1. Academic Validation
  2. FOXA2-initiated transcriptional activation of INHBA induced by methylmalonic acid promotes pancreatic neuroendocrine neoplasm progression

FOXA2-initiated transcriptional activation of INHBA induced by methylmalonic acid promotes pancreatic neuroendocrine neoplasm progression

  • Cell Mol Life Sci. 2024 Jan 22;81(1):50. doi: 10.1007/s00018-023-05084-0.
Chunhua Hu # 1 Mujie Ye # 1 Jianan Bai 1 Pengfei Liu # 2 Feiyu Lu 1 Jinhao Chen 1 Yanling Xu 1 Lijun Yan 1 Ping Yu 1 Zequan Xiao 3 Danyang Gu 1 Lin Xu 1 Ye Tian 1 Qiyun Tang 4
Affiliations

Affiliations

  • 1 Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, China.
  • 2 Department of Gastroenterology, Jiangyin People's Hospital, Jiangyin, Jiangsu Province, China.
  • 3 Department of Gastroenterology, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili State, China.
  • 4 Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, China. qytang@njmu.edu.cn.
  • # Contributed equally.
Abstract

Pancreatic neuroendocrine neoplasms (PanNENs) are a group of highly heterogeneous neoplasms originating from the endocrine islet cells of the pancreas with characteristic neuroendocrine differentiation, more than 60% of which represent metastases when diagnosis, causing major tumor-related death. Metabolic alterations have been recognized as one of the hallmarks of tumor metastasis, providing attractive therapeutic targets. However, little is known about the molecular mechanism of metabolic changes regulating PanNEN progression. In this study, we first identified methylmalonic acid (MMA) as an oncometabolite for PanNEN progression, based on serum metabolomics of metastatic PanNEN compared with non-metastatic PanNEN patients. One of the key findings was the potentially novel mechanism of epithelial-mesenchymal transition (EMT) triggered by MMA. Inhibin βA (INHBA) was characterized as a key regulator of MMA-induced PanNEN progression according to transcriptomic analysis, which has been validated in vitro and in vivo. Mechanistically, INHBA was activated by FOXA2, a neuroendocrine (NE) specific transcription factor, which was initiated during MMA-induced progression. In addition, MMA-induced INHBA upregulation activated downstream MITF to regulate EMT-related genes in PanNEN cells. Collectively, these data suggest that activation of INHBA via FOXA2 promotes MITF-mediated EMT during MMA inducing PanNEN progression, which puts forward a novel therapeutic target for PanNENs.

Keywords

Epithelial–mesenchymal transition; FOXA2; INHBA; Metabolic alterations; Pancreatic neuroendocrine neoplasm; Tumor progression.

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