Shen Sheng, Liu Han, Wang Yueqi, Wang Jiwen, Ni Xiaolin, Ai Zhilong, Pan Hongtao, Liu Houbao, Shao Yebo
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Oncotarget. 2016 Nov 8;7(45):72833-72844. doi: 10.18632/oncotarget.12023.
Deleted in malignant brain tumors 1 (DMBT1) is deleted during cancer progression and as a potential tumor-suppressor gene in various types of cancer. However, its role in Gallbladder cancer remains poorly understood. DMBT1 has low-expression and deletion of copy number were detected in normal tissues and GBC cancer tissues by qRT-PCR. Knockdown of DMBT1 increased migration and invasion and overexpressed DMBT1 impaired migration and invasion in GBC cells. We also evaluated the molecular mechanism of DMBT1 by RNA sequencing and GSEA analysis. RNA-Pulldown and RIP assay authenticated CRNDE can specified binding with DMBT1 and c-IAP1. Downregulation of DMBT1 resulted in significant change of gene expression (at least 2-fold) in PI3K-AKT pathway, increased expression of MMP-9, JUK-1, ERK and AKT, activating PI3K-AKT pathway lead to GBC carcinogenesis.We for the first time reported, DMBT1 as a prognosis biomarker, is low-expressed in GBC tumors, and CRNDE act as a scaffold to recruit the DMBT1 and c-IAP1, promotes the PI3K-AKT pathway. Our study reveals DMBT1 may be an important contributor to GBC cancer development.
恶性脑肿瘤缺失基因1（DMBT1）在癌症进展过程中缺失，是多种癌症中潜在的肿瘤抑制基因。然而，其在胆囊癌中的作用仍知之甚少。通过qRT-PCR检测发现，DMBT1在正常组织和胆囊癌组织中低表达且存在拷贝数缺失。敲低DMBT1可增加胆囊癌细胞的迁移和侵袭能力，而过表达DMBT1则会削弱其迁移和侵袭能力。我们还通过RNA测序和GSEA分析评估了DMBT1的分子机制。RNA下拉实验和RIP实验证实CRNDE可以与DMBT1和c-IAP1特异性结合。DMBT1的下调导致PI3K-AKT通路中基因表达发生显著变化（至少2倍），MMP-9、JUK-1、ERK和AKT的表达增加，激活PI3K-AKT通路导致胆囊癌发生。我们首次报道，DMBT1作为一种预后生物标志物，在胆囊癌肿瘤中低表达，CRNDE作为支架招募DMBT1和c-IAP1，促进PI3K-AKT通路。我们的研究表明DMBT1可能是胆囊癌发展的重要因素。
