# Hypoxia-Induced TGFBI Promotes Bladder Cancer Progression by Creating a Stemness Regulation Loop through Stabilizing the Disulfide Bonds of GDF15

## TL;DR

This study shows how hypoxia-induced TGFBI promotes bladder cancer by maintaining cancer stem cell properties through a feedback loop involving GDF15.

## Contribution

The study reveals a novel hypoxia-driven TGFBI-GDF15 regulatory loop that sustains cancer stemness in bladder cancer.

## Key findings

- Hypoxia-induced TGFBI correlates with poor prognosis and malignant features in bladder cancer.
- TGFBI stabilizes GDF15 disulfide bonds, enhancing its function and secretion.
- Inhibiting TGFBI or GDF15 reduces stemness and improves chemotherapy effectiveness in bladder cancer.

## Abstract

The maintenance and regulation of cancer stem cell (CSC) stemness are crucial for tumor progression; however, the mechanisms underlying tumor stemness regulation remain poorly understood. Herein, we discovered that the enhanced hypoxia-induced transforming growth factor beta induced protein (TGFBI) in bladder cancer (BLCA) promotes the establishment of a stemness loop in the tumor microenvironment, facilitating the maintenance of CSC stemness and malignant proliferation. Clinically, the upregulation of hypoxic TGFBI in BLCA correlates with malignant BLCA features and poor prognosis. Mechanically, TGFBI can stabilize the structural integrity of disulfide bonds in Cys48 and Cys77 of growth differentiation factor 15 (GDF15), leading to aberrant function activity of GDF15 and secretion. Interestingly, secreted GDF15 consequently not only further upregulates CSC-related gene expression but also induces the activation of cancer-associated fibroblasts through the transforming growth factor beta receptor type 2 (TGFBR2)–transforming growth factor β (TGFβ)–TGFBI self-regulatory feedback loop to promote stemness in BLCA. TGFBI knockdown or GDF15 inhibition results in a decrease in functional proteins associated with stemness maintenance, which suppresses bladder CSCs’ self-renewal and effectively improves the efficacy of chemotherapy. Together, these findings demonstrate the pivotal role of TGFBI in BLCA’s stemness maintenance and BLCA progression, highlighting that the inhibition of the TGFBI/GDF15 axis is a potential therapeutic strategy for the amelioration of cancer chemotherapy.