Research articles
ScienceAsia 50 (2024):ID 2024108 1-9 |doi:
10.2306/scienceasia1513-1874.2024.108
CDKN3 acts as a tumor promoter enhancing proliferation of
cholangiocarcinoma cells
Orawan Waenphimaia,?, Ubonrat Thamrongwaranggoona,?, Sonexai Kidoikhammouanb, Supannika Sorina, Nattakarn Klinhom-ona, Wunchana Seubwaic,d, Charupong Saengboonmeea,d, Marutpong Detaryaa, Prin Sungwanb, Sopit Wongkhama,d, Worachart Lert-itthiporna,d,*
ABSTRACT: Cholangiocarcinoma (CCA) is a biliary tract tumor with high metastasis, often diagnosed at advanced
stages when surgical treatment is challenging. Cyclin-dependent kinase inhibitor 3 (CDKN3) is a member of the dualspecificity protein phosphatase family that can dephosphorylate CDK2, thus preventing the activation of CDK2 and
suppressing cell proliferation. Increased or decreased CDKN3 expression was reported in different cancer types with a
debatable role of tumor suppressor or promoter. The expression and roles of CDKN3 in CCA have never been explored.
The aim of this study was to clarify for the first time the oncogenic role of CDKN3 in CCA. GEO database analysis revealed
a substantially significant expression of CDKN3 mRNA in CCA tissues, regardless of tumor type, location, and etiology.
However, the clinical impacts of CDKN3 expression on clinico-pathological features and the overall survival of CCA
patients were not clearly seen. In contrast, in vitro study showed that CDKN3 gene silencing with siRNA dramatically
decreased proliferation and colony formation of CCA cell lines. Western blot analysis revealed that expression of cell
proliferation markers, cyclin D1 and p21, was significantly reduced when CDKN3 was suppressed. The combination
treatment of siCDKN3 with gemcitabine significantly enhanced the cytotoxic effect of gemcitabine against CCA and
gemcitabine-resistant CCA cells, as shown by the values of combination index and dose reduction index retrieved from
the isobologram. The results of this study address the oncogenic functions of CDKN3 in CCA and identify it as a viable
target for CCA therapy
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| a |
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 Thailand |
| b |
Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen 40002 Thailand |
| c |
Department of Forensic Medicine, Faculty of Medicine, and Cholangiocarcinoma Research Institute,
Khon Kaen University, Khon Kaen 40002 Thailand |
| d |
Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 Thailand
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* Corresponding author, E-mail: woracle@kku.ac.th
Received 17 Jun 2023, Accepted 8 Oct 2024
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