Shi Weidong, Zhang Chenyue, Ning Zhouyu, Hua Yongqiang, Li Ye, Chen Lianyu, Liu Luming, Chen Zhen, Meng Zhiqiang
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Ann Transl Med. 2021 Jan;9(1):42. doi: 10.21037/atm-20-1013.
Lysophosphatidic acid (LPA) is known to promote cancer cell invasiveness through LPA1, but the downstream signaling cascades are still not fully clarified. The CKLF-like MARVEL transmembrane domain-containing (CMTM) family regulates aggressive phenotype in many cancers.
We performed LPA1 co-immunoprecipitation combined with mass spectrometry to search for LPA1-associated proteins. The role of CMTM8 in mediating the pro-invasive activity of LPA was investigated in pancreatic cancer.
We identified CMTM8 as an LPA1-interacting protein. LPA1 and CMTM8 were co-localized in pancreatic cancer cells. LPA treatment led to stabilization of CMTM8 protein, which was impaired by knockdown of LPA1. Depletion of CMTM8 significantly suppressed the migration and invasion of pancreatic cancer cells. Conversely, ectopic expression of CMTM8 enhanced the migratory and invasive capacity of pancreatic cancer cells. CMTM8 depletion blocked the formation of metastatic lesions in the lung. Knockdown of CMTM8 attenuated LPA-induced migration and invasion in pancreatic cancer cells. CMTM8 overexpression stimulated β-catenin activation through reduction of GSK3β. In addition, knockdown of β-catenin dramatically antagonized CMTM8-mediated migration and invasion in pancreatic cancer cells.
CMTM8 serves as a key mediator of LPA-induced invasiveness in pancreatic cancer. The interaction between CMTM8 and LPA1 leads to activation of oncogenic β-catenin signaling. CMTM8 represents a potential therapeutic target for pancreatic cancer.
已知溶血磷脂酸（LPA）通过LPA1促进癌细胞侵袭，但下游信号级联仍未完全阐明。含CKLF样MARVEL跨膜结构域（CMTM）家族调节多种癌症中的侵袭性表型。
我们进行了LPA1免疫共沉淀结合质谱分析以寻找与LPA1相关的蛋白。在胰腺癌中研究了CMTM8在介导LPA促侵袭活性中的作用。
我们鉴定出CMTM8是一种与LPA1相互作用的蛋白。LPA1和CMTM8在胰腺癌细胞中共定位。LPA处理导致CMTM8蛋白稳定，而LPA1敲低则损害了这种稳定性。CMTM8的缺失显著抑制了胰腺癌细胞的迁移和侵袭。相反，CMTM8的异位表达增强了胰腺癌细胞的迁移和侵袭能力。CMTM8的缺失阻止了肺部转移灶的形成。CMTM8的敲低减弱了LPA诱导的胰腺癌细胞迁移和侵袭。CMTM8的过表达通过降低GSK3β刺激β-连环蛋白激活。此外，β-连环蛋白的敲低显著拮抗了CMTM8介导的胰腺癌细胞迁移和侵袭。
CMTM8是LPA诱导的胰腺癌侵袭的关键介质。CMTM8与LPA1之间的相互作用导致致癌性β-连环蛋白信号激活。CMTM8是胰腺癌的一个潜在治疗靶点。
