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

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

doi:10.1007/s00432-022-03960-z

Abstract

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). 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. 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. 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.

Highlights

Angiopoietin-like 4 (ANGPTL4) is a secreted member of the angiopoietin-like protein family, which includes ANGPTL1–7 (Hato et al 2008)
We found that ANGPTL4 expression is related to the progression of colorectal cancer (CRC), as suggested by the increased levels of tumour invasion and perineural invasion in ANGPTL4-high tumours
ANGPTL4 is uniquely induced by hypoxia, and its expression is essential for tumour growth and resistance to anoikis through the activation of the prosurvival FAK/Src/PI3K–AKT/ERK pathway (Baba et al 2017)

Summary

Introduction

Angiopoietin-like 4 (ANGPTL4) is a secreted member of the angiopoietin-like protein family, which includes ANGPTL1–7 (Hato et al 2008). It contains a C-terminal fibrinogen-like domain (cANGPTL4) and an N-terminal coiled-coil fragment (nANGPTL4). Journal of Cancer Research and Clinical Oncology glucose metabolism or hyperlipidaemia (Barchetta et al 2020; Yoshida et al 2002). Both tissue expression and serum concentration could be useful markers in clinical practice. ANGPTL4 is strongly related to glucose metabolism, little is known about its contribution to cancer metabolism

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