# Furin Drives Colorectal Cancer Progression and Chemoresistance Through the TGF-β/ERK Signaling Pathway

## TL;DR

Furin promotes colorectal cancer growth and resistance to chemotherapy by activating a TGF-β/ERK signaling pathway, suggesting new treatment strategies.

## Contribution

The discovery of a furin–TGF-β–ERK signaling pathway as a driver of tumor aggressiveness and chemoresistance in colorectal cancer.

## Key findings

- Furin overexpression is associated with TGF-β and ERK1/2 activation in 46.9% of CRC cases.
- Furin silencing reduces tumor growth and TGF-β/ERK signaling in CRC cell lines and xenograft models.
- Furin knockdown restores sensitivity to 5-fluorouracil in resistant CRC cell lines.

## Abstract

What are the main findings?
Furin enhances colorectal cancer growth and contributes to resistance against 5-fluorouracil.A new furin–TGF-β–ERK signaling pathway is identified as a key driver of tumor aggressiveness.

Furin enhances colorectal cancer growth and contributes to resistance against 5-fluorouracil.

A new furin–TGF-β–ERK signaling pathway is identified as a key driver of tumor aggressiveness.

What are the implications of the main findings?
Inhibiting furin or its signaling pathway could improve treatment response in CRC.Furin may serve as a promising biomarker for identifying aggressive and chemoresistant colorectal tumors.

Inhibiting furin or its signaling pathway could improve treatment response in CRC.

Furin may serve as a promising biomarker for identifying aggressive and chemoresistant colorectal tumors.

Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with 5-fluorouracil (5-Fu) as a mainstay of treatment. However, intrinsic and acquired resistance to 5-Fu significantly limits therapeutic success. Furin, a proprotein convertase, is known to activate multiple substrates critical for tumor progression, yet its precise role in CRC remains unclear. In this study, we examined furin expression in a large cohort of CRC patient samples and performed functional analyses in CRC cell lines and xenograft models. Furin overexpression was seen in 46.9% (530/1131) of CRC cases and was significantly correlated with TGF-β and ERK1/2 activation. In vitro, induced furin overexpression enhanced proliferation and clonogenicity, accompanied by upregulation of TGF-β and ERK1/2 phosphorylation, whereas furin silencing attenuated tumor cell growth and TGF-β/ERK signaling. Manipulation of TGF-β revealed a reciprocal regulatory loop, whereby TGF-β upregulated furin expression, establishing a feed-forward circuit that augmented ERK signaling and tumor growth. Notably, 5-Fu-resistant CRC cell lines displayed elevated furin, TGF-β, and phospho-ERK1/2, while furin knockdown restored drug sensitivity. In vivo, furin overexpression enhanced tumor growth in xenografts, whereas its depletion markedly reduced tumor burden and TGF-β/ERK signaling activity. Collectively, these findings demonstrate that furin promotes CRC progression and chemoresistance through a positive feedback loop with TGF-β that sustains ERK activation. Targeting furin, alone or in combination with TGF-β/ERK inhibitors, may offer a promising therapeutic strategy for CRC.