Angiopoietin-like 4 promotes glucose metabolism by regulating glucose transporter expression in colorectal cancer
Angiopoietin-like 4 promotes glucose metabolism by regulating glucose transporter expression in colorectal cancer
复制标题
血管生成素样4通过调节结直肠癌中葡萄糖转运蛋白的表达促进葡萄糖代谢
DOI：
10.1007/s00432-022-03960-z
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
Kitagawa Yuko
中科院分区：
文献类型：
--
作者：
Mizuno Shodai;Seishima Ryo;Yamasaki Juntaro;Hattori Kaoru;Ogiri Masayo;Matsui Shimpei;Shigeta Kohei;Okabayashi Koji;Nagano Osamu;Li Liang;Kitagawa Yuko
血管生成素样蛋白4（Angiopoietin-like 4，ANGPTL 4）是近年来发现的与肿瘤进展相关的蛋白质，但其在肿瘤代谢中的作用尚不清楚。本研究旨在探讨ANGPTL 4在结直肠癌（CRC）葡萄糖代谢中的作用。比较两组患者的临床病理特征、通过下一代测序获得的基因突变状态和通过正电子发射断层扫描/计算机断层扫描（PET/CT）测量的氟代脱氧葡萄糖（FDG）摄取。此外，通过皮下异种移植小鼠模型使用ANGPTL 4敲除CRC细胞系研究ANGPTL 4表达对癌症代谢的影响，并评估葡萄糖转运蛋白（GLUT）表达。ANGPTL 4高表达组与低表达组相比，神经侵犯（42.9%vs22.4%，P = 0.046）的发生率明显降低（94.3%vs57.1%，P < 0.001）。基因检测显示ANGPTL 4高表达的肿瘤中KRAS突变频率较高（54.3%vs.22.4%，P = 0.003）。所有FDG摄取参数在ANGPTL 4高肿瘤中均显著较高。结论ANGPTL 4基因敲除可显著降低结直肠癌组织中GLUT 1和GLUT 3的表达，抑制AKT的磷酸化。这些发现确立了ANGPTL 4在癌症进展中的新功能作用，并为开发新的治疗靶点奠定了基础。
PurposeAngiopoietin-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).MethodsImmunohistochemical 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.ResultsThere 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 ofKRASmutation (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.ConclusionANGPTL4 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.
影响因子：
3
作者：
Yunokawa, Mayu;Yoshida, Hiroshi;Tamura, Kenji
通讯作者：
Tamura, Kenji