J Cancer 2020; 11(19):5601-5611. doi:10.7150/jca.46173

Research Paper

Involvement of the NF-κB signaling pathway in proliferation and invasion inhibited by Zwint-1 deficiency in Pancreatic Cancer Cells

Jae Hyeong Kim1, Yuna Youn1, Jong-chan Lee1,2, Jaihwan Kim1, Jin-Hyeok Hwang1,2✉

1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

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Citation:
Kim JH, Youn Y, Lee Jc, Kim J, Hwang JH. Involvement of the NF-κB signaling pathway in proliferation and invasion inhibited by Zwint-1 deficiency in Pancreatic Cancer Cells. J Cancer 2020; 11(19):5601-5611. doi:10.7150/jca.46173. Available from http://www.jcancer.org/v11p5601.htm

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Abstract

Pancreatic cancer (PC) is an intractable cancer that is difficult to diagnose early and has a 5-year survival rate of less than 8%. ZW10-interacting kinetochore protein (ZWINT) is a crucial gene that contributes to chromosome instability and is essential for spindle assembly and kinetochore-microtubule attachment during meiosis and mitosis. However, the mechanism through which Zwint-1 promotes PC progression is yet to be elucidated. Here, we report that Zwint-1 is highly expressed in clinical PC specimens (based on analysis of the Gene Expression Profiling Interactive Analysis database) and various PC cell lines. Importantly, Zwint-1-deficient PC cells showed reduced nuclear factor-kappa B (NF-κB) (Ser536) phosphorylation along with inhibited proliferation and colony formation due to downregulation of NF-κB-regulated genes such as CCND1, cIAP1/2, and XIAP. In addition, Zwint-1-deficient PC cells showed reduced invasion and migration abilities, and decreased expression levels of the metalloproteinases MMP2 and MMP9. Furthermore, Zwint-1 deficiency arrested the PC cell cycle at the G2/M phase because the chromosomes failed to segregate properly, and the apoptosis rate in these cells gradually increased, accompanied by increased caspase-3 activation and anti-poly (ADP ribose) polymerase cleavage. Apoptosis caused by Zwint-1 deficiency was demonstrated to occur through caspase-dependent pathways based on experiments involving treatment with a pan-caspase inhibitor (Z-VAD-Fmk). Thus, Zwint-1 contributes to cell growth, invasion, and survival through NF-κB signaling pathways, suggesting that it could serve as a PC biomarker and new therapeutic target.

Keywords: Zwint-1, NF-κB, CCAN, KMN, RZZ, pancreatic cancer, cancer biology