Int J Biol Sci 2021; 17(7):1716-1730. doi:10.7150/ijbs.56694

Research Paper

NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity

Batuer Aikemu1,2,3*, Yanfei Shao1,2,3*, Guang Yang1,2,3*, Junjun Ma1,2, Sen Zhang1,2, Xiao Yang1,2, Hiju Hong1,2, Galiya Yesseyeva1,2,3, Ling Huang1,2,3, Hongtao Jia1,2,3, Chenxing Wang1,2,3, Lu Zang1,2✉, Jing Sun1,2✉, Minhua Zheng1,2✉

1. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
*First authors with equal contributions to this work.

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Citation:
Aikemu B, Shao Y, Yang G, Ma J, Zhang S, Yang X, Hong H, Yesseyeva G, Huang L, Jia H, Wang C, Zang L, Sun J, Zheng M. NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity. Int J Biol Sci 2021; 17(7):1716-1730. doi:10.7150/ijbs.56694. Available from https://www.ijbs.com/v17p1716.htm

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Abstract

N-myc downstream regulated gene-1 (NDRG1) has been identified as a putative metastasis suppressor gene and proved to be a key player in cancer spreading and proliferation in our previous work. However, the effects of NDRG1 on tumor invasion and the mechanisms behind it are rarely understood. Here we provided in silico evidence that NDRG1 plays a crucial role in actin reorganization in colorectal cancer (CRC). Through in vitro experiments, we next observed filopodia formation was altered in NDRG1-modified cell lines, while cell division cycle-42 (CDC42) displayed excessive activation in NDRG1-silenced cells. Mechanistically, NDRG1 loss disrupts the binding between RhoGDIα and CDC42 and triggers the activation of CDC42 and the downstream cascades PAK1/Cofilin, thereby promotes the formation of filopodia and invasiveness of CRC. The knockdown of NDRG1 led to enhanced dissemination of CRC cells in vivo and correlates with active CDC42 expression. Using clinical sample analysis, we found an elevated level of active CDC42 in patients with advanced T stage, and it was negatively related to NDRG1 expression. In sum, these results uncover a mechanism utilized by NDRG1 to regulate CDC42 activity in coordinating cytoskeleton reorganization, which was crucial in cancer invasion.

Keywords: colorectal cancer, NDRG1, cytoskeleton, invasion, CDC42