Proteinase-activated receptor 2 promotes cancer cell migration through RNA methylation-mediated repression of miR-125b.
Proteinase activated-receptor 2 (PAR2) participates in cancer metastasis promoted by serine proteinases. The current study aimed to test the molecular mechanism by which PAR2 promotes cancer cell migration. In different cancer cells, activation of PAR2 by activating peptide (PAR2-AP) dramatically increased cell migration, whereas knock down of PAR2 inhibited cellular motility. The PAR2 activation also repressed miR-125b expression while miR-125b mimic successfully blocked PAR2-induced cell migration. Moreover, Grb associated-binding protein 2 (Gab2) was identified as a novel target gene of miR-125b and it mediated PAR2-induced cell migration. The correlation of PAR2 with miR-125b and Gab2 was further supported by the findings obtained from human colorectal carcinoma specimens. Remarkably, knock down of NOP2/Sun domain family, member 2 (NSun2), a RNA methyltransferase, blocked the reduction in miR-125b induced by PAR2. Furthermore, PAR2 activation increased the level of N(6)-methyladenosine (m(6)A)-containing pre-miR-125b in NSun2-dependent manner. Taken together, our results demonstrated that miR-125b mediates PAR2-induced cancer cell migration by targeting Gab2 and that NSun2-dependent RNA methylation contributes to the down-regulation of miR-125b by PAR2 signaling. These findings suggest a novel epigenetic mechanism by which microenvironment regulates cancer cell migration by altering miRNA expression.
From the State Key Laboratory of Molecular Oncology.
Lan
L
Yang
From the State Key Laboratory of Molecular Oncology.
Yiming
Y
Ma
From the State Key Laboratory of Molecular Oncology.
Wenxiao
W
Han
From the State Key Laboratory of Molecular Oncology.
Weiwei
W
Li
Department of Abdominal Surgical Oncology, and.
Liang
L
Cui
From the State Key Laboratory of Molecular Oncology.
Xinhua
X
Zhao
Department of Abdominal Surgical Oncology, and.
Yantao
Y
Tian
Department of Gastrointestinal Surgical Oncology, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 100021 Beijing, PR China and.
Zhixiang
Z
Zhou
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 100191 Beijing, PR China.
Wengong
W
Wang
From the State Key Laboratory of Molecular Oncology, hongyingwang@cicams.ac.cn.
Hongying
H
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009843:Oligoribonucleotides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics
C487404:2-furoyl-LIGRLO-amide; D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D009842:Oligopeptides; D009843:Oligoribonucleotides; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; C010223:N-methyladenosine; D008780:Methyltransferases; C515610:NSUN2 protein, human; D000241:Adenosine
Gab2; RNA methylation; cell biology; cell signaling; mi-125b; microRNA (miRNA); migration; proteinase-activated receptor 2; tumor metastasis