LncRNA GAL promotes colorectal cancer liver metastasis through stabilizing GLUT1
LncRNA GAL promotes colorectal cancer liver metastasis through stabilizing GLUT1
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LncRNA GAL通过稳定GLUT1促进结直肠癌肝转移
DOI：
10.1038/s41388-022-02230-z
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发表时间：
2022-02-11
期刊：
影响因子：
8
通讯作者：
Yang, Shiming
中科院分区：
文献类型：
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作者：
Li, Bosheng;Kang, Houyi;Yang, Shiming
结直肠癌肝转移（CRLM）是结直肠癌相关死亡的主要原因，仍然是临床挑战。葡萄糖摄取的增强参与CRLM;然而，长链非编码RNA（lncRNA）是否参与这些分子事件仍不清楚。在这里，我们报告了一种lncRNA，GAL（葡萄糖转运蛋白1（GLUT 1）相关lncRNA），与原发性结直肠癌（CRC）组织或匹配的正常组织相比，它在CRLM组织中上调，并与CRLM患者的总生存率相关。在功能上，GAL作为癌基因，因为它在体外促进CRC细胞迁移和侵袭，并在体内增强CRC细胞从肠转移到肝脏的能力。在机制上，GAL与GLUT 1蛋白相互作用以增加GLUT 1 SUMO化，抑制泛素-蛋白酶体系统对GLUT 1蛋白的作用。GLUT 1敲除（-/+）抑制了GAL介导的CRC细胞对葡萄糖的摄取增加，体外迁移和侵袭，以及体内从肠转移到肝脏，并且GLUT 1的增强表达挽救了CRC细胞中GAL敲除诱导的生物学功能。综上所述，我们的研究结果表明GAL通过稳定GLUT 1促进CRLM，这表明GAL-GLUT 1复合物可能作为CRLM的潜在治疗靶点。
Colorectal cancer liver metastasis (CRLM) is the leading cause of colorectal cancer-related deaths and remains a clinical challenge. Enhancement of glucose uptake is involved in CRLM; however, whether long noncoding RNAs (lncRNAs) participate in these molecular events remains largely unclear. Here, we report an lncRNA, GAL (glucose transporter 1 (GLUT1)associatedlncRNA), that was upregulated in CRLM tissues compared with primary colorectal cancer (CRC) tissues or matched normal tissues and was associated with the overall survival rates of CRLM patients. Functionally, GAL served as an oncogene because it promoted CRC cell migration and invasion in vitro and enhanced the ability of CRC cells to metastasize from the intestine to the liver in vivo. Mechanistically, GAL interacted with the GLUT1 protein to increase GLUT1 SUMOylation, inhibiting the effect of the ubiquitin-proteasome system on the GLUT1 protein. GLUT1-knockout (−/+) repressed the GAL-mediated increase in CRC cell uptake of glucose, migrate, and invade in vitro, as well as metastasis from the intestine to the liver in vivo, and enforced expression of GLUT1 rescued GAL knockout-induced biological functions in CRC cells. Taken together, our findings demonstrated that GAL promotes CRLM by stabilizing GLUT1, suggesting that the GAL-GLUT1 complex may act as a potential therapeutic target for CRLM.