Ricuphan Khamko1,2, Jureerut Daduang2, Chatri Settasatian3, Temduang Limpaiboon4,5. 1. Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand. 2. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand. 3. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 4. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand; temduang@kku.ac.th. 5. Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Abstract
BACKGROUND/AIM: Opioid-binding protein/cell adhesion molecule-like (OPCML) plays a crucial role in the suppression of tumor progression in several cancer types. Nevertheless, the association between OPCML functions and cholangiocarcinoma (CCA) progression remains unknown. We aimed to investigate biological functions of OPCML and related signaling pathways in CCA cell lines. MATERIALS AND METHODS: Methylation status and ectopic expression of OPCML were determined in CCA cell lines using methylation-specific polymerase chain reaction and pcDNA3.1+/C-(K)DYK-OPCML, respectively. Cell proliferation, migration and invasion were investigated. RESULTS: OPCML was found to be epigenetically silenced by DNA methylation. Ectopic expression of OPCML inhibited CCA proliferation by inducing apoptosis via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. It also suppressed cell migration and invasion via down-regulation of Rho GTPases, ras homolog family member A (RHOA), Rac family small GTPase 1 (RAC1) and cell division cycle 42 (CDC42). CONCLUSION: We are the first to unravel the antitumor effects and the related signaling pathways of OPCML in CCA. The loss of OPCML expression due to promoter hypermethylation can cause a decrease in cell death but increase in cell migration and invasion, which may at least in part contribute to CCA progression. Copyright
BACKGROUND/AIM: Opioid-binding protein/cell adhesion molecule-like (OPCML) plays a crucial role in the suppression of tumor progression in several cancer types. Nevertheless, the association between OPCML functions and cholangiocarcinoma (CCA) progression remains unknown. We aimed to investigate biological functions of OPCML and related signaling pathways in CCA cell lines. MATERIALS AND METHODS: Methylation status and ectopic expression of OPCML were determined in CCA cell lines using methylation-specific polymerase chain reaction and pcDNA3.1+/C-(K)DYK-OPCML, respectively. Cell proliferation, migration and invasion were investigated. RESULTS: OPCML was found to be epigenetically silenced by DNA methylation. Ectopic expression of OPCML inhibited CCA proliferation by inducing apoptosis via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. It also suppressed cell migration and invasion via down-regulation of Rho GTPases, ras homolog family member A (RHOA), Rac family small GTPase 1 (RAC1) and cell division cycle 42 (CDC42). CONCLUSION: We are the first to unravel the antitumor effects and the related signaling pathways of OPCML in CCA. The loss of OPCML expression due to promoter hypermethylation can cause a decrease in cell death but increase in cell migration and invasion, which may at least in part contribute to CCA progression. Copyright
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