CDKN3 regulates cisplatin resistance to colorectal cancer through TIPE1

W.-H. Li, L. Zhang, Y.-H. Wu

Department of Pharmacy, North China University of Science and Technology Affiliated Hospital, Tangshan, China. Lwh_1919@163.com

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• Oncology

OBJECTIVE: The aim of this study was to investigate the level of cyclin-dependent kinase inhibitor 3 (CDKN3) in colorectal cancer (CRC), to explore the underlying mechanism of CDKN3 in modulating cisplatin resistance and promoting the malignant progression of CRC.

PATIENTS AND METHODS: 43 pairs of CRC tissues and para-cancerous tissues were collected from CRC patients. CDKN3 expression was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The relationship between CDKN3 expression and the prognosis of CRC patients was analyzed. Meanwhile, qRT-PCR was performed to verify CDKN3 level in CRC cell lines. Next, CDKN3 knockdown model was constructed in CRC cisplatin-resistant cell lines. The influence of CDKN3 on the biological function of CRC cells was analyzed by Cell Counting Kit-8 (CCK-8) and plate cloning assays. Furthermore, the mechanism of its regulation of TIPE1 affecting cisplatin resistance to CRC was explored.

RESULTS: QRT-PCR results showed that CDKN3 level in CRC tissues was remarkably higher than that of the adjacent tissues (p<0.05). Compared with patients with low expression of CDKN3, the prognosis of patients with high expression of CDKN3 was significantly worse (p<0.05). Similarly, the proliferation and colony formation ability of cells in CDKN3 knockdown group remarkably decreased when compared with the sh-NC group (p<0.05). In addition, CDKN3 level was remarkably elevated in CRC patients with cisplatin resistance. In cisplatin-resistant cell lines (including HT28 and HCT-116), the knockdown of CDKN3 remarkably reduced cell viability (p<0.05). Furthermore, TIPE1 expression was remarkably downregulated in CRC tissues (p<0.05). A negative correlation was observed between the expressions of TIPE1 and CDKN3. Cell reverse experiment demonstrated that TIPE1 could reverse the promoting effect of CDKN3 on the malignant progression of CRC. All these findings suggested that there might exist a mutual regulation between CDKN3 and TIPE1.

CONCLUSIONS: CDKN3 was highly expressed in CRC, which might be closely correlated with poor prognosis of CRC patients. In addition, CDKN3 regulated cisplatin resistance to CRC by modulating TIPE1, thereby promoting the proliferation of CRC.

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