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

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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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Abbreviations

Akt:

Protein kinase B (PKB)

CCA:

Cholangiocarcinoma

CRISPR/Cas9:

Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9

DMEM:

Dulbecco’s modified Eagle’s medium

DHMEQ:

Dehydroxymethylepoxyquinomicin

EMT:

Epithelial-mesenchymal transition

Fox:

Forkhead protein

IHC:

Immunohistochemistry

CD147 KO:

CD147 knockout

HRP:

Horseradish peroxidase

MCT:

Monocarboxylate transporter

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Acknowledgements

The authors would like to thank Dr. Brett Stringer for LentiCRISPRv2 puro, Prof. Didier Trono for pCMVR8.74 and pMD2.G, Prof. Kazuo Umezawa, Aichi Medical University, Japan for providing DHMEQ and Prof. James A Will for editing this manuscript via the KKU Publication Clinic, Khon Kaen University, Thailand.

Funding

This project was supported by a TRF-MRC (Newton fund) project grant to C. Pairojkul (DBG5980004), TRF Senior Research Scholar Grant to S. Wongkham (RTA5780012) and Khon Kaen University, Thailand (#KKU61003502 to K. Vaeteewoottacharn).

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40005, Thailand

    Paweena Dana, Saowaluk Saisomboon, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham & Kulthida Vaeteewoottacharn

  2. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand

    Paweena Dana, Saowaluk Saisomboon, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Chawalit Pairojkul, Sopit Wongkham & Kulthida Vaeteewoottacharn

  3. Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan

    Paweena Dana, Ryusho Kariya, Seiji Okada, Sopit Wongkham & Kulthida Vaeteewoottacharn

  4. Department of Biochemistry, Faculty of Science, Prince of Songkla University, Songkhla, 90110, Thailand

    Sumalee Obchoei

  5. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chawalit Pairojkul

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  1. Paweena Dana
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Correspondence to Kulthida Vaeteewoottacharn.

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The authors declare no potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Human CCA tissues were obtained from the specimen bank of the Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand. The patients had undergone liver resection at Srinagarind Hospital, Thailand. Informed patient consents were obtained prior to initiation of the study. The research protocol (#HE571283 and #HE581369) was approved by the Human Research Ethics Committee at Khon Kaen University.

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Figure S1

Characteristics of CD147 KO clones. (a) Morphologies of WT and CD147 KO cell clones. (b) Invasion and (c) proliferation abilities of CD147 KO cell clones. (d) MMP activities of CD147 KO cell clones and WT measured by gelatin zymography. (e) FoxO3 nuclear localization in CD147 KO cell clones and WT cells determined by immunofluorescence staining. Hoechst 33342 (Hoechst) was used as nuclear staining dye. (PPTX 647 kb)

Figure S2

Effect of PI3K inhibition on Akt phosphorylation and MCT-4 expression. The expression of CD147, PI3K, pAkt, Akt and MCT-4 was assessed in LY294002-treated KKU-213 cells (0-24 h). β-actin was used as loading control. (PPTX 269 kb)

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Dana, P., Saisomboon, S., Kariya, R. et al. CD147 augmented monocarboxylate transporter-1/4 expression through modulation of the Akt-FoxO3-NF-κB pathway promotes cholangiocarcinoma migration and invasion. Cell Oncol. 43, 211–222 (2020). https://doi.org/10.1007/s13402-019-00479-3

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