compared to normal bile duct tissues. In addition, we found that CD147 knockdown significantly alleviated CCA cell migration and invasion, concomitant with decreased pAkt, pFoxO3, pNF-κB (pp65) and MCT-1/4 levels. Conversely, we found that FoxO3 knockdown led to recovered migration/invasion abilities and increased pp65 and MCT-1/4 expression levels. The involvement of Akt in the regulation of MCT-1/4 expression through CD147 was established by inhibition and activation of Akt phosphorylation.
CONCLUSION
Our data indicate that CD147 promotes the malignant progression of CCA cells by activating the Akt-FoxO3-NF-κB-MCT-1/4 axis. As such, CD147 may serve as a possible target for advanced CCA treatment.
目的
胆管癌（CCA）是一种侵袭性癌症。治疗的主要障碍是其晚期表现和转移的发生。针对转移过程可能是一种治疗选择。CD147 是一种促进 CCA 转移的膜蛋白。CCA 中高乳酸水平预计是由乳酸脱氢酶 A 的表达和对单羧酸转运体（MCT）抑制剂的敏感性引起的。据报道，CD147 参与 MCT 的成熟，但 MCT 在 CCA 中的确切作用尚不清楚。在这里，我们旨在通过 MCT 调节评估 CD147 促进 CCA 进展的机制。
方法
通过免疫组织化学法测定人 CCA 组织中 CD147 和 MCT-1/4 的表达水平。使用 CRISPR/Cas9 系统建立了两个 CD147 敲除（CD147 KO）CCA 细胞（KKU-213）克隆。使用 Boyden 室测定法测定细胞迁移和侵袭。通过 siRNA、特异性抑制剂和/或激活剂来改变瞬时蛋白水平。使用 Western blot 分析测定靶蛋白的表达。
结果
与正常胆管组织相比，CCA 组织中 CD147 和 MCT-1/4 表达上调。此外，我们发现 CD147 敲低显著减轻 CCA 细胞迁移和侵袭，同时降低 pAkt、pFoxO3、pNF-κB（pp65）和 MCT-1/4 水平。相反，我们发现 FoxO3 敲低导致迁移/侵袭能力恢复和 pp65 和 MCT-1/4 表达水平增加。通过抑制和激活 Akt 磷酸化，证实了 Akt 通过 CD147 调节 MCT-1/4 表达的参与。
结论
我们的数据表明，CD147 通过激活 Akt-FoxO3-NF-κB-MCT-1/4 轴促进 CCA 细胞的恶性进展。因此，CD147 可能是晚期 CCA 治疗的一个潜在靶点。
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