Hiromi Kumon

Okayama University, Okayama, Okayama, Japan

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Publications (545)893.23 Total impact

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    ABSTRACT: Background and aim: REIC/DKK3 is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the anti-tumor immunological effects of human REIC/DKK3 protein against pancreatic cancer. Methods: Activation of Erk1/2, mTOR and STAT3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1, MIA Paca-2) were co-cultured with peripheral blood mononuclear cells and the anti-cancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and ELISPOT assays. The anti-tumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice. Results: REIC/DKK3 protein activated Erk1/2, mTOR and STAT3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of IFN-γ from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when co-cultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anti-cancer immunostimulatory effects on pancreatic cancer cells. Conclusions: REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anti-cancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy, and provides important clues to the therapeutic mechanisms involving immune cells. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Journal of Gastroenterology and Hepatology
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    ABSTRACT: In this study, we aimed to identify the influence of exonuclease 1 (EXO1) single-nucleotide polymorphism rs9350, which is involved in DNA mismatch repair, on prostate cancer risk in Chinese people. In our hospital-based case-control study, 214 prostate cancer patients and 253 cancer-free control subjects were enrolled from three hospitals in China. Genotyping for rs9350 was performed by the SNaPshot(®) method using peripheral blood samples. Consequently, a significantly higher prostate cancer risk was observed in patients with the CC genotype [odds ratio (OR) = 1.678, 95 % confidence interval (CI) = 1.130-2.494, P = 0.010] than in those with the CT genotype. Further, the CT/TT genotypes were significantly associated with increased prostate cancer risk (adjusted OR = 1.714, 95 % CI = 1.176-2.500, P = 0.005), and the C allele had a statistically significant compared with T allele (P = 0.009) of EXO1 (rs9350). Through stratified analysis, significant associations were revealed for the CT/TT genotype in the subgroup with diagnosis age >72 (adjusted OR = 1.776, 95 % CI = 1.051-3.002, P = 0.032) and in patients with localized disease subgroup (adjusted OR = 1.798, 95 % CI = 1.070-3.022, P = 0.027). In addition, we observed that patients with prostate-specific antigen (PSA) levels of ≤10 ng/mL were more likely to have the CT/TT genotypes than those with PSA levels of >10 ng/mL (P = 0.006). For the first time, we present evidence that the inherited EXO1 polymorphism rs9350 may have a substantial influence on prostate cancer risk in Chinese people. We believe that the rs9350 could be a useful biomarker for assessing predisposition for and early diagnosis of prostate cancer.
    No preview · Article · Dec 2015 · Tumor Biology
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    ABSTRACT: REIC/DKK-3 is a tumor suppressor, however, its intracellular physiological functions and interacting molecules have not been fully clarified. Using yeast two-hybrid screening, we found that small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, is a novel interacting partner of REIC/DKK-3. Mammalian two-hybrid and pull-down assay results indicated that the SGTA-REIC/DKK-3 interaction involved the N-terminal regions of both REIC/DKK-3 and SGTA and that REIC/DKK-3 interfered with the dimerization of SGTA, which is a component of the AR complex and a suppressor of dynein motor-dependent AR transport and signaling. A reporter assay in human prostate cancer cells that displayed suppressed AR signaling by SGTA showed recovery of AR signaling by REIC/DKK-3 expression. Considering these results and our previous data that REIC/DKK-3 interacts with the dynein light chain TCTEX-1, we propose that the REIC/DKK-3 protein interferes with SGTA dimerization, promotes dynein-dependent AR transport and then upregulates AR signaling.
    Full-text · Article · Dec 2015 · Oncotarget
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    ABSTRACT: In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 × 10(10) , 1.0 × 10(11) , and 1.0 × 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 × 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199) Clin Trans Sci 2015; Volume #: 1-4.
    No preview · Article · Dec 2015 · Clinical and Translational Science
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    ABSTRACT: To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the Japanese Society of Chemotherapy, the Japanese Association of Infectious Disease, and the Japanese Society of Clinical Microbiology conducted the second nationwide surveillance from January to September 2011. With the cooperation of 42 medical institutions throughout Japan, 1036 strains belonging to 8 clinically relevant bacterial species were collected. Among methicillin-resistant Staphylococcus aureus (MRSA) strain, the vancomycin (VCM) MIC for 5.5% (3/55) of the strains was 2 μg/mL. Ampicillin, VCM, and linezolid were relatively active against 209 Enterococcus faecalis strains. The proportion of fluoroquinolone (FQ)-resistant strains was >20%. The MIC90 of FQs against the 382 Escherichia coli strains was 2-64 mg/L and the proportion resistant to FQs was approximately 30%. However, susceptibility of E. coli to sitafloxacin was still high (MIC90 = 2 mg/L). Fifty-eight (15.2%) of 382 E. coli, 6 (4.5%) of 132 Klebsiella pneumoniae, 1 (2.4%) of 41 Klebsiella oxytoca and 4 (6.8%) of 59 Proteus mirabilis strains were suspected of producing extended-spectrum beta-lactamase. Of 93 Pseudomonas aeruginosa strains, the proportions resistant to imipenem, amikacin, and ciprofloxacin were 21.5%, 4.3%, and 20.4%, respectively. Four strains (4.3%) were found to be multidrug-resistant. In complicated UTI cases, all of MRSA and E. faecalis were susceptible to all anti-MRSA agents. Sitafloxacin was active against other FQ-resistant E. coli strains. The isolation of extended-spectrum beta-lactamase-producing and multidrug-resistant strains increased. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jun 2015 · Journal of Infection and Chemotherapy
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    ABSTRACT: Currently, androgen replacement therapy (ART) which is provided clinically in the field of urology is a common treatment for many of the patients with LOH syndrome or gender identity disorder (GID) Female to Male (FTM). We herein describe the current situation and the challenges regarding ART for these two diseases. ART has been provided according to LOH syndrome treatment guidelines. However, the opinion of any individual clinician and/or the patient's own adherence in continuing treatment will be seen as influencing treatment decisions at any particular moment. With regard to ART in our department, cases where ART has been judged to be effective for LOH syndrome comprised 51% of cases (23 out of 45 cases). No significant difference was showen between cases which hoped treatment continuation and didn't hope. Guidelines for correctly evaluating the response to treatment and the feasibility of providing such treatment are awaited. ART provided for GID-FTM is particular in that its therapeutic effect is expected to differ greatly from that obtained when ART is provided for LOH syndrome. Order to obtain a cessation of the expected virilization and physiology of a patient's body, the hormone dose and interval need to be carefully considered. Data accumulated in our department have demonstrated that in most patients, a sufficient therapeutic effect is obtained by the administration of 125 mg testosterone enanthate for 2 weeks, and serious adverse events have not been observed. Guidelines regarding GID androgen replacement therapy are also awaited, in particular with regard to a more detailed evaluation of its predicted therapeutic effect.
    No preview · Article · Jun 2015
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    ABSTRACT: YM155, a small molecule inhibitor of the antiapoptotic protein survivin, has been developed as a potential anti-cancer drug. We investigated a combination therapy of YM155 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). YM155 caused cell cycle arrest and apoptosis in renal cancer (RENCA) cells. Next, luciferase-expressing RENCA cells were implanted in the left kidney and the lung of BALB/c mice to develop RCC metastatic model. In this orthotopic renal and metastatic lung tumors models, YM155 and IL-2 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Also, the combination significantly suppressed regulatory T cells and myeloid-derived suppressor cells compared with single agent treatment. We suggest that a combination of YM155 and IL-2 can be tested as a potential therapeutic modality in patients with RCC.
    Full-text · Article · May 2015 · Oncotarget
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    ABSTRACT: Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with (64)Cu via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that (64)Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The (64)Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than (18)F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.
    Full-text · Article · Apr 2015 · Journal of Immunology Research
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    Full-text · Article · Apr 2015 · The Journal of Urology
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    Preview · Article · Apr 2015 · The Journal of Urology

  • No preview · Article · Apr 2015 · The Journal of Urology

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell‑specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3β (GSK-3β) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony‑stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.
    No preview · Article · Mar 2015 · Oncology Reports
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    ABSTRACT: A 63-year-old man with metastatic castration-resistant prostate cancer (CRPC) was successfully treated for two years with in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk‑3 gene (Ad-REIC), following chemotherapy. Ad-REIC mediates simultaneous induc-tion of cancer-selective apoptosis and augmentation of antitumor immunity, and a Phase I/IIa clinical study on Ad-REIC has been conducted at Okayama University Hospital since January 2011. At the time of enrollment in December 2012, the patient presented with rapid progression of lymph node (LN) metastases. Two scheduled Ad-REIC injections and 10 additional Ad-REIC injections into metastatic pelvic and para-aortic LNs under CT guidance, with an average four weeks’ interval, exhibited the potent direct and indirect effects of Ad-REIC as a therapeutic cancer vaccine. During the next 12 months, three additional injections into para-aortic LNs showing regrowth achieved adequate control of all metastatic LNs with prostate-specific antigen (PSA) decline, without any particular adverse events. © the authors, publisher and licensee Libertas Academica Limited.
    Full-text · Article · Mar 2015 · Clinical Medicine Insights: Oncology
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    ABSTRACT: Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects.
    Full-text · Article · Jan 2015 · Oncology Reports
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    ABSTRACT: The Japanese guidelines for the prevention of perioperative infection in urology were published by the Japanese Urological Association in 2007. According to these guidelines, the first choice for prophylaxis to prevent perioperative infection following prostate needle biopsy is the administration of a high dosage of oral fluoroquinolones for 1 day for low - risk patients (e. g. levofloxacin [LVFX] 200 mg t.i.d. (600 mg/day)). Subsequently the LVFX 500 mg tablet became available in Japan in June 2009 in place of the 100 mg tablet, and accordingly we prospectively evaluated the effectiveness and safety of a single dose of levofloxacin (LVFX) 500 mg as prophylaxis for patients who undergo transrectal ultrasonography-guided prostate needle biopsy. Between January 2010 and February 2011, a single oral dose of LVFX was administered several hours before the P-biopsy. Informed consent was obtained from all patients. They were given a questionnaire about the symptoms of complications prior to discharge. Questionnaires were collected at their first clinical visit. Complications and perioperative infections were analyzed. One hundred and thirty-four patients were enrolled and 100 patients completed the study. There were no complications from LVFX, and only 1 patient developed acute prostatitis and sepsis following P-biopsy. The low incidence of prostatitis in this study suggests that preoperative single-dose LVFX is effective and safe when compared with the previously recommended prophylaxis.
    No preview · Article · Dec 2014 · Nishinihon Journal of Urology
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    ABSTRACT: Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.Gene Therapy advance online publication, 13 November 2014; doi:10.1038/gt.2014.100.
    No preview · Article · Nov 2014 · Gene Therapy
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    ABSTRACT: Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10−9. Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r2 = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.
    Full-text · Article · Oct 2014 · Human Molecular Genetics

  • No preview · Article · Oct 2014
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    ABSTRACT: The Wnt signaling pathway plays a crucial role in human cancer development, and axis inhibition protein 2 (Axin2) is a master scaffold protein involved in Wnt signaling. Axin2 negatively regulates Wnt signaling and acts as a tumor suppressor protein. The present study evaluated the association between the Axin2 single nucleotide polymorphism (SNP) rs2240308 [guanine (G)/adenine (A)] and the incidence of prostate cancer. In total, 103 patients with prostate cancer and 100 cancer-free control males were included in this case-control study, and were genotyped using the genomic DNA extracted from peripheral blood samples. The results revealed a higher incidence of prostate cancer in the subjects with the homozygous GG genotype and a reduced cancer incidence in the patients with the GA genotype of the rs2240308 SNP (G/A) in the Axin2 gene. The adjusted odds ratio for carriers with the GA genotype was 0.377 (95% CI, 0.206-0.688; P=0.001) and that for the AA genotype was 0.830 (95% CI, 0.309-2.232; P=0.712) compared with the GG genotype. Therefore, the GA genotype was found to exhibit a protective effect that decreased the risk of prostate cancer. To the best of our knowledge, this is the first study to demonstrate the significant association between this SNP (rs2240308, G/A) and the risk of prostate cancer. This association indicates the possibility that the variations in the Axin2 gene in this position may play a significant role in promoting the development of cancer in the prostate. We believe that the Axin2 SNP (rs2240308) could be a useful biomarker for the predisposition and early diagnosis of the disease.
    Full-text · Article · Aug 2014 · Oncology letters

Publication Stats

5k Citations
893.23 Total Impact Points

Institutions

  • 1981-2015
    • Okayama University
      • • Department of Urology
      • • Innovation Center Okayama for Nanobio-targeted Therapy (ICONT)
      • • Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
      Okayama, Okayama, Japan
  • 2011
    • Minami Okayama Medical Center
      Okayama, Okayama, Japan
  • 2008
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
  • 2007
    • Fujita Health University
      Nagoya, Aichi, Japan
    • The University of Tokyo
      • Department of Applied Biological Chemistry
      Edo, Tōkyō, Japan
  • 2003
    • Sapporo Medical University
      • Division of Urology
      Sapporo, Hokkaidō, Japan
  • 2000
    • University of Michigan
      • Department of Microbiology and Immunology
      Ann Arbor, Michigan, United States
  • 1999
    • Harper University Hospital
      Detroit, Michigan, United States
  • 1998
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 1996
    • Thomas Jefferson University
      • Department of Urology
      Filadelfia, Pennsylvania, United States
  • 1990
    • Okayama Rosai Hospital
      Okayama, Okayama, Japan