Publications by authors named "Yuko Ueda"

48 Publications

Radiation inducible MafB gene is required for thymic regeneration.

Sci Rep 2021 May 17;11(1):10439. Epub 2021 May 17.

Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8509, Japan.

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and thymic epithelial cells in such processes, the roles of stromal transcription factors in these remain incompletely understood. MafB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a transcription factor expressed in thymic stroma and its expression was induced a day after radiation exposure. Hence, the roles of mesenchymal MafB in the process of thymic regeneration offers an intriguing research topic also for radiation biology. The current study investigated whether MafB plays roles in the adult thymus. MafB/green fluorescent protein knock-in mutant (MafB) mice showed impaired thymic regeneration after the sublethal irradiation, judged by reduced thymus size, total thymocyte number and medullary complexity. Furthermore, IL4 was induced after irradiation and such induction was reduced in mutant mice. The mutants also displayed signs of accelerated age-related thymic involution. Altogether, these results suggest possible functions of MafB in the processes of thymic recovery after irradiation, and maintenance during aging.
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http://dx.doi.org/10.1038/s41598-021-89836-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129107PMC
May 2021

Pharmacological Inhibition of miR-130 Family Suppresses Bladder Tumor Growth by Targeting Various Oncogenic Pathways via PTPN1.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

Previously, we have revealed that the miR-130 family (miR-130b, miR-301a, and miR-301b) functions as an oncomiR in bladder cancer. The pharmacological inhibition of the miR-130 family molecules by the seed-targeting strategy with an 8-mer tiny locked nucleic acid (LNA) inhibits the growth, migration, and invasion of bladder cancer cells by repressing stress fiber formation. Here, we searched for a functionally advanced target sequence with LNA for the miR-130 family with low cytotoxicity and found LNA #9 (A(L)^i^i^A(L)^T(L)^T(L)^G(L)^5(L)^A(L)^5(L)^T(L)^G) as a candidate LNA. LNA #9 inhibited cell growth in vitro and in an in vivo orthotopic bladder cancer model. Proteome-wide tyrosine phosphorylation analysis suggested that the miR-130 family upregulates a wide range of receptor tyrosine kinases (RTKs) signaling via the expression of phosphorylated Src (pSrc). SILAC-based proteome analysis and a luciferase assay identified protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is implicated as a negative regulator of multiple signaling pathways downstream of RTKs as a target gene of the miR-130 family. The miR-130-targeted LNA increased and decreased PTPN1 and pSrc expressions, respectively. PTPN1 knockdown led to increased tumor properties (cell growth, invasion, and migration) and increased pSrc expression in bladder cancer cells, suggesting that the miR-130 family upregulates multiple RTK signaling by targeting PTPN1 and subsequent Src activation in bladder cancer. Thus, our newly designed miR-130 family targeting LNA could be a promising nucleic acid therapeutic agent for bladder cancer.
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http://dx.doi.org/10.3390/ijms22094751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124864PMC
April 2021

ALKBH4 promotes tumourigenesis with a poor prognosis in non-small-cell lung cancer.

Sci Rep 2021 Apr 21;11(1):8677. Epub 2021 Apr 21.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.

The human AlkB homolog family (ALKBH) of proteins play a critical role in some types of cancer. However, the expression and function of the lysine demethylase ALKBH4 in cancer are poorly understood. Here, we examined the expression and function of ALKBH4 in non-small-cell lung cancer (NSCLC) and found that ALKBH4 was highly expressed in NSCLC, as compared to that in adjacent normal lung tissues. ALKBH4 knockdown significantly induced the downregulation of NSCLC cell proliferation via cell cycle arrest at the G phase of in vivo tumour growth. ALKBH4 knockdown downregulated E2F transcription factor 1 (E2F1) and its target gene expression in NSCLC cells. ALKBH4 and E2F1 expression was significantly correlated in NSCLC clinical specimens. Moreover, patients with high ALKBH4 expression showed a poor prognosis, suggesting that ALKBH4 plays a pivotal tumour-promoting role in NSCLC.
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http://dx.doi.org/10.1038/s41598-021-87763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060266PMC
April 2021

3D reconstruction and histopathological analyses on murine corporal body.

Reprod Med Biol 2021 Apr 9;20(2):199-207. Epub 2021 Feb 9.

Department of Developmental Genetics Institute of Advanced Medicine Wakayama Medical University Wakayama Japan.

Purpose: Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three-dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the status of regulatory signals for such abnormality are also performed.

Methods: To analyze the 3D structure of sinusoid, 3D reconstruction from serial sections of murine CC were performed. Histological analyses between young (2 months old) and aged (14 months old) CC were performed. As for chondrogenic signaling status of aged CC, SOX9 and RBPJK staining was examined.

Results: Sinusoids prominently developed in the outer regions of CC adjacent to tunica albuginea. Aged CC samples contained ectopic chondrocytes in such regions. Associating with the appearance of chondrocytes, the expression of SOX9, chondrogenic regulator, was upregulated. The expression of RBPJK, one of the Notch signal regulators, was downregulated in the aged CC.

Conclusions: Prominent sinusoids distribute in the outer region of CC which may possess important roles for erection. A possibility of ectopic chondrogenesis induced by alteration of SOX9/Notch signaling with aging is indicated.
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http://dx.doi.org/10.1002/rmb2.12369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022099PMC
April 2021

Development of a highly sensitive method for the quantitative analysis of modified nucleosides using UHPLC-UniSpray-MS/MS.

J Pharm Biomed Anal 2021 Apr 2;197:113943. Epub 2021 Feb 2.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

There are more than 150 types of naturally occurring modified nucleosides, which are believed to be involved in various biological processes. Recently, an ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) technique has been developed to measure low levels of modified nucleosides. A comprehensive analysis of modified nucleosides will lead to a better understanding of intracellular ribonucleic acid modification, but this analysis requires high-sensitivity measurements. In this perspective, we established a highly sensitive and quantitative method using the newly developed ion source, UniSpray. A mass spectrometer was used with a UniSpray source in positive ion mode. Our UHPLC-UniSpray-MS/MS methodology separated and detected the four major nucleosides, 42 modified nucleosides, and dG15N5 (internal standard) in 15 min. The UniSpray method provided good correlation coefficients (>0.99) for all analyzed nucleosides, and a wide range of linearity for 35 of the 46 nucleosides. Additionally, the accuracy and precision values satisfied the criteria of <15% for higher concentrations and <20% for the lowest concentrations of all nucleosides. We also investigated whether this method could measure nucleosides in biological samples using mouse tissues and non-small cell lung cancer clinical specimens. We were able to detect 43 and 31 different modified nucleosides from mouse and clinical tissues, respectively. We also found significant differences in the levels of N6-methyl-N6-threonylcarbamoyladenosine (m6t6A), 1-methylinosine (m1I), 2'-O-methylcytidine (Cm), 5-carbamoylmethyluridine (ncm5U), 5-methoxycarbonylmethyl-2-thiouridine (mcm5S2U), and 5-methoxycarbonylmethyl-2'-O-methyluridine (mcm5Um) between cancerous and noncancerous tissues. In conclusion, we developed a highly sensitive methodology using UHPLC-UniSpray-MS/MS to simultaneously detect and quantify modified nucleosides, which can be used for analysis of biological samples.
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http://dx.doi.org/10.1016/j.jpba.2021.113943DOI Listing
April 2021

Natural History of Asymptomatic Pseudoaneurysm Soon After Robot-assisted Partial Nephrectomy: Single-center Prospective Study.

Urology 2021 Feb 25;148:145-150. Epub 2020 Nov 25.

Department of Urology, Wakayama Medical University, Wakayama, Japan.

Objective: To prospectively investigate the natural history of asymptomatic pseudoaneurysm after robotic-assisted partial nephrectomy.

Methods: Robotic-assisted partial nephrectomy was undertaken for 67 patients between July 2014 and July 2018. Patients who could not undergo enhanced CT were excluded, so 60 patients were finally included in the present study. We prospectively investigated the presence of pseudoaneurysm based on early enhanced CT scan on postoperative day 7. According to our treatment policy, patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Meanwhile, patients with asymptomatic pseudoaneurysm were observed with follow-up CT imaging, regardless of the size of the aneurysm.

Results: Overall incidence of pseudoaneurysm on postoperative day 7 was 18% (11/60 cases). The median size of the pseudoaneurysm was 9 mm (quartile: 6-12 mm). Two patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Nine patients had asymptomatic pseudoaneurysm; in 8 of these it disappeared without therapeutic intervention. The median period from surgery to confirmed disappearance of the aneurysm was 19 days (quartile 14-32 days). In the remaining 1 patient, small asymptomatic pseudoaneurysm (2 mm) could still be observed even 1 year after surgery.

Conclusion: Our study showed high incidence of pseudoaneurysm 1 week after robotic-assisted partial nephrectomy that mostly disappeared without therapeutic intervention. Routine enhanced CT screening and pre-emptive embolization may not be necessary for asymptomatic renal artery pseudoaneurysm.
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http://dx.doi.org/10.1016/j.urology.2020.09.053DOI Listing
February 2021

Conventional Direct Smear Yields Diagnostic Indicators of Gastric-Type Mucinous Carcinoma Compared with Cytomorphological Features Identified by Liquid-Based Cervical Cytology.

Acta Cytol 2021 11;65(2):150-157. Epub 2020 Nov 11.

Department of Clinical Laboratory, Osaka International Cancer Institute Hospital, Osaka, Japan.

Introduction: Gastric-type mucinous carcinoma (GAS) of the uterine cervix is an adenocarcinoma subtype with a gastric phenotype that poses diagnostic pitfalls in cervical screening cytology because of its blunt morphologic atypia and the limited utility of human papillomavirus testing and ancillary immunochemical staining. Despite the recent widespread uptake of liquid-based cytology (LBC) systems, the cytomorphological features of GAS in LBC samples and the differential features between GAS and usual-type endocervical adenocarcinoma (UEA) remain unclear.

Methods: Eight GAS cases, all of which were surgically treated following histological confirmation, were examined. Direct Papanicolaou-stained smears and LBC samples were reviewed and compared with 10 UEA cases as controls. Featured cytomorphological findings were as follows: background (mucinous, inflammatory, or necrotic), cell crowding (size of neoplastic cell clusters), cytoplasm (golden mucin and cell border), and nuclei (nuclear chromatin and nucleoli).

Results: Of 18 adenocarcinomas, 16 were detected against a non-mucinous background in LBC samples, most of which were accompanied by mild to moderate inflammation. Clusters comprising >300 neoplastic cells were identified in both GAS and UEA in conventional smears (CSs), while no LBC samples harboured clusters as large as these. Cell borders of GAS were more distinct than those of UEA in CSs (p < 0.001), although fewer populations of neoplastic clusters revealed distinct cell borders in both GAS and UEA in LBC samples. Three of 8 and 2 of 8 GAS cases had golden mucin in CSs and in LBC samples, respectively, which was not detected in UEA at all. Nucleoli against fine nuclear chromatin were more pronounced in GAS than in UEA on CS (p = 0.03), although the difference between GAS and UEA was not apparent in LBC samples.

Discussion/conclusion: This study demonstrated that the diagnostic clues to detect GAS using the conventional approach, namely distinct cell borders and prominent nucleoli, are not useful for excluding UEA in LBC samples. Conventional cervical smears may indicate a diagnosis of GAS; however, specific high-risk HPV detection approaches, such as HPV test or immunocytochemical p16/Ki-67 dual staining, are desirable to differentiate GAS from UEA in the setting of LBC with ambiguous cytomorphological features.
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http://dx.doi.org/10.1159/000511337DOI Listing
March 2021

Cancer type‑SLCO1B3 promotes epithelial‑mesenchymal transition resulting in the tumour progression of non‑small cell lung cancer.

Oncol Rep 2021 01 6;45(1):309-316. Epub 2020 Nov 6.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565‑0871, Japan.

Non‑small cell lung cancer (NSCLC) is one of the most common histologically defined subtypes of lung cancer. To identify a promising molecular target for NSCLC therapy, we performed gene expression analysis at the exon level using postoperative specimens of NSCLC patients. Exon array and real‑time PCR analyses revealed that an alternative splicing variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3) called cancer type‑SLCO1B3 (Ct‑SLCO1B3) was significantly upregulated in the NSCLC samples. SLCO1B3 expressed in the liver [liver type (Lt)‑SLCO1B3] was found to be localised in the cell membrane, whereas Ct‑SLCO1B3 was detected in the cytoplasm of NSCLC cells. RNAi‑mediated knockdown of Ct‑SLCO1B3 inhibited in vitro anchorage‑independent cell growth, cell migration, and in vivo tumour growth of A549 cells. Overexpression of Ct‑SLCO1B3 but not Lt‑SLCO1B3 upregulated anchorage‑independent cell growth and cell migration of NCI‑H23 cells. Mechanistically, Ct‑SLCO1B3 was found to regulate the expression of epithelial‑mesenchymal transition (EMT)‑related genes. The upregulation of E‑cadherin was discovered to be especially pivotal to phenotypes of Ct‑SLCO1B3‑suppressed A549 cells. These findings suggest that Ct‑SLCO1B3 functions as a tumour‑promoting factor via regulating EMT‑related factors in NSCLC.
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http://dx.doi.org/10.3892/or.2020.7839DOI Listing
January 2021

A report of three cancer patients on opioid analgesia receiving spinal anesthesia: abrupt pain elimination without respiratory depression.

JA Clin Rep 2020 Jul 1;6(1):49. Epub 2020 Jul 1.

Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Chiba, 260-8670, Japan.

Background: Complete removal of pain with regional anesthesia has been reported to cause fatal respiratory depression in opioid-dependent patients, which leads us to choose general anesthesia. We hereby report three cases of chronically opioid-treated cancer patients operated under spinal anesthesia without respiratory event.

Case Presentation: Case 1: a 32-year-old female treated with high-dose morphine for her cancer pain was planned for cesarean section. Case 2: a 65-year-old female on moderate dose of oxycodone was planned for surgery of her femoral bone fracture. Case 3: a 65-year-old male on low-dose oxycodone was planned for intramedullary nailing for metastatic femoral bone tumor. In all three cases, spinal anesthesia was chosen. Continuous respiratory monitoring revealed no apnea or bradypnea.

Conclusion: Spinal anesthesia was safely performed without respiratory depression in chronic opioid users for cancer pain.
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http://dx.doi.org/10.1186/s40981-020-00355-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329962PMC
July 2020

Ten-year temporal trends (2006-2015) and seasonal-differences in urinary metabolite concentrations of novel, hygiene-used pyrethroids in Japanese children.

Int J Hyg Environ Health 2020 04 18;225:113448. Epub 2020 Jan 18.

Department of Pathophysiological Laboratory Sciences, Field of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya, 461-8673, Japan. Electronic address:

Background And Aim: Metofluthrin, profluthrin, tefluthrin, and transfluthrin are pyrethroid (PYR) insecticides increasingly used to control mosquitoes, flies, and moths in households and public places (hygiene-PYRs). Currently, there is limited data available concerning exposure to these novel hygiene-PYRs. The goal of this study was to monitor exposure to these hygiene-PYRs by analysing their urinary metabolites and to investigate the temporal and seasonal trends in the concentrations of these metabolites.

Methods: First morning urine samples were obtained from 50 Japanese children (four-six years old) in October of 2006, 2011, and 2015 (total = 150 children) in order to investigate temporal trends. Additionally, first-morning urine samples were collected from 44 three-year-old children in August-September of 2012 (summer) and in February of 2013 (winter) to investigate seasonal differences. The urinary concentrations of 2,3,5,6-tetrafluorobenzyl alcohol (FB-Al; a specific metabolite of transfluthrin), 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (CH-FB-Al; a common metabolite of tefluthrin and profluthrin), 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (CHOCH-FB-Al; a specific metabolite of metofluthrin), and 2,3,5,6-tetrafluoro-1,4-benzenedimethanol (HOCH-FB-Al; a common metabolite of metofluthrin, tefluthrin, and profluthrin) were measured using GC-MS/MS.

Results: For the investigated years, rapid increases in the detection rates of the hygiene-PYR metabolites were observed. In 2015, FB-Al was identified in 64% of the samples, CH-FB-Al in 46%, CHOCH-FB-Al in 50%, and HOCH-FB-Al in 83%. Significant increasing trends were found for the concentrations of all hygiene-PYR metabolites from 2006 to 2015 (Jonckheere-Terpstra test, p < 0.001). The concentrations of FB-Al and CHOCH-FB-Al were higher in summer than in winter (Mann Whitney-U test, p < 0.05).

Conclusions: These findings suggest that, in Japanese children, exposure to hygiene-PYRs has increased over the past decade, and that children are exposed to higher levels of hygiene-PYRs in summer than in winter.
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http://dx.doi.org/10.1016/j.ijheh.2019.113448DOI Listing
April 2020

Biomonitoring method for neonicotinoid insecticides in urine of non-toilet-trained children using LC-MS/MS.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 Feb 11;37(2):304-315. Epub 2019 Dec 11.

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

There is a growing appreciation of the importance of determining chemical exposure levels in early childhood, as well as in embryonic and foetal life, which are now widely believed to be essential for gaining insight into potential health risks associated with these chemicals. To facilitate the assessment of exposure to neonicotinoid insecticides (NEOs) in non-toilet-trained children, a new method using disposable diapers (nappies) was developed for the simultaneous determination of the NEOs acetamiprid and its metabolite -desmethylacetamiprid, clothianidin, dinotefuran, imidacloprid, thiacloprid, and thiamethoxam (NEO biomarkers). The urine absorbed in disposable diapers was extracted with acetone (diaper urine) and was cleaned using a solid-phase extraction column, before analysis with LC-MS/MS. The absolute recoveries of NEO biomarkers were 19-50%. Good results were observed for the linearity of the matrix-matched calibration curves ( = 0.983-0.996; concentration range LOQ-20 µg L) and the precision of intra-day (% relative standard deviation (%RSD): 3.3-12.7%) and inter-day (%RSD: 4.3-19.5%) analyses. The lowest and highest limits of detection of the developed method were 0.07 µg L for acetamiprid and 0.75 µg L for clothianidin. The developed method was applied for the evaluation of fifty diapered three-year-old children in Japan. Importantly, the study revealed relatively high detection rates for dinotefuran and -desmethylacetamiprid; 84% and 78% respectively. The highest geometric mean of dinotefuran urinary concentration was 2.01 µg L. Thus, a method for determining NEO biomarkers in urine extracted from disposable diapers was established. This is the first report on the simultaneous quantitative analysis of NEO biomarkers of diaper-absorbed urine samples.
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http://dx.doi.org/10.1080/19440049.2019.1696020DOI Listing
February 2020

Postoperative Progress after Stone Removal Following Treatment for Obstructive Acute Pyelonephritis Associated with Urinary Tract Calculi: A Retrospective Study.

Urol J 2020 03 16;17(2):118-123. Epub 2020 Mar 16.

Department of Urology, Wakayama Medical University, Kimiidera 811-1, Wakayama, Japan.

Purpose: We aimed to identify the prevalence and risk factors of three outcomes after stone removal following treatment for obstructive acute pyelonephritis (APN) associated with urinary tract calculi: immediate postoperative febrile urinary tract infection (UTI), stone recurrence, and APN recurrence during the follow-up period.

Materials And Methods: We retrospectively reviewed the charts of 107 patients who underwent stone removal following treatment for obstructive APN associated with urinary tract calculi. Logistic regression analysis was used to identify the factors that contributed to postoperative febrile UTI after stone removal. Cox proportional hazard analyses were used to identify the factors contributing to stone recurrence and APN recurrence during the follow-up period.

Results: Postoperative febrile UTI was observed in 23 out of  107 patients (21.5%). Multivariate logistic regression analysis revealed that female sex (P = .02) and having multiple stones (P < .01) were independently significant predictors of postoperative febrile UTI. One-year recurrence-free survival rates of stone disease and APN were 76.1% and 82.5%, respectively. Multivariable cox proportional hazard analyses revealed that presence of residual fragments was the only significant risk factor for stone recurrence (P < .01) and marginally significant for APN recurrence (P = .05).

Conclusion: Patients presenting with obstructive APN  frequently develop postoperative febrile UTI after active stone removal with the risk factors being female sex and having multiple stones. Residual fragments after stone removal in patients with obstructive APN can cause urolithiasis  and APN recurrence, indicating that complete removal of stone fragments ? 4 mm is imperative to the disease management.
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http://dx.doi.org/10.22037/uj.v0i0.4847DOI Listing
March 2020

MicroRNA-130b functions as an oncomiRNA in non-small cell lung cancer by targeting tissue inhibitor of metalloproteinase-2.

Sci Rep 2019 05 6;9(1):6956. Epub 2019 May 6.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b. Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.
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http://dx.doi.org/10.1038/s41598-019-43355-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502853PMC
May 2019

The Effectiveness of Saireito, a Traditional Japanese Herbal Medicine, in Reducing Postoperative Edema after Acquired Ptosis Surgery: A Prospective Controlled Trial.

Evid Based Complement Alternat Med 2018 27;2018:4742305. Epub 2018 Jun 27.

Department of Plastic and Reconstructive Surgery, Kansai Medical University, Japan.

Background: Persistent edema is a common complication after the surgical treatment of blepharoptosis; however, no objective methods have been established for evaluating or treating this condition. We focused on the Japanese herbal medicine, Saireito, and evaluated its efficacy in reducing postoperative edema.

Methods: This was a prospective, nonrandomized, and controlled study. We evaluated the incidence of postoperative edema in a Control group using a subjective patient-assessed visual analog scales (VASs) to assess swelling, pain, itching, and local warmth and an objective surgeon-assessed VAS to evaluate swelling. Swelling was also assessed by an objective computer-based analysis of digital images. These methods were used to evaluate the effects of Saireito (8.1 g/day) for 8 weeks.

Results: A total of 49 patients and 80 eyelids were enrolled. Twenty-nine patients and 48 eyelids were assigned to the Control group, and 20 patients and 32 eyelids were assigned to the Saireito group. Our analysis of the Control group indicated that postoperative edema persisted for up to 8 weeks. On the other hand, the postoperative edema in the Saireito group was mostly eliminated at 8 weeks. The computer-based analysis of digital images showed that the edema tended to be reduced in the Saireito group compared with the Control group.

Conclusion: Saireito might be effective for reducing postoperative edema after blepharoptosis surgery and almost completely eliminated it at 8 weeks after surgery. This study was a preliminary and nonrandomized study; therefore, the randomized and placebo-controlled study will be needed in the next step.
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http://dx.doi.org/10.1155/2018/4742305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040292PMC
June 2018

A sensitive and efficient procedure for the high-throughput determination of nine urinary metabolites of pyrethroids by GC-MS/MS and its application in a sample of Japanese children.

Anal Bioanal Chem 2018 Sep 26;410(24):6207-6217. Epub 2018 Jul 26.

Department of Pathophysiological Laboratory Sciences, Field of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya, 461-8673, Japan.

Four pyrethroids (PYRs), metofluthrin, profluthrin, tefluthrin, and transfluthrin, which were newly developed and have relatively high vapor activity at ambient temperature, are now playing a key role in safely controlling insects in our daily lives. We developed a sensitive and high-throughput determination method for urinary metabolites derived from the newly developed PYR, e.g., 2,3,5,6-tetrafluoro-1,4-benzenedimethanol (HOCH-FB-Al), 2,3,5,6-tetrafluorobenzyl alcohol (FB-Al), and other PYR metabolites such as trans-chrysanthemumdicarboxylic acid (trans-CDCA) and 3-phenoxybenzoic acid (3PBA). After high temperature acid hydrolysis of 2 mL urine sample in 24-deep well plate, the PYR metabolites were extracted by semi-automated liquid-liquid extraction with tert-butyl methyl ether. N,O-Bis (trimethylsilyl) trifluoroacetamide containing 1% trimethylchlorosilane or 1,1,1,3,3,3-hexafluoroisopropanol were used for the derivatization of PYR metabolites, and the derivatized metabolites were analyzed separately by GC-MS/MS equipped with dual injector system (DB-5MS and mid- to high-polarity phase Rtx-65 columns). The derivatization and evaporation conditions were mainly optimized for improving sensitivity and reproducibility. The mean within-run day precisions were less than 18.4% (relative standard deviation, %RSD) with low detection limits ranging from 0.01 μg/L for HOCH-FB-Al to 0.06 μg/L for trans-CDCA. This method was successfully applied to urine samples obtained from 50 3-year-old children with high detection frequencies (e.g., 82% for HOCH-FB-Al and 84% for FB-Al). This method may be a pivotal tool for developing risk assessment from PYR exposure in the general population.
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http://dx.doi.org/10.1007/s00216-018-1229-xDOI Listing
September 2018

Loss of SWI/SNF complex expression in undifferentiated renal carcinoma in acquired cystic kidney.

Pathol Int 2018 Apr 19. Epub 2018 Apr 19.

Department of Human Pathology, Wakayama Medical University, Wakayama, Japan.

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http://dx.doi.org/10.1111/pin.12671DOI Listing
April 2018

Effects of processing and cooking on the reduction of dinotefuran concentration in Japanese rice samples.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2018 Jul 23;35(7):1316-1323. Epub 2018 May 23.

c Food Safety and Quality Research Center , Tokai COOP Federation , Aichi , Japan.

Dinotefuran is an insecticide belonging to the neonicotinoid class, which is frequently used to control pests in paddy rice owing to its permeability and effectiveness against sucking insects. Since 2002, this insecticide has been commercially available in Japan, and has become controversial due to its high detection frequency in brown rice for primary consumption. In this study, the effects of processing and cooking on the reduction of dinotefuran residues in commercially available brown rice were investigated. Boiled rice is difficult to homogenise and extract with acetonitrile. Using pre-freezing and cryogenic milling with powdered dry ice, dinotefuran in boiled rice was extracted well. A measurement method comprising sample preparation (acetonitrile extraction, gel permeation chromatography, and SPE) and detection with anLC-MS/MS system was used. In 10 out of 25 commercial brown rice samples, dinotefuran was detected at a concentration of 0.04 μg/g (mean), which was more than the limit of quantitation of 0.01 μg/g. The dinotefuran levels were significantly less than the MRL of 2 μg/g in Japan. Even after polishing, washing, and boiling, dinotefuran was detected in 10 brown rice samples, with mean residue levels of 74.7%, 60.8%, and 39.6%, respectively, of the original concentration in brown rice. Based on these data, the processing factor of dinotefuran in boiled rice has been estimated to be approximately 0.4. Dinotefuran residues were reduced in the boiled rice, but less so than other pesticides. Although the maximum daily intake of dinotefuran in boiled rice was 0.0065 mg/person/day, its percent ratio to the ADI of dinotefuran in Japan was less than 0.05%. These results suggest that the daily intake of dinotefuran from rice might not be a critical problem at present, in spite of its relatively high detection frequency in boiled rice.
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http://dx.doi.org/10.1080/19440049.2018.1451659DOI Listing
July 2018

Novel Metabolically Stable PCA-1/ALKBH3 Inhibitor Has Potent Antiproliferative Effects on DU145 Cells .

Anticancer Res 2018 01;38(1):211-218

Advanced Medical Research Center, Hyogo University of Health Sciences, Kobe, Japan

Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer.
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http://dx.doi.org/10.21873/anticanres.12210DOI Listing
January 2018

Expression level of CXCL7 in peripheral blood cells is a potential biomarker for the diagnosis of renal cell carcinoma.

Cancer Sci 2017 Dec 25;108(12):2495-2502. Epub 2017 Oct 25.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

There are no blood biomarkers for the diagnosis of renal cell carcinoma (RCC) in routine clinical use. We focused on the gene expression profile of peripheral blood cells obtained from RCC patients to discover novel biomarkers for RCC diagnosis. Using microarray analysis and quantitative verification, CXCL7 was shown to be significantly upregulated in the peripheral blood cells of RCC patients. Importantly, aberrant CXCL7 expression was confirmed even in peripheral blood cells obtained from early stage (pT1a) RCC patients, and the expression level of CXCL7 in peripheral blood cells was a potential independent biomarker for the diagnosis of RCC by receiver operating characteristic curve analysis (sensitivity, 70.0%; specificity, 64.0%; area under the curve = 0.722; multiple logistic regression analysis: odds ratio, 1.07; 95% confidence interval, 1.03-1.11; P = 0.0004). Moreover, CXCL7 expression in peripheral blood cells significantly decreased after resection of the primary tumor. CXCL7 is more highly expressed in PBMCs than in neutrophils from both healthy controls and RCC patients. Interestingly, CXCL7 expression in PBMCs from healthy volunteers was significantly elevated following coculture with RCC cells compared to those cocultured with normal cells as a control. These results suggest that aberrant CXCL7 expression in peripheral blood cells is induced by RCC cells and may serve as a novel biomarker in the diagnosis of RCC.
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http://dx.doi.org/10.1111/cas.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715254PMC
December 2017

Development of Rapid Cleanup Method Using New Cleanup Agents for Analysis of Pesticide Residues in Tea.

Shokuhin Eiseigaku Zasshi 2017 ;58(4):188-194

Faculty of Agriculture, Ehime University.

Cleanup using two types of agents (S-NH and S-Si) developed by the authors was investigated with the aim of removing interfering substances such as catechin and caffeine to enable analysis of pesticide residues in tea. S-NH and S-Si removed approximately 100% of catechin and caffeine in 6 species of tea. Recoveries of 61 pesticides in tea were tested at the level of 0.1 μg/g, and 44 pesticides showed recovery within the range from 70 to 120%, with RSD of less than 10%. With cleanup using S-NH and S-Si, pesticide residues in tea could be analyzed within two hours.
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http://dx.doi.org/10.3358/shokueishi.58.188DOI Listing
February 2018

Evaluation of New Cleanup Agents for Analysis of Pesticide Residues in Tea.

Shokuhin Eiseigaku Zasshi 2017 ;58(3):155-159

Faculty of Agriculture, Ehime University.

We evaluated the effectiveness of new cleanup agents (S-NH and S-Si) compared with other previously reported cleanup agents (octadecylsilane, graphitized carbon, aminopropyl and silica gel) for removal of interfering substances such as catechin and caffeine prior to analysis of pesticide residues in tea. S-NH and S-Si were highly efficient in removal of catechin and caffeine, respectively. Recoveries of 80 pesticides using S-NH and S-Si were tested, and more than 70% of pesticides showed recovery greater than 70%. These results indicate that S-NH and S-Si agents will be useful for analysis of pesticide residues in tea.
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http://dx.doi.org/10.3358/shokueishi.58.155DOI Listing
September 2017

High miR-122 expression promotes malignant phenotypes in ccRCC by targeting occludin.

Int J Oncol 2017 Jul 22;51(1):289-297. Epub 2017 May 22.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.

Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. Although several studies have reported high expression of miR-122 in ccRCC, its physiological role remains unclear. To clarify the role of miR-122 in ccRCC, we compared miR-122 expression levels in non-cancerous tissue and ccRCC. Significant upregulation of miR-122 was observed in ccRCC specimens. Moreover, ccRCC patients with high miR-122 expression showed poor progression-free survival compared to those with low miR-122 expression. Overexpression of miR-122 using an miRNA mimic promoted proliferation, migration, and invasion activities of ccRCC cells. miR-122 directly targets occludin, a known component of tight junctions. Occludin knockdown promoted the cell migration activity but not proliferation or invasion activities of ccRCC cells. In human clinical specimens, miR-122 expression inversely correlated with occludin protein expression. These findings show that miR-122 is an oncomiR in ccRCC.
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http://dx.doi.org/10.3892/ijo.2017.4016DOI Listing
July 2017

TP53 gene status is a critical determinant of phenotypes induced by ALKBH3 knockdown in non-small cell lung cancers.

Biochem Biophys Res Commun 2017 06 4;488(2):285-290. Epub 2017 May 4.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

Human AlkB homolog 3 (ALKBH3) is overexpressed in non-small cell lung cancers (NSCLC) and its high expression is significantly correlated with poor prognosis. While ALKBH3 knockdown induces apoptosis in NSCLC cells, the underlying anti-apoptotic mechanisms of ALKBH3 in NSCLC cells remain unclear. Here we show that ALKBH3 knockdown induces cell cycle arrest or apoptosis depending on the TP53 gene status in NSCLC cells. In comparison to parental cells, TP53-knockout A549 cells showed DNA damage-responsive signal induced by ALKBH3 knockdown. TP53 knockout shifted the phenotypes of A549 cells induced by ALKBH3 knockdown from cell cycle arrest to apoptosis induction, suggesting that the TP53 gene status is a critical determinant of the phenotypes induced by ALKBH3 knockdown in NSCLC cells.
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http://dx.doi.org/10.1016/j.bbrc.2017.05.024DOI Listing
June 2017

Systematic Trial for Evaluating Docetaxel in a Human Prostate Cancer Cell DU145 Xenograft Model.

Anticancer Res 2017 04;37(4):1665-1676

School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan

The inhibitory activities of docetaxel at a wide range of doses (0.1-10 mg/kg; subcutaneously (s.c.), once/week) in nude mice bearing a human prostate cancer cell (DU145), xenograft model with implantation of DU145 cells or a DU145 solid tumor were examined. This systematic trial demonstrated that (i) docetaxel was more effective in the xenograft model formed by implantation of DU145 cells than in the solid DU145 tumor; (ii) administration of 2.5 mg/kg docetaxel was the critical dose because inhibitory activities were not observed at 2.5 mg/kg, while they were noted at 5 mg/kg and 10 mg/kg in both implantation approaches; (iii) edema-like effects (plump body shape and legs) were observed in both groups at 2.5 mg/kg and the tumor sizes, often increased by blood plasma and other fluids, as well as body weights were higher than at other doses; and (iv) suppression of body weight gain was observed at 10 mg/kg docetaxel.
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http://dx.doi.org/10.21873/anticanres.11496DOI Listing
April 2017

AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells.

Sci Rep 2017 02 13;7:42271. Epub 2017 Feb 13.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.

The mammalian AlkB homolog (ALKBH) family of proteins possess a 2-oxoglutarate- and Fe(II)-dependent oxygenase domain. A similar domain in the Escherichia coli AlkB protein catalyzes the oxidative demethylation of 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) in both DNA and RNA. AlkB homolog 3 (ALKBH3) was also shown to demethylate 1-meA and 3-meC (induced in single-stranded DNA and RNA by a methylating agent) to reverse the methylation damage and retain the integrity of the DNA/RNA. We previously reported the high expression of ALKBH3 in clinical tumor specimens and its involvement in tumor progression. In this study, we found that ALKBH3 effectively demethylated 1-meA and 3-meC within endogenously methylated RNA. Moreover, using highly purified recombinant ALKBH3, we identified N6-methyladenine (N6-meA) in mammalian transfer RNA (tRNA) as a novel ALKBH3 substrate. An in vitro translation assay showed that ALKBH3-demethylated tRNA significantly enhanced protein translation efficiency. In addition, ALKBH3 knockdown in human cancer cells impaired cellular proliferation and suppressed the nascent protein synthesis that is usually accompanied by accumulation of the methylated RNAs. Thus, our data highlight a novel role for ALKBH3 in tumor progression via RNA demethylation and subsequent protein synthesis promotion.
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http://dx.doi.org/10.1038/srep42271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304225PMC
February 2017

MiR-21-5p in urinary extracellular vesicles is a novel biomarker of urothelial carcinoma.

Oncotarget 2017 Apr;8(15):24668-24678

Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: Extracellular vesicles are lipid bilayer vesicles containing protein, messengerRNA and microRNA. Cancer cell-derived extracellular vesicles may be diagnostic and therapeutic targets. We extracted extracellular vesicles from urine of urothelial carcinoma patients and the control group to identify cancer-specific microRNAs in urinary extracellular vesicles as new biomarkers.

Materials And Methods: microRNA from urinary extracellular vesicles extracted from 6 urothelial carcinoma patients and 3 healthy volunteers was analyzed. We verified candidate microRNAs in an independent cohort of 60 urinary extracellular vesicles samples. To normalize the microRNA expression level in extracellular vesicles, we examined the following in extracellular vesicles: protein concentration, CD9 intensity, amounts of whole miRNAs, RNA U6B small nuclear expression and the creatinine concentration of original urine correlating with the counts of extracted extracellular vesicles measured by the NanoSight™ system.

Results: From the microarray results 5 microRNAs overexpressed in urinary extracellular vesicles of urothelial carcinoma patients were identified. Creatinine concentration of original urine correlated most with particle counts of extracellular vesicles, indicating that creatinine could be a new tool for normalizing microRNA expression. MiR-21-5p was the most potent biomarker in urinary extracellular vesicles (sensitivity, 75.0%; specificity, 95.8%) and was also overexpressed in urinary extracellular vesicles from urothelial carcinoma patients with negative urine cytology. For the subgroup with negative urine cytology, the sensitivity was 75.0% and specificity was 95.8%.

Conclusion: MiR-21-5p in urinary extracellular vesicles could be a new biomarker of urothelial carcinoma, especially for urothelial carcinoma patients with negative urine cytology.
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http://dx.doi.org/10.18632/oncotarget.14969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421878PMC
April 2017

ALKBH8 promotes bladder cancer growth and progression through regulating the expression of survivin.

Biochem Biophys Res Commun 2016 08 18;477(3):413-8. Epub 2016 Jun 18.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Human AlkB homolog 8 (ALKBH8) is highly expressed in high-grade, superficially and deeply invasive bladder cancer. Moreover, ALKBH8 knockdown induces apoptosis in bladder cancer cells. However, the underlying anti-apoptotic mechanism of ALKBH8 in bladder cancer cells has thus far remained unclear. Moreover, there is no direct evidence that highly expressed ALKBH8 is involved in tumor progression in vivo. We here show that ALKBH8 knockdown induced apoptosis via downregulating the protein expression of survivin, an anti-apoptotic factor also exhibiting increased levels in bladder cancer. We also clarify that ALKBH8 transgenic mice showed an accelerated rate of bladder tumor mass and invasiveness in an N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced bladder cancer model. These findings suggest that the high expression of ALKBH8 is critical for the growth and progression of bladder cancer.
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http://dx.doi.org/10.1016/j.bbrc.2016.06.084DOI Listing
August 2016

A real-time PCR-based quantitative assay for 3-methylcytosine demethylase activity of ALKBH3.

Biochem Biophys Rep 2016 Mar 10;5:476-481. Epub 2016 Feb 10.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.

Human AlkB homolog 3 (ALKBH3), a homolog of the protein AlkB, demethylates 1-methyladenine and 3-methylcytosine (3-meC) in single-stranded DNA and RNA by oxidative demethylation. Immunohistochemical analyses on clinical cancer specimens and knockdown experiments using RNA interference and indicate that ALKBH3 is a promising molecular target for the treatment of prostate, pancreatic, and non-small cell lung cancer. Therefore, an inhibitor for ALKBH3 demethylase is expected to be a first-in-class molecular-targeted drug for cancer treatment. Here, we report the development of a novel, quantitative real-time PCR-based assay for ALKBH3 demethylase activity against 3-meC by highly active recombinant ALKBH3 protein using a silkworm expression system. This assay enables us to screen for inhibitors of ALKBH3 demethylase, which may result in the development of a novel molecular-targeted drug for cancer therapy.
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http://dx.doi.org/10.1016/j.bbrep.2016.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600452PMC
March 2016

The miR-130 family promotes cell migration and invasion in bladder cancer through FAK and Akt phosphorylation by regulating PTEN.

Sci Rep 2016 Feb 3;6:20574. Epub 2016 Feb 3.

Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, currently used targeted therapy for malignant bladder cancer is still not efficient. We focused on the miR-130 family (miR-130b, miR-301a, and miR-301b) that was significantly upregulated in bladder cancer specimens than that of the normal urothelial specimens. We analyzed the functional significance of miR-130 family using a 5637 bladder cancer cell line and revealed that miR-130 family of inhibitors suppressed cell migration and invasion by downregulating focal adhesion kinase (FAK) and Akt phosphorylation. Mechanistic analyses indicate that the miR-130 family directly targets phosphatase and tensin homolog deleted from chromosome 10 (PTEN), resulting in the upregulation of FAK and Akt phosphorylation. In clinical bladder cancer specimens, downregulation of PTEN was found to be closely correlated with miR-130 family expression levels. Overall, the miR-130 family has a crucial role in malignant progression of bladder cancer and thus the miR-130 family could be a promising therapeutic target for invasive bladder cancer.
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http://dx.doi.org/10.1038/srep20574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738343PMC
February 2016

Expression of miR-27a-3p is an independent predictive factor for recurrence in clear cell renal cell carcinoma.

Oncotarget 2015 Aug;6(25):21645-54

The Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression and function in tumor development and progression. We previously identified up-regulated miRNAs in clear cell renal cell carcinoma (ccRCC) compared to matched-pair normal kidney by microarray. Here, we identify miRNAs that are up-regulated in ccRCC and are also correlated with survival and/or recurrence. Twenty-four samples from ccRCC patients who underwent nephrectomies between 2011 and 2012 were divided into two groups: one of eleven patients who experienced recurrence (Group 1), and one of thirteen patients with no evidence of disease (Group 2) 2 years after surgery. Analyzing 22 miRNAs that were up-regulated in ccRCC in our previous study, we identify five miRNAs that were statistically up-regulated in Group 1 versus Group 2 by quantitative real-time PCR. We then evaluated these miRNAs in an independent cohort of 159 frozen ccRCC samples. High levels of miR-27a-3p (p < 0.01) correlated with a worse progression-free survival rate. Multivariate analysis revealed that miR-27a-3p was an independent predictive factor for recurrence. For functional analysis, miR-27a-3p controlled cell proliferation, migration and invasion in RCC cell lines. MiR-27a-3p could act as oncogenic miRNA and may be a candidate for targeted molecular therapy in ccRCC.
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http://dx.doi.org/10.18632/oncotarget.4064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673293PMC
August 2015