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RPL17 Promotes Colorectal Cancer Proliferation and Stemness through ERK and NEK2/β-catenin Signaling Pathways

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Author(s)
Min Ji KoYu-Ri SeoDaekwan SeoSo-Young ParkJi Hae SeoEun-Hye JeonSang-Woo KimKeon Uk ParkDeog-Bon KooShin KimJae-Hoon BaeDae-Kyu SongChi Heum ChoKwang Seok KimYun-Han Lee
Keimyung Author(s)
Seo, Ji HyePark, Keon UkKim, ShinBae, Jae HoonSong, Dae KyuCho, Chi HeumLee, Yun Han
Department
Dept. of Biochemistry (생화학)
Dept. of Internal Medicine (내과학)
Dept. of Immunology (면역학)
Dept. of Physiology (생리학)
Dept. of Obstetrics & Gynecology (산부인과학)
Dept. of Molecular Medicine (분자의학)
Journal Title
J Cancer
Issued Date
2022
Volume
13
Issue
8
Keyword
colorectal cancerRPL17ERKNEK2proliferationstemness
Abstract
Aims:
Ribosomal protein L17 (RPL17), a 60S subunit component, is up-regulated in colorectal cancer (CRC). However, its oncogenic role in CRC progression remains unexplored. Thus, we aimed to investigate the effect of RPL17 targeting on CRC in vitro and in vivo and whether RPL17 gained an extra-ribosomal function during CRC development.

Methods:
RPL17-specific siRNAs complexed with cationic lipids were transfected to CRC cells to silence target gene expression and then real-time RT-PCR and western blotting were applied to observe the change of expression or activity of genes or proteins of interest. Cell proliferation assay, clonogenic assay and cell cycle analysis were used to determine the in vitro effects of RPL17siRNAs on CRC cell growth, and a subcutaneous xenograft assay was applied to test the effect of RPL17siRNAs on in vivo tumor growth. RNA sequencing and western blotting were used to investigate the underlying mechanisms. Sphere-forming assay, invasion assay and migration assay were used to evaluate the effects of RPL17siRNAs on CRC stemness.

Results:
siRNA-mediated inhibition of RPL17 expression suppressed CRC cell growth and long-term colony formation by inducing apoptotic cell death. Similarly, targeting RPL17 effectively suppressed tumor formation in a mouse xenograft model. RNA sequencing of RPL17-silenced CRC cells revealed the same directional regulation of 159 (93 down- and 66 up-regulated) genes. Notably, NIMA-related kinase 2 (NEK2), which functionally cooperates with extracellular-regulated protein kinase (ERK) and plays a pivotal role in mitotic progression and stemness maintenance, was down-regulated. RPL17 silencing reduced NEK2, β-catenin, and p-ERK protein levels. These molecular alterations reflected the reduction in sphere-forming capacity, expression of stem cell marker genes, migration, and invasion. Reversely, RPL17 overexpression increased the ability of long-term colony formation, migration, and invasion.

Conclusion:
Our findings indicate that RPL17 promotes CRC proliferation and stemness via the ERK and NEK2/β-catenin signaling axis, and targeting RPL17 could be the next molecular strategy for both primary CRC treatment and prevention of secondary tumor formation.
Keimyung Author(s)(Kor)
서지혜
박건욱
김신
배재훈
송대규
조치흠
이윤한
Publisher
School of Medicine (의과대학)
Citation
Min Ji Ko et al. (2022). RPL17 Promotes Colorectal Cancer Proliferation and Stemness through ERK and NEK2/β-catenin Signaling Pathways. J Cancer, 13(8), 2570–2583. doi: 10.7150/jca.69428
Type
Article
ISSN
1837-9664
Source
https://www.jcancer.org/v13p2570.htm
DOI
10.7150/jca.69428
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44317
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
1. School of Medicine (의과대학) > Dept. of Obstetrics & Gynecology (산부인과학)
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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