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Clinicopathological Examination of Dipeptidase 1 Expression in Colorectal Cancer

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Clinicopathological Examination of Dipeptidase 1 Expression in Colorectal Cancer BIOMEDICAL REPORTS 6: 423-428, 2017 Clinicopathological examination of dipeptidase 1 expression in colorectal cancer KAZUNOSHIN TACHIBANA1, MOTONOBU SAITO1, JUN-ICHI IMAI2, EMI ITO2, YUKA YANAGISAWA3, REIKO HONMA3, KATSUHARU SAITO1, JIN ANDO1, TOMOYUKI MOMMA1, SHINJI OHKI1, TOHRU OHTAKE1, SHINYA WATANABE2, SATOSHI WAGURI4 and SEIICHI TAKENOSHITA1 1Department of Organ Regulatory Surgery; 2Medical-Industrial Translational Research Center, Fukushima Medical University School of Medicine, Fukushima 960-1295; 3Nippon Gene Co., Ltd., Tokyo 104-0054; 4Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan Received December 22, 2016; Accepted February 2, 2017 DOI: 10.3892/br.2017.870 Abstract. Dipeptidase 1 (DPEP1) is a zinc-dependent metal- Western lifestyle (1,2). Early detection and surgical resection loproteinase that is fundamental in glutathione and leukotriene is the most effective measure to improve CRC-associated metabolism. DPEP1 was initially considered as a tumor mortality (3). Despite recent advances in CRC treatment, such suppressor gene in Wilms' tumor and breast cancer. However, as chemotherapy and molecular targeted therapy, the prognosis it has been reported that DPEP1 is upregulated in colorectal remains poor in advanced CRC cases (1,2). Recurrence and cancers (CRCs) and high DPEP1 expression levels are associ- metastasis are the main obstacles for improving the prognosis ated with poorer patient survival. The role of DPEP1 genes of postoperative CRC patients (2,4). In Japan, ~15% of patients in CRC, as well as their expression, requires investigation. with stage II and 30% of patients with stage III will develop Therefore, the present study investigated DPEP1 expression recurrence within 5 years of surgical resection of CRC (5). using reverse transcription-quantitative polymerase chain reac- The treatment of advanced CRC remains essentially palliative tion or immunohistochemistry on surgically resected samples currently; therefore, it is necessary to understand the processes from CRC cases, and further examined the biological signifi- that contribute to tumor progression, particularly those that cance of DPEP1 by comparing the expression of the epithelial facilitate invasion and metastasis, to prevent CRC recurrence. to mesenchymal transition (EMT) markers, including epithelial Cancer metastasis is a complex process in which malig- cadherin and Vimentin to clarify the function of DPEP1 in nant cancer cells disseminate from the primary tumor site to a CRC, particularly in metastasis. The level of DPEP1 expression secondary tumor at a distant site. During this multistep process, was identified to be significantly increased in tumorous tissue transition between epithelial and mesenchymal states occurs samples compared with that in non-tumorous tissue samples. in cancer cells (6,7). Initially, metastasis is triggered by the In addition, increased DPEP1 mRNA expression levels were epithelial to mesenchymal transition (EMT), which enhances associated with positive lymph node metastasis in the included cancer cell motility and intravasation into blood vessels (8). cohort. However, no positive correlations were observed Notably, the reversible process of EMT, mesenchymal to between DPEP1 and EMT markers in the cohort. The results epithelial transition (MET), is also observed at the metastatic indiciates that further investigations into the upregulation of site, and is involved in the metastatic process (6). EMT and DPEP1 in colorectal carcinogenesis and the role of therapeutic MET are controlled by multiple molecular mechanisms, such or prognostic biomarkers are required. as transcription factors, epigenetic modifications, alternative splicing, and miRNA networks, resulting in the modification Introduction of epithelial or mesenchymal gene expression levels (6,7). Among the molecular mechanisms, the downregulation and Colorectal cancer (CRC) is one of the most commonly diag- re-expression of epithelial (E-) cadherin are reportedly asso- nosed types of cancer and is closely linked to aspects of the ciated with EMT and MET, respectively (9). Accumulating evidence has revealed the important roles of EMT and MET in cancer metastasis; however, this modulation is complicated and further research is required. Correspondence to: Dr Seiichi Takenoshita, Department of Organ Dipeptidase 1 (DPEP1), located on chromosome 16q24.3, is Regulatory Surgery, Fukushima Medical University School of a zinc-dependent metalloproteinase, which is fundamental in Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan glutathione and leukotriene metabolism (10). Leukotrienes are E-mail: [email protected] pro‑inflammatory mediators that are associated with cancer development (11,12) and, as such, the dysregulation of DPEP1 Key words: dipeptidase 1, colorectal cancer, lymph node metastasis, potentially leads to the development of malignant tumors. poorly differentiated histological types, epithelial to mesenchymal transition Initially, loss of DPEP1 expression is associated with Wilms' tumor (13). Consistent with this, DPEP1 is considered to be a 424 TACHIBANA et al: DPEP1 IS UPREGULATED IN COLORECTAL CANCER tumor suppressor gene in breast cancer and pancreatic ductal GenePix 4000B scanner (Axon Instruments Inc., Union City, adenocarcinoma (14,15). However, DPEP1 is upregulated in CA, USA) and processed into primary expression ratios. CRC and its high expression level is associated with poorer The primary expression ratios were then converted into log2 patient survival (16). Furthermore, a recent report demon- values and compiled into a matrix. An expression ratio of 1 strated that DPEP1 is highly expressed in CRC and promotes (log ratio of 0) was assigned for spots that exhibited fluores- metastasis via regulation of E-cadherin expression levels (17). cence intensities under the detection limits, and these were Therefore, further investigations are required to evaluate the included in the signal calculation of the mean averages. Data expression of DPEP1 in an additional independent CRC cohort were processed using MDI gene expression analysis software and the role of DPEP1 in CRC metastasis. package (MicroDiagnostic, Inc.). In the present study, DPEP1 expression levels were investigated using comprehensive gene expression analyses, RT‑qPCR. Total RNA was extracted from cells using TRIzol reverse transcription-quantitative polymerase chain reac- reagent (Thermo Fisher Scientific, Inc.) according to the tion (RT-qPCR) and immunohistochemical (IHC) staining manufacturer's instructions. Complementary DNA (cDNA) in surgically resected CRC cases. In addition, the biological was synthesized from 5 µg of total RNA with a random significance of DPEP1 was examined by comparing the hexamer using the SuperScript III First-Strand Synthesis expression levels of EMT markers to clarify the function of System (Thermo Fisher Scientific, Inc.). These cDNAs DPEP1 in CRC metastasis. were used for the measurement of gene expression with a 7500 Real‑time PCR system (Thermo Fisher Scientific, Inc.) Materials and methods using TaqMan probes. The assessors were blinded to the patient information and performed the experiments in trip- Clinical samples of patients. A total of 78 surgical speci- licate. Taqman expression assays, DPEP1 (Hs01116752_m1) mens were obtained from CRC patients who had undergone and β-actin (Hs99999903_m1) were purchased from Thermo surgical resection at Fukushima Medical University Fisher Scientific, Inc. andβ -actin served as an internal control. Hospital (Fukushima, Japan) between January 2008 and Relative DPEP1 gene expression was calculated using the December 2010. Specimens from all 78 cases were used for 2-ΔΔCq method, according to the supplier's protocol (Thermo comprehensive gene expression analysis, specimens from five Fisher Scientific, Inc.) (21). cases were used for protein expression analysis by western blotting, and specimens from 55 cases were used for IHC Western blotting. Surgical specimens were homogenized staining. Information regarding age, gender, TNM stage in a 100-mM Tris-HCl (pH 7.6) buffer containing 0.15 M and pathological diagnosis, including lymphatic and venous NaCl, 5 mM EDTA, 1% Triton X-100, and 5% glycerol using invasion were retrospectively collected. The carcinomas at a Polytron PT3100 homogenizer (Kinematica AG, Luzern, the time of primary tumor resection were staged according Switzerland). After centrifugation at 17,400 x g for 15 min to the Union for International Cancer Control (UICC) TNM at 4˚C, the supernatants were collected. Next, 20 µg of classification (the 7th classification) (18,19). Written informed each protein sample was run on SDS-polyacrylamide gels consent was obtained from all patients and the current study (5‑15% gradient; Thermo Fisher Scientific, Inc.) and blotted was approved by the ethics committee of Fukushima Medical onto Immun-Blot PVDF membranes (Bio-Rad Laboratories, University. Inc., Hercules, CA, USA). The blotted membranes were incubated with the following primary antibodies overnight Comprehensive gene expression analysis. DPEP1 expression at 4˚C: Rabbit polyclonal anti‑DPEP1 [(cat. no. HPA012783) data were obtained using custom microarray analysis, as Sigma-Aldrich; Merck KGaA, Darmstadt, Germany] at a previously described (20). Briefly, the surgical specimen was dilution of 1:100, and mouse monoclonal anti-β-actin anti- homogenized and mixed with ISOGEN® reagent (Nippon body (cat. no. sc-69879; Santa Cruz Biotechnology, Inc.,
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