Wang Xiaohong, Zhang Lianhai, Liang Qiaoyi, Wong Chi Chun, Chen Huarong, Gou Hongyan, Dong Yujuan, Liu Weixin, Li Ziyu, Ji Jiafu, Yu Jun
Key laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China.
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR of China.
Oncogenesis. 2022 Oct 28;11(1):66. doi: 10.1038/s41389-022-00441-3.
We elucidated the functional significance and molecular mechanisms of DUSP5P1 lncRNA (dual specificity phosphatase 5 pseudogene 1) in gastric carcinogenesis. We demonstrated that gastric cancer (GC) patients with high DUSP5P1 expression had shortened survival in two independent cohorts. DUSP5P1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Mechanistically, DUSP5P1 activated ARHGAP5 transcription by directly binding to the promoter of ARHGAP5 with a binding motif of TATGTG. RNA-seq revealed that ARHGAP5 activated focal adhesion and MAPK signaling pathways to promote GC metastasis. DUSP5P1 also dysregulated platinum drug resistance pathway. Consistently, DUSP5P1 overexpression in GC cells antagonized cytotoxic effect of Oxaliplatin, and shDUSP5P1 plus Oxaliplatin exerted synergistic effect on inhibiting GC metastasis in vitro and in vivo. DUSP5P1 depletion also suppressed the growth of platinum drug-resistant PDO models. In conclusion, DUSP5P1 promoted GC metastasis by directly modulating ARHGAP5 expression to activate focal adhesion and MAPK pathways, serves as therapeutic target for platinum drug resistant GC, and is an independent prognostic factor in GC.
我们阐明了双特异性磷酸酶5假基因1（DUSP5P1）长链非编码RNA在胃癌发生中的功能意义和分子机制。我们证明，在两个独立队列中，DUSP5P1高表达的胃癌（GC）患者生存期缩短。DUSP5P1在体外促进GC细胞迁移和侵袭，在体内促进转移。机制上，DUSP5P1通过与ARHGAP5启动子直接结合，结合基序为TATGTG，从而激活ARHGAP5转录。RNA测序显示，ARHGAP5激活粘着斑和MAPK信号通路以促进GC转移。DUSP5P1还使铂类药物耐药途径失调。一致地，GC细胞中DUSP5P1过表达拮抗奥沙利铂的细胞毒性作用，而shDUSP5P1加奥沙利铂在体外和体内对抑制GC转移发挥协同作用。DUSP5P1缺失也抑制了铂类药物耐药性PDO模型的生长。总之，DUSP5P1通过直接调节ARHGAP5表达以激活粘着斑和MAPK通路促进GC转移，是铂类药物耐药GC的治疗靶点，也是GC的独立预后因素。
