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01-04-2020 | Cholangiocarcinoma | Original paper

CD147 augmented monocarboxylate transporter-1/4 expression through modulation of the Akt-FoxO3-NF-κB pathway promotes cholangiocarcinoma migration and invasion

Authors: Paweena Dana, Saowaluk Saisomboon, Ryusho Kariya, Seiji Okada, Sumalee Obchoei, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Chawalit Pairojkul, Sopit Wongkham, Kulthida Vaeteewoottacharn

Published in: Cellular Oncology | Issue 2/2020

Abstract

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.

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Title: CD147 augmented monocarboxylate transporter-1/4 expression through modulation of the Akt-FoxO3-NF-κB pathway promotes cholangiocarcinoma migration and invasion
Authors: Paweena Dana
Saowaluk Saisomboon
Ryusho Kariya
Seiji Okada
Sumalee Obchoei
Kanlayanee Sawanyawisuth
Chaisiri Wongkham
Chawalit Pairojkul
Sopit Wongkham
Kulthida Vaeteewoottacharn
Publication date: 01-04-2020
Publisher: Springer Netherlands
Keywords: Cholangiocarcinoma
Cholangiocarcinoma
Published in: Cellular Oncology / Issue 2/2020
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-019-00479-3

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