Villin-1 regulates ferroptosis in colorectal cancer progression

Hu, Bangli, Yin, Yixin, Zhang, Birong, Li, Siqi, Li, Kezhi, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291 and Huang, Qinghua 2024. Villin-1 regulates ferroptosis in colorectal cancer progression. The FEBS Journal 10.1111/febs.17350 Item availability restricted.

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Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	Wiley
ISSN:	1742-464X
Funders:	National Natural Science Foundation of China
Date of First Compliant Deposit:	22 January 2025
Date of Acceptance:	13 September 2024
Last Modified:	22 Jan 2025 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/174944

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