title: USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration.
abstract: Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor-suppressing gene for CRC by mediating the inhibitory function of Slit-Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.
authors.affiliation: Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China; Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Huang
authors.forename: Pushuai
authors.initials: P
authors.lastname: Wen
authors.forename: Ruirui
authors.initials: R
authors.lastname: Kong
authors.forename: Haipeng
authors.initials: H
authors.lastname: Cheng
authors.forename: Binbin
authors.initials: B
authors.lastname: Zhang
authors.forename: Cao
authors.initials: C
authors.lastname: Quan
authors.forename: Zehua
authors.initials: Z
authors.lastname: Bian
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Chen
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Du
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fushimi
authors.forename: Dong
authors.initials: D
authors.lastname: Hua
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D043222:Ubiquitin Thiolesterase; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C449799:USP33 protein, human
keywords: Robo1; Slit2; USP33; cell migration; colorectal cancer