SFTA2 reduced colorectal cancer ferroptosis promoting metastasis through regulating EMT transition by degradation of Nrf2

Jian Huang; Guihua Wei; Shengxun Mao

doi:10.29219/fnr.v70.13267

Jian Huang Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of General Surgery, Jiujiang First People’s Hospital, Jiujiang, China
Guihua Wei Intensive Care Unit, Jiujiang First People’s Hospital, Jiujiang, China
Shengxun Mao Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China

DOI: https://doi.org/10.29219/fnr.v70.13267

Keywords: colon cancer, SFTA2, Nrf2, ferroptosis, mitochondrial damage

Abstract

Colon cancer is a common malignancy of the digestive system, tumor disease, and its prevalence in China shows a consistently increasing trend. This study aimed to investigate the role of surfactant associated 2 (SFTA2) in colorectal cancer (CRC) and its molecular mechanism involving ferroptosis.

Colon cancer tissues were obtained from patients and normal volunteers from our hospital, and a mouse model of CRC was established using azoxymethane (AOM)/dextran sulfate sodium (DSS) induction.

SFTA2 expression was significantly up-regulated at both the messenger RNA (mRNA) and protein levels in CRC tissues and cell lines. Patients with high SFTA2 expression exhibited a shorter survival time compared to those with low SFTA2 expression. SFTA2 was found to be expressed in cancer cells of CRC patients, associated with key signaling molecules.

Sh-SFTA2 reduced cancer proliferation in the mice model of CRC. SFTA2 up-regulation promoted cell proliferation of CRC. SFTA2 down-regulation promoted cell proliferation of CRC. SFTA2 up-regulation reduced oxidative stress and ferroptosis of CRC. SFTA2 up-regulation reduced ferroptosis of CRC through mitochondrial damage-tricarboxylic acid cycle (TAC). SFTA2 down-regulation suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the model of CRC. SFTA2 up-regulation reduced Nrf2 ubiquitination in the model of CRC. Nrf2 reversed the effects of si-SFTA2 on ferroptosis of CRC. Furthermore, SFTA2 down-regulation suppressed Nrf2 expression, while SFTA2 up-regulation decreased Nrf2 ubiquitination in the CRC model. Nrf2 was shown to reverse the pro-ferroptotic effects of si-SFTA2, indicating that SFTA2 activates the Nrf2 pathway by inhibiting its ubiquitination, thereby reducing mitochondrial damage and TCA cycle disruption in CRC.

SFTA2 induced the Nrf2 pathway to reduce mitochondrial damage-TAC of the CRC model through the inhibition of Nrf2 ubiquitination. SFTA2 is thus a potentiallyeffective therapeutic strategy for patients with CRC or other cancers.

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