title: Gankyrin activates IL-8 to promote hepatic metastasis of colorectal cancer.
abstract: Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC.
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Zhaofang
authors.initials: Z
authors.lastname: Bai
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Tai
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhen
authors.forename: Weiting
authors.initials: W
authors.lastname: Gu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jian
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Wang
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Weili
authors.initials: W
authors.lastname: Gong
authors.forename: Bing
authors.initials: B
authors.lastname: Liang
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C530104:CCND1 protein, human; D016209:Interleukin-8; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex