Yang Tang, Zhiheng Huang, Zhanhuai Wang, Qian Xiao, Yue Liu, Xiaoxu Ge, Jingsun Wei, Shu Zheng, Kefeng Ding
Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Otorhinolaryngology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Front Oncol. 2020 Sep 23;10:1747. doi: 10.3389/fonc.2020.01747. eCollection 2020.
RAB family proteins participate in the dynamic regulation of cellular membrane compartments and are dysregulated in a variety of tumor types, which may alter the biological properties of cancer cells such as proliferation, migration, and invasion. In our previous study, we found that Ras-related protein Rab-31 (RAB31) expression was increased in late-stage colorectal cancer (CRC). The role of RAB31 has never been investigated in CRC. In this study, we found that expression of RAB31 in the tumor stroma but not cancer cells of colon cancer predicted poor survival. RAB31 can be detected in primary cancer-associated fibroblasts (CAFs) and paired normal fibroblasts. Conditioned medium (CM) from RAB31 overexpressing CAFs significantly promoted migration of colon cancer cell lines and . This process may be mediated by paracrine action of hepatocyte growth factor (HGF), which was increased in the CM of RAB31-overexpressing CAFs. Blockade of HGF/MET signaling by drug inhibition, knockdown of mesenchymal to epithelial transition factor (MET) in RKO, or antibody neutralization of HGF abolished migration of RKO cells mediated by RAB31 expression in CAFs. We propose that in colon cancer, increased RAB31 expression in CAFs may contribute to tumor progression by regulating the secretion of HGF in the tumor stroma.
RAB家族蛋白参与细胞膜区室的动态调节，并且在多种肿瘤类型中表达失调，这可能会改变癌细胞的生物学特性，如增殖、迁移和侵袭。在我们之前的研究中，我们发现晚期结直肠癌（CRC）中Ras相关蛋白Rab-31（RAB31）的表达增加。RAB31在CRC中的作用从未被研究过。在本研究中，我们发现结肠癌肿瘤基质而非癌细胞中RAB31的表达预示着较差的生存率。在原发性癌相关成纤维细胞（CAF）和配对的正常成纤维细胞中均可检测到RAB31。来自过表达RAB31的CAF的条件培养基（CM）显著促进结肠癌细胞系的迁移。这一过程可能由肝细胞生长因子（HGF）的旁分泌作用介导，HGF在过表达RAB31的CAF的CM中含量增加。通过药物抑制阻断HGF/MET信号通路、在RKO细胞中敲低间充质上皮转化因子（MET）或用抗体中和HGF，均可消除CAF中RAB31表达介导的RKO细胞迁移。我们提出，在结肠癌中，CAF中RAB31表达的增加可能通过调节肿瘤基质中HGF的分泌促进肿瘤进展。
