Liu Tengfei, Liu Binbin, Liu Yiting, Feng Xingzhi, Jiang Xuefei, Long Jiahui, Gao Qianling, Yang Zihuan
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China.
Cancer Cell Int. 2021 May 31;21(1):287. doi: 10.1186/s12935-021-01991-z.
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer death worldwide. Hallmark proteins processing is usually dysregulated in cancers. Finding key regulatory molecules is of great importance for CRC metastasis intervention. GOLT1B is a vesicle transport protein which is involved in cytosolic proteins trafficking. However, its role in cancer has never been addressed.
CRC cell lines and subcutaneous xenograft animal model were utilized to investigate the biological function of GOLT1B. Patients samples were used to validate the correlation between GOLT1B and clinical outcome. In vivo targeted delivery of GOLT1B-siRNA was investigated in PDX (Patient derived tumor xenograft) model.
We found that GOLT1B was highly expressed in CRC, and was an independent prognostic marker of overall survival (OS) and progression free survival (PFS). GOLT1B could promote CRC metastasis in vitro and in vivo. GOLT1B overexpression could increase DVL2 level and enhance its plasma membrane translocation, which subsequently activated downstream Wnt/β-catenin pathway and increase the nuclear β-catenin level, hence induce epithelial-mesenchymal transition (EMT). In addition, GOLT1B could also interact with PD-L2 and increase its membrane level. Co-culture of GOLT1B-overexpresed CRC cells with Jurkat cells significantly induced T cells apoptosis, which might further promote cancer cell the migration and invasion. Further, targeted delivery of GOLT1B siRNA could significantly inhibit tumor progression in GOLT1B highly expressed PDX model.
Taken together, our findings suggest that the vesicle transporter GOLT1B could promote CRC metastasis not only by assisting DVL2 translocation and activating Wnt/β-catenin pathway, but also facilitating PD-L2 membrane localization to induce immune suppression. Targeted inhibition of GOLT1B could be a potential therapeutic strategy for CRC treatment.
结直肠癌（CRC）是全球第三大最常被诊断出的癌症，也是癌症死亡的第二大主要原因。癌症中标志性蛋白的加工过程通常失调。寻找关键调控分子对于结直肠癌转移的干预至关重要。GOLT1B是一种囊泡运输蛋白，参与胞质蛋白的运输。然而，其在癌症中的作用从未被研究过。
利用结直肠癌细胞系和皮下异种移植动物模型来研究GOLT1B的生物学功能。使用患者样本验证GOLT1B与临床结果之间的相关性。在患者来源的肿瘤异种移植（PDX）模型中研究GOLT1B-siRNA的体内靶向递送。
我们发现GOLT1B在结直肠癌中高表达，并且是总生存期（OS）和无进展生存期（PFS）的独立预后标志物。GOLT1B在体外和体内均可促进结直肠癌转移。GOLT1B的过表达可增加DVL2水平并增强其质膜易位，随后激活下游Wnt/β-连环蛋白通路并增加核β-连环蛋白水平，从而诱导上皮-间质转化（EMT）。此外，GOLT1B还可与PD-L2相互作用并增加其膜水平。将过表达GOLT1B的结直肠癌细胞与Jurkat细胞共培养可显著诱导T细胞凋亡，这可能进一步促进癌细胞的迁移和侵袭。此外，在GOLT1B高表达的PDX模型中，靶向递送GOLT1B siRNA可显著抑制肿瘤进展。
综上所述，我们的研究结果表明，囊泡转运蛋白GOLT1B不仅可通过协助DVL2易位和激活Wnt/β-连环蛋白通路促进结直肠癌转移，还可促进PD-L2膜定位以诱导免疫抑制。靶向抑制GOLT1B可能是结直肠癌治疗的一种潜在治疗策略。
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