Angiopoietin-like 4 promotes glucose metabolism by regulating glucose transporter expression in colorectal cancer

Shodai Mizuno, Ryo Seishima, Juntaro Yamasaki, Kaoru Hattori, Masayo Ogiri, Shimpei Matsui, Kohei Shigeta, Koji Okabayashi, Osamu Nagano, Liang Li, Yuko Kitagawa

研究成果: Article査読

抄録

Purpose: Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC). Methods: Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated. Results: There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation. Conclusion: ANGPTL4 regulates the expression of GLUTs by activating the PI3K–AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target.

本文言語English
ページ(範囲)1351-1361
ページ数11
ジャーナルJournal of Cancer Research and Clinical Oncology
148
6
DOI
出版ステータスPublished - 2022 6月

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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