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Tumor Suppressive Microrna-375 Regulates Lactate Dehydrogenase B in Maxillary Sinus Squamous Cell Carcinoma

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Tumor Suppressive Microrna-375 Regulates Lactate Dehydrogenase B in Maxillary Sinus Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF ONCOLOGY 40: 185-193, 2012 Tumor suppressive microRNA-375 regulates lactate dehydrogenase B in maxillary sinus squamous cell carcinoma TAKASHI KINoshita1,2, NIjIRo Nohata1,2, HIRoFUMI YoSHINo3, ToYoYUKI HANAzAwA2, NAoKo KIKKAwA2, LISA FUjIMURA4, TAKeSHI CHIYoMARU3, KAzUMoRI KAwAKAMI3, HIDeKI eNoKIDA3, Masayuki NAKAGAwA3, Yoshitaka oKAMoTo2 and NAoHIKo SeKI1 Departments of 1Functional Genomics, 2otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670; 3Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520; 4Biomedical Research Center, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, japan Received july 6, 2011; Accepted August 23, 2011 DoI: 10.3892/ijo.2011.1196 Abstract. The expression of microRNA-375 (miR-375) is head and neck tumors, with an annual incidence of 0.5-1.0 per significantly reduced in cancer tissues of maxillary sinus squa- 100,000 people (1,2). Since the clinical symptoms of patients mous cell carcinoma (MSSCC). The aim of this study was to with MSSCC are very insidious, tumors are often diagnosed at investigate the functional significance ofmiR-375 and a possible advanced stages. Despite advances in multimodality therapy regulatory role in the MSSCC networks. Restoration of miR-375 including surgery, radiotherapy and chemotherapy, the 5-year significantly inhibited cancer cell proliferation and invasion survival rate for MSSCC has remained ~50%. Although regional in IMC-3 cells, suggesting that miR-375 functions as a tumor lymph node metastasis and distant metastasis are uncommon suppressor in MSSCC. Genome-wide gene expression data and (20%), the high rate of locoregional recurrence (60%) contributes luciferase reporter assays indicated that lactate dehydro genase B to poor survival (3). The results of epidemiological studies have (LDHB) was directly regulated by miR-375. Cancer cell prolif- suggested that occupational exposures to leather, wood dust, eration and invasion were significantly inhibited by transfection nickel, arsenic and formaldehyde are risk factors for MSSCC of si-LDHB into IMC-3 cells, suggesting that LDHB may play (4-6); a point of divergence from head and neck squamous cell a role in MSSCC oncogenic function. In clinical MSSCC carcinomas (HNSCC) of the tongue, oral cavity and pharynx. specimens, LDHB mRNA levels were up-regulated in cancer Few reports have performed genome analysis of MSSCC. tissues, which were inversely correlated with the expression of Understanding the molecular oncogenic pathways underlying miR-375. In addition, Kaplan-Meier curves and log-rank tests MSSCC could significantly improve diagnosis, therapy, and revealed that the high mRNA expression levels of LDHB had disease prevention. a significant adverse effect on survival rate. The identification Growing evidence suggests that carcinogenesis is induced of a cancer network regulated by the miR-375 tumor suppressor by overactivation of pro-oncogenic pathways and inactivation could provide new insights into the molecular mechanisms of of tumor-suppressive pathways (7). In cancer pathways, normal MSSCC oncogenesis. regulatory mechanisms are disrupted by aberrant expression of microRNA (miRNA) (8). miRNAs are a class of small Introduction non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes including Maxillary sinus squamous cell carcinoma (MSSCC) is a development, differentiation, apoptosis, and cell proliferation. malignant epithelial tumor originating in the respiratory They regulate gene expression through translational repression mucosa of the maxillary sinus. MSSCC comprises 2-3% of all and mRNA cleavage (9). Bioinformatic predictions indicate that miRNAs regulate >30% of protein coding genes (10). So far, 1424 human miRNAs have been registered at miRBase release 17.0 (http://microrna.sanger.ac.uk/). miRNAs contribute to the initiation and development of various types of cancers (11). Correspondence to: Dr Naohiko Seki, Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 miRNAs are aberrantly expressed in many human cancers, and Inohana Chuo-ku, Chiba 260-8670, japan can function either as tumor suppressors or oncogenes (12). e-mail: [email protected] Down-regulated miRNAs in cancer cells might normally function as tumor suppressive miRNAs that negatively regu- Key words: microRNA, miR-375, lactate dehydrogenase B, maxillary late oncogenes. Based on this hypothesis, we have profiled the sinus squamous cell carcinoma, tumor suppressor miRNA expression signatures of human cancers, including HNSCC (13-17). In human squamous cell carcinoma (SCC), tumor suppressive miRNAs such as miR-1, miR-133a and 186 kinoshita et al: miR-375 RegulateS LDHB in MSSCC miR-489 were identified through direct repression of several Reagent (Invitrogen) as described previously (13). Transfection oncogenes (15,16,18-20). The miRNA expression signatures of efficiency of Pre-miRTM in the IMC-3 cell line was confirmed hypopharyngeal SCC, esophageal SCC and MSSCC revealed based on down-regulation of TWF1 (PTK9) mRNA following that miR-375 is significantly reduced in cancer cells (15,16). transfection with miR-1 as previously reported (14,15). miR-375 was originally cloned and identified as an evolutionarily conserved pancreatic islet-specific miRNA (21).miR-375 -/- mice Cancer cell proliferation and invasion assays. Cells were were hyperglycemic and exhibited an increase in the number of transfected with 10 nM miRNA and siRNA by reverse trans- pancreatic α cells (22). Although several studies have indicated fection and plated in 96-well plates at 3x103 cells per well. that miR-375 is down-regulated in human cancers, the function After 72 or 96 h, cell proliferation was determined with the of miR-375 and its target genes in MSSCC remains unclear XTT assay, using the Cell Proliferation kit II (Roche Molecular (23-26). Biochemicals, Mannheim, Germany) as previously reported The aim of this study was to clarify the functional signifi- (15,16). Triplicate wells were measured for cell viability in cance of miR-375 in MSSCC and to identify molecular pathways each treatment group. regulated by miR-375. we analyzed the effect of miR-375 on cell A cell invasion assay was carried out using modified Boyden proliferation and cell invasion in the MSSCC cell line IMC-3. chambers containing transwell-precoated Matrigel membrane Genome-wide expression analysis identified lactate dehydro- filter inserts with 8-µm pores in 24-well tissue culture plates genase B (LDHB) as a candidate gene target of miR-375. The at 1x105 cells per well (BD Biosciences, Bedford, MA, USA) identification of a novel miR-375-regulated tumor suppressive (14). Triplicate wells were measured for cell invasion in each pathway could further reveal the molecular mechanism of treatment group. MSSCC oncogenesis. Microarray expression analysis. A genome-wide screen was Materials and methods performed to identify gene targets of miR-375 in the IMC-3 cell line. oligo-microarray Human 44K (Agilent Technologies) MSSCC cell culture. IMC-3, a human MSSCC cell line, was was used for expression profiling of miR-375 transfectants derived from a primary lesion of MSSCC (27). MSSCC cells in comparison with miRNA-negative-control transfectants. were grown in RPMI-1640 medium supplemented with 10% Microarray hybridization and data collection were performed fetal bovine serum in a humidified atmosphere containing 5% as previously described (28). TargetScan (release 5.1, http:// CO2 at 37˚C. www.targetscan.org/) was used to identify predicted target genes and their miRNA binding site seed regions. Sequences of Clinical specimens of MSSCC. written consent for tissue the predicted mature miRNAs were confirmed using miRBase donation for research purposes was obtained from each patient (release 17.0, http://microrna.sanger.ac.uk/). before tissue collection. The protocol was approved by the Institutional Review Board of Chiba University. Twenty pairs Quantitative reverse-transcription-PCR (qRT-PCR). First- of primary tumor tissues and corresponding normal epithelial strand cDNA was synthesized from 1.0 µg of total RNA tissues were obtained from patients with MSSCC in Chiba using a High Capacity cDNA Reverse Transcription kit University Hospital (Chiba, japan) from 2007 to 2010. The (Applied Biosystems). Gene-specific PCR products were normal tissue was confirmed to be free of cancer cells by patho- assayed con tinuously using a 7900-HT Real-Time PCR System logic examination. The specimens were immersed in RNAlater according to the manufacturer's protocol. TaqMan® probes and (Qiagen, Valencia, CA, USA) and stored at -20˚C until RNA was primers for LDHB (P/N: Hs00929956_m1), and GUSB ( P / N : extracted. Clinical information of the twenty patients is shown Hs99999908_m1) internal control were obtained from Applied in Table I. Biosystems (Assay-on-Demand Gene expression Products). The expression levels of miR-375 (Assay ID: 000564) was analyzed RNA isolation. Total RNA was isolated using TRIzol Reagent by TaqMan quantitative real-time PCR (TaqMan MicroRNA (Invitrogen, Carlsbad, CA, USA) according to the manu- Assay; Applied Biosystems) and normalized to RNU48 (Assay facturer's protocol. RNA concentration was determined ID: 001006). All reactions were performed in triplicate, and spectrophoto metrically, and molecular integrity was
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