title: Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer.
abstract: Purpose:Dysregulated expression of miRNAs has emerged as a hallmark feature in human cancers. Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. Although XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer remains unclear.Experimental Design:The expression levels of XPO5 were initially assessed in three genomic datasets, followed by determination and validation of the relationship between XPO5 expression and clinicopathologic features in two independent colorectal cancer patient cohorts. A functional characterization of XPO5 in colorectal cancer was examined by targeted gene silencing in colorectal cancer cell lines and a xenograft animal model.Results:XPO5 is upregulated, both at mRNA and protein levels, in colorectal cancers compared with normal tissues. High XPO5 expression is associated with worse clinicopathologic features and poor survival in colorectal cancer patient cohorts. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1-S cell-cycle arrest, and downregulation of key oncogenic miRNAs in colorectal cancer cells. These findings were confirmed in a xenograft animal model, wherein silencing of XPO5 resulted in the attenuation of tumor growth.Conclusions:XPO5 acts like an oncogene in colorectal cancer by regulating the expression of miRNAs and may be a potential therapeutic target in colorectal cancer.Clin Cancer Res; 23(5); 1312-22. ©2016 AACR.
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.|Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Shigeyasu
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.|Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Toden
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. ajay.goel@bswhealth.org.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D058990:Molecular Targeted Therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D028884:Karyopherins; D035683:MicroRNAs; C446511:XPO5 protein, human