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Exportin-5 Functions As an Oncogene and a Potential Therapeutic Target in Colorectal Cancer Kunitoshi Shigeyasu1,2, Yoshinaga Okugawa1,3, Shusuke Toden1, C

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Exportin-5 Functions As an Oncogene and a Potential Therapeutic Target in Colorectal Cancer Kunitoshi Shigeyasu1,2, Yoshinaga Okugawa1,3, Shusuke Toden1, C Published OnlineFirst August 23, 2016; DOI: 10.1158/1078-0432.CCR-16-1023 Biology of Human Tumors Clinical Cancer Research Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer Kunitoshi Shigeyasu1,2, Yoshinaga Okugawa1,3, Shusuke Toden1, C. Richard Boland1, and Ajay Goel1 Abstract Purpose: Dysregulated expression of miRNAs has emerged as a Results: XPO5 is upregulated, both at mRNA and protein hallmark feature in human cancers. Exportin-5 (XPO5), a karyo- levels, in colorectal cancers compared with normal tissues. High pherin family member, is a key protein responsible for transport- XPO5 expression is associated with worse clinicopathologic fea- ing precursor miRNAs from the nucleus to the cytoplasm. tures and poor survival in colorectal cancer patient cohorts. The Although XPO5 is one of the key regulators of miRNA biogenesis, siRNA knockdown of XPO5 resulted in reduced cellular prolifer- its functional role and potential clinical significance in colorectal ation, attenuated invasion, induction of G1–S cell-cycle arrest, and cancer remains unclear. downregulation of key oncogenic miRNAs in colorectal cancer Experimental Design: The expression levels of XPO5 were cells. These findings were confirmed in a xenograft animal model, initially assessed in three genomic datasets, followed by determi- wherein silencing of XPO5 resulted in the attenuation of tumor nation and validation of the relationship between XPO5 expres- growth. sion and clinicopathologic features in two independent colorectal Conclusions: XPO5actslikeanoncogeneincolorectal cancer patient cohorts. A functional characterization of XPO5 in cancer by regulating the expression of miRNAs and may be colorectal cancer was examined by targeted gene silencing in a potential therapeutic target in colorectal cancer. Clin Cancer colorectal cancer cell lines and a xenograft animal model. Res; 1–11. Ó2016 AACR. Introduction The biogenesis of miRNAs is mediated by a group of proteins, including Drosha, Dicer, TRBP, and exportin-5 (XPO5; ref. 8). Colorectal cancer is the second leading cause of cancer-related Among these, XPO5, a member of the karyopherin family, is a key deaths in the United States (1), and more than 1.2 million patients protein responsible for the transportation of precursor miRNAs are diagnosed with colorectal cancer annually, with 5-year sur- (pre-miRNAs) from the nucleus to the cytoplasm (9). Although vival rates of approximately 64% (2, 3). Accumulating evidence XPO5 is perhaps the most critical regulator of miRNA biogenesis, indicates that epigenetic modifications play a critical role in the the clinical significance of altered XPO5 expression in colorectal progression of colorectal cancer. In particular, over the last decade, cancer remains unclear. Furthermore, the functional role of dysregulated expression of miRNAs has emerged as a hallmark altered XPO5 expression, its impact on downstream target miR- feature of human cancers, including colorectal cancer. miRNAs are NAs, and its influence on colorectal cancer biology have not been small noncoding RNAs, 19–24 nucleotides in length, which interrogated. regulate the expression of few to hundreds of downstream target Although no comprehensive studies have been performed in genes posttranscriptionally (4, 5). In addition to their biological colorectal cancer, limited evidence in previous studies has role, dysregulated expression of miRNAs is of clinical significance, observed overexpression of XPO5 in urothelial (10) and breast as it often associates with key cancer-related clinicopathologic cancer (11, 12). Another recent study showed that XPO5 is a features (6, 7). critical regulator of cell cycle (13). These studies suggest the oncogenic potential of XPO5, but systematic studies are required to further elucidate its functional and clinical role as a biomarker 1Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention, and as a potential therapeutic target in colorectal cancer. and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Herein, we systematically and comprehensively characterize Center, Baylor University Medical Center, Dallas, Texas. 2Department of Gas- the role of XPO5 in colorectal cancer by analyzing colorectal troenterological Surgery, Okayama University Graduate School of Medicine, cancer cell lines, a xenograft animal model, and multiple cohorts 3 Dentistry, and Pharmaceutical Sciences, Okayama, Japan. Department of of clinical specimens. Our data firstly demonstrate that XPO5 is Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute upregulated in colorectal cancers and that patients with high of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan. XPO5 expression are associated with higher tumor burdens, worse Note: Supplementary data for this article are available at Clinical Cancer clinicopathologic features and poor survival. Furthermore, we Research Online (http://clincancerres.aacrjournals.org/). studied the functional role of altered XPO5 expression and Corresponding Author: Ajay Goel, Baylor University Medical Center, 3410 demonstrated that it functions as an oncogene by upregulating Worth Street, Dallas, TX 75246. Phone: 214-820-2603; Fax: 121-4818-9292; the expression of important growth-promoting miRNAs in colo- E-mail: [email protected] rectal cancer. Taken together, our data highlighted the oncogenic doi: 10.1158/1078-0432.CCR-16-1023 role of XPO5, and high expression of XPO5 may serve as a Ó2016 American Association for Cancer Research. potential therapeutic target in colorectal cancer. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 23, 2016; DOI: 10.1158/1078-0432.CCR-16-1023 Shigeyasu et al. ization of pri-miRNA expression. The relative expression level of Translational Relevance each miRNA was determined using the DDCt method. All assays Exportin-5 (XPO5) plays a key role in miRNA biogenesis were performed in duplicate. and is known to transport precursor miRNAs from nucleus to cytoplasm. However, the clinical significance of XPO5 expres- Immunohistochemical analysis sion in colorectal cancer remains unclear. Herein, we system- Paraffin-embedded sections derived from 10 matched cancer/ atically and comprehensively characterize the role of XPO5 in normal tissues were deparaffinized by xylene and ethanol. colorectal cancer by analyzing colon cancer cell lines, a xeno- Following elimination of endogenous peroxidase activity by graft animal model, and multiple cohorts of clinical speci- H2O2 and antigen retrieval by autoclaving at 121 C for 15 mens. We demonstrate that high XPO5 expression resulted in minutes, slides were incubated with anti-XPO5 antibody worse clinicopathologic features in two independent colorec- (EPR8452, Abcam, 1:400 dilution) for 1 hour. The color was tal cancer clinical cohorts. XPO5 showed oncogenic potential developed using EnVision þ Dual Link Kit (DAKO) and hema- in a series of in vitro and in vivo experimental models by toxylin. The staining with an isotype antibody was used as the regulation of miRNA expression. Knockdown of XPO5 showed negative control. The staining levels of XPO5 were analyzed significant antitumor effect. The current study identified pre- microscopically by two independent experts using staining viously unrecognized oncogenic role and clinical significance score (from 1–5). of XPO5 in colorectal cancer. Our data suggest that XPO5 may be a potential therapeutic target in colorectal cancer. Immunofluorescence analysis After the fixation of cells by methanol, cultured cells were reacted with anti-XPO5 antibody (EPR8452, Abcam, 1:400 dilu- tion), followed by secondary fluorescence antibody (A-11034, Invitrogen, 10 mg/mL). Fluorescence signal was analyzed using a Materials and Methods fluorescence microscope. Patient cohorts and specimens This study included analysis of 661 colorectal tissues, which Cell lines were analyzed in a three-phase study that included an initial The microsatellite stable (MSS) colorectal cancer cell lines, discovery cohort and two subsequent validation cohorts. In the SW480 and Caco-2, were purchased from the ATCC. All cell lines discovery cohort, we analyzed data from the Oncomine micro- were cultured according to the manufacturer's specifications. array database comprising 181 tissue specimens from normal and Every few months, all cell lines were tested and authenticated colorectal cancer tissues (14). This database included results from using a panel of genetic and epigenetic markers. three independent gene expression profiles obtained from normal and colorectal cancer tissues (15–18). The Cancer Genome Atlas siRNA knockdown (TCGA) validation cohort included data from 234 tissue speci- XPO5-specific validated locked nucleic acid–modified Silencer mens in the TCGA dataset (19). The information on patient Select siRNA (siXPO5; s33190; Ambion) and control siRNA survival was obtained via cBioPortal (20). The clinical validation (siControl; Ambion) were selected for transfection. All experi- cohort included analysis of 246 matched normal and neoplastic ments were performed by forward transfection according to the tissues from patients enrolled at the Mie University (Mie, Japan). manufacturer's protocol with a mixture of Optimem I (Invitro- Patients with histologically confirmed stage I, II, III, or IV colo- gen), Lipofectamine RNAiMAX Transfection Reagent (Thermo
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