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ABSTRACT: The purpose of this study was to investigate the mechanism of photodynamic therapy (PDT) supplemented with exogenously added 5-aminolevulinic acid (ALA) on human urothelial cancer (UC). Moreover, we aimed to determine whether the therapeutic effects of ALA-based PDT (ALA-PDT) for UC could be enhanced by deferoxamine (DFX), an inhibitor of ferrochelatase. The efficiency of ALA-PDT on these cells was analyzed by flow cytometry and the type of cell death was also assessed ALA-PDT promoting effect of DFX was examined on both UC cells and human umbilical vein endothelial cells (HUVECs). ALA-PDT decreased the levels of mitochondrial membrane potential, and induced cell death mainly via apoptosis in these cells. Moreover, inhibition of ferrochelatase by DFX led to increase of PpIX accumulation and enhanced effect of ALA-PDT on UC cells. We further investigated effect of DFX on in vivo-PDT with a tumor-bearing animal model and found that DFX efficiently enhanced tumor cell apoptosis. ALA-PDT induced death of neovascular endothelial cells in tumors but did not affect small vessel endothelial cells in tumor-surrounding normal tissues. Furthermore DFX enhanced inhibition of neovascularization. These results demonstrated ALA-PDT dominantly induced apoptosis over necrosis by direct action on UC as well as via anti-angiogenic action on neovacular endothelial cells, suggesting that the therapeutic damage by ALA-PDT could be kept to the minimum in the surrounding normal tissues. In addition, increased accumulation of PpIX by DFX could enhance this effectiveness of ALA-PDT.
Cancer Science 03/2013; · 3.33 Impact Factor
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ABSTRACT: Gastric cancer with the invasive micropapillary carcinoma (IMPC) pattern has been reported to be a variant with poor prognosis and rapid progression. To the best of our knowledge, only 4 cases of gastric cancer from Japan and 11 cases from Korea have been reported to contain the IMPC pattern. In the present study, 4 cases of gastric cancer containing the IMPC pattern from 2 Japanese men and 2 Japanese women are reported. The cancer tissues, including a recurrent lesion in 1 case and lymph node metastases in 2 other cases, were examined immunohistochemically to identify suitable markers for demonstrating the peculiar "inside out" pattern of IMPC and for analyzing HER2 expression. A characteristic IMPC pattern occupied more than 10 % of each cancer tissue in these 4 cases. Lymphatic invasions were very often detected; in fact, lymph node metastases were detected in 3 out of 4 cases. The unique "inside out" pattern in IMPC was clearly revealed in all cases by staining with antibodies to both epithelial membrane antigen (EMA) and KL-6, but not with an antibody to CD10. HER2 was positive in 3 of 4 cases with the IMPC pattern, including cases with a recurrent lesion or lymph node metastases. Fluorescence in situ hybridization (FISH) analyses disclosed positive results in case 1, and case 3 including lymph node metastatic foci. Highest FISH titer was 6.8 in case 1, revealing marked amplification of HER-2 gene. Four cases of gastric cancer with the IMPC pattern were reported. EMA and KL-6, but not CD10, were particularly useful markers for visualizing the characteristic "inside out" pattern of the IMPC pattern in stomach cancers, similar to the markers for breast and urinary bladder cancers.
Medical Molecular Morphology 03/2013; · 1.39 Impact Factor
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ABSTRACT: The cAMP-dependent protein kinase inhibitor-β (PKIB) is presumed to be one of the regulatory factors controlling the cAMP-dependent protein kinase A signaling pathway. The aim of this study was to investigate the frequency and patterns of PKIB overexpression in human breast cancer. We also examined the relationship between PKIB and phosphorylated Akt (pAkt) expression in the tumors. Using immunohistochemical techniques, we examined the expression of PKIB, ER, PR, HER2, and pAkt in 148 primary human breast carcinomas. We then analyzed the relationships between PKIB expression and that of pAkt, ER, PR, and HER2, as well as between PKIB expression and various clinicopathological characteristics. We assessed 64 and 27 cases, respectively, as positive for either PKIB or pAkt expression; 20 cases were positive for both PKIB and pAkt. We observed a significant positive correlation between the expression of PKIB and that of pAkt (P = 0.006). We showed by immunohistochemical analyses that PKIB expression was positively correlated with triplenegative breast cancers (P = 0.0004). These findings provide evidence for PKIB overexpression associated with pAkt expression. Furthermore, PKIB expression was strongly correlated with triple-negative breast cancer, suggesting that PKIB expression might contribute to the tumor behavior and development of breast cancer.
Medical Molecular Morphology 12/2012; 45(4):229-33. · 1.39 Impact Factor
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ABSTRACT: It is known that after transurethral resection of the prostate (TUR-P) or a bladder tumor (TUR-BT), necrotizing granuloma formation associated with massive eosinophil accumulation can be detected at the site of the scar, revealing marked eosinophilia. This condition is called post-TUR prostatitis or cystitis. In the present study, we noticed a similar phenomenon in five patients who underwent cholecystectomy, of whom four had gallbladder adenocarcinoma and one had metastatic liver cancer originating from the rectum. We detected necrotizing granulomas with massive eosinophil accumulation, associated with marked eosinophilia. To induce these phenomena, the interval between the first operation (i.e., cholecystectomy) and the second operation (i.e., resection of the hepatic bed and extrahepatic bile duct) is very important. If the interval was 1 week, no granuloma formation was detected. On the other hand, if it was more than 2 weeks, the resected hepatic bed contained necrotizing granulomas with substantial eosinophil accumulation combined with an increase in peripheral eosinophilia (up to 34% in one case). Secondary resection was necessary to induce eosinophilia after cholecystectomy. In this sense, malignancies possessed a relationship with delayed eosinophilia. In the granulomas, some foreign body-type multinucleated giant cells were positive for both anti-interleukin (IL)-5 and CD68 antibodies. In sharp contrast, no eosinophilia was detected after cholecystectomy, with or without hepatic resection consequent to severe adhesion. Clinicians as well as pathologists should keep in mind that these peculiar phenomena of eosinophil accumulation surrounding the necrotizing granulomas and peripheral eosinophilia after cholecystectomy could occur.
Medical Molecular Morphology 12/2012; 45(1):53-7. · 1.39 Impact Factor
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International Journal of Experimental Pathology 10/2012; · 2.57 Impact Factor
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Chie Nishioka,
Takayuki Ikezoe, Mutsuo Furihata,
Jing Yang,
Satoshi Serada,
Tetsuji Naka,
Atsuya Nobumoto,
Sayo Kataoka,
Masayuki Tsuda,
Keiko Udaka,
Akihito Yokoyama
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ABSTRACT: To identify molecular targets in leukemia stem cells (LSCs), this study compared the protein expression profile of freshly isolated CD34(+) /CD38(-) cells with that of CD34(+) /CD38(+) counterparts from individuals with acute myelogenous leukemia (n=2, AML) using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 98 proteins were overexpressed, while six proteins were underexpressed in CD34(+) /CD38(-) AML cells compared with their CD34(+) /CD38(+) counterparts. Proteins overexpressed in CD34(+) /CD38(-) AML cells included a number of proteins involved in DNA repair, cell cycle arrest, gland differentiation, anti-apoptosis, adhesion, and drug resistance. Aberrant expression of CD82, a family of adhesion molecules, in CD34(+) /CD38(-) AML cells was noted in additional clinical samples (n=12) by flow cytometry. Importantly, down-regulation of CD82 in CD34(+) /CD38(-) AML cells by a short hairpin RNA (shRNA) inhibited adhesion to fibronectin via up-regulation of matrix metalloproteinases 9 (MMP9) and colony forming ability of these cells as assessed by transwell assay, real time RT-PCR, and colony forming assay, respectively. Moreover, we found that down-regulation of CD82 in CD34(+) /CD38(-) AML cells by an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice. Taken together, aberrant expression of CD82 might play a role in adhesion of LSCs to bone marrow microenvironment and survival of LSCs. CD82 could be an attractive molecular target to eradicate LSCs. © 2012 Wiley Periodicals, Inc.
International Journal of Cancer 10/2012; · 5.44 Impact Factor
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ABSTRACT: BACKGROUND: Merkel cell polyomavirus (MCPyV) was identified originally in Merkel cell carcinoma (MCC), a rare form of human skin neuroendocrine carcinoma. Evidence of MCPyV existence in other forms of malignancy such as cutaneous squamous cell carcinomas (SCCs) is growing. Cervical cancers became the focus of our interest in searching for potentially MCPyV-related tumors because: (i) the major histological type of cervical cancer is the SCC; (ii) the uterine cervix is a common site of neuroendocrine carcinomas histologically similar to MCCs; and (iii) MCPyV might be transmitted during sexual interaction as demonstrated for human papillomavirus (HPV). In this study, we aimed to clarify the possible presence of MCPyV in cervical SCCs from Japanese patients. Cervical adenocarcinomas (ACs) were also studied. RESULTS: Formalin-fixed paraffin-embedded tissue samples from 48 cervical SCCs and 16 cervical ACs were examined for the presence of the MCPyV genome by polymerase chain reaction (PCR) and sequencing analyses. PCR analysis revealed that 9/48 cervical SCCs (19 %) and 4/16 cervical ACs (25 %) were positive for MCPyV DNA. MCPyV-specific PCR products were sequenced to compare them with reference sequences. The nucleotide sequences in the MCPyV large-T (LT)-sequenced region were the same among MCPyV-positive cervical SCCs and AC. Conversely, in the MCPyV viral protein 1 (VP1)-sequenced, two cervical SCCs and three cervical ACs showed several nucleotide substitutions, of which three caused amino acid substitutions. These sequencing results suggested that three MCPyV variants of the VP1 were identified in our cases. Immunohistochemistry showed that the LT antigen was expressed in tumor cells in MCPyV-positive samples. Genotyping of human HPV in the MCPyV-positive samples revealed that infected HPVs were HPV types 16, 31 and 58 for SCCs and HPV types 16 and 18 for ACs. CONCLUSIONS: This study provides the first observation that MCPyV coexists in a subset of HPV-associated cervical cancers from Japanese patients. The prevalence of MCPyV in these lesions was close to that observed in the cutaneous SCCs. Further worldwide epidemiological surveys are warranted to determine the possible association of MCPyV with pathogenesis of cervical cancers.
Virology Journal 08/2012; 9(1):154. · 2.34 Impact Factor
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ABSTRACT: We have recently reported that recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage associated with engraftment, as well as sinusoidal obstructive syndrome after hematopoietic stem cell transplantation. These observations prompted us to explore whether rTM possessed cytoprotective effects on endothelial cells.
Exposure of human umbilical vein endothelial cells to rTM induced expression of antiapoptotic protein myeloid leukemia cell-1 through the activation of extracellular signal-regulated kinase in these cells. Additional studies found that exposure of human umbilical vein endothelial cells to cyclosporine A and FK506, an immunosuppressant used for the individuals receiving hematopoietic stem cell transplantation, induced apoptosis, which was attenuated when human umbilical vein endothelial cells were exposed to these agents in the presence of rTM. Further studies using deletion mutants of thrombomodulin (TM) identified that the epidermal growth factor domain of TM possessed cytoprotective effects. A single nucleotide substitution at codon 376 or 424 of TM, which impairs the ability of TM to produce activated protein C or bind to thrombin, respectively, did not hamper the cytoprotective effects of TM, which suggested that cytoprotective effects of rTM were distinctive from those of activated protein C.
TM may be useful for prevention, as well as treatment of endothelial cell damage after hematopoietic stem cell transplantation.
Arteriosclerosis Thrombosis and Vascular Biology 07/2012; 32(9):2259-70. · 6.37 Impact Factor
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ABSTRACT: Posttransurethral resection (TUR) status in the prostate and urinary bladder has been infrequently documented. Furthermore,
sequential changes in eosinophil count in peripheral blood (PB) after TUR have not been investigated in detail. In the present
study, eosinophil counts and changes in eosinophils in PB were examined before to after TUR of the prostate (P) in 20 patients
with benign prostatic hyperplasia. Among them, 14 patients exhibited increased numbers of eosinophils, the greatest increase
being 17%. After TUR to treat bladder tumor (BT), massive infiltration of eosinophils into the resected areas, peaking 1 month
later, was also detected in 8 of 15 cases of post-TUR cystitis. The PB eosinophil counts increased by more than 5% in two
of five cases of post-TUR cystitis in which eosinophil counts were obtained before and after surgery. Most infiltrating eosinophils
reacted positively to antibodies to eosinophil cationic proteins. These results indicated that, in patients with post-TUR
prostatitis, the number of eosinophils in PB increased, and peaked 1 month later, with infiltration by eosinophils observed.
Pathologists and urologists should be aware of the potential for increase in eosinophils not only in regions of TUR but also
in PB.
Medical Molecular Morphology 04/2012; 40(1):29-33. · 1.39 Impact Factor
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Hai Ha Nguyen,
Ryo Takata,
Shusuke Akamatsu,
Daichi Shigemizu,
Tatsuhiko Tsunoda, Mutsuo Furihata,
Atsushi Takahashi,
Michiaki Kubo,
Naoyuki Kamatani,
Osamu Ogawa,
Tomoaki Fujioka,
Yusuke Nakamura,
Hidewaki Nakagawa
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ABSTRACT: Recent genome-wide association studies (GWAS) identified a number of prostate cancer (PC) susceptibility loci, but most of their functional significances are not elucidated. Through our previous GWAS for PC in a Japanese population and subsequent resequencing and fine mapping, we here identified that IRX4 (Iroquois homeobox 4), coding Iroquois homeobox 4, is a causative gene of the PC susceptibility locus (rs12653946) at chromosome 5p15. IRX4 is expressed specifically in the prostate and heart, and quantitative expression analysis revealed a significant association between the genotype of rs12653946 and IRX4 expression in normal prostate tissues. Knockdown of IRX4 in PC cells enhanced their growth and IRX4 overexpression in PC cells suppressed their growth, indicating the functional association of IRX4 with PC and its tumor suppressive effect. Immunoprecipitation confirmed its protein-protein interaction to vitamin D receptor (VDR), and we found a significant interaction between IRX4 and VDR in their reciprocal transcriptional regulation. These findings indicate that the PC-susceptibility locus represented by rs12653946 at 5p15 is likely to regulate IRX4 expression in prostate which could suppress PC growth by interacting with the VDR pathway, conferring to PC susceptibility.
Human Molecular Genetics 02/2012; 21(9):2076-85. · 7.64 Impact Factor
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Takashi Anchi,
Kenji Tamura, Mutsuo Furihata,
Hirofumi Satake,
Hatsune Sakoda,
Chiaki Kawada,
Maiko Kamei,
Tsutomu Shimamoto,
Hideo Fukuhara,
Satoshi Fukata,
Shingo Ashida,
Takashi Karashima,
Ichiro Yamasaki,
Masaharu Yasuda,
Masayuki Kamada,
Keiji Inoue,
Taro Shuin
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ABSTRACT: Clinically high-grade prostate cancers (PC) with high Gleason scores of 8-10 exhibit rapid growth and are more likely to spread beyond the prostate. These cancer types demonstrate a poor response to androgen deprivation therapy and eventually acquire a castration-resistant phenotype. To identify novel molecular cancer drug targets, we previously analyzed the gene expression profiles of high-grade PC using a cDNA microarray combined with laser microbeam microdissection and found a number of genes that are transactivated in high-grade PC. Among these genes, we report the identification of a novel molecular target, small nuclear ribonucleoprotein polypeptide E (SNRPE). Semi-quantitative RT-PCR confirmed that SNRPE is overexpressed in high-grade PC cells compared with normal prostatic epithelial cells. Knockdown of SNRPE expression by short interfering RNA (siRNA) resulted in the marked suppression of PC cell proliferation. By contrast, SNRPE overexpression promoted PC cell proliferation, indicating its oncogenic effects. Furthermore, we demonstrated that SNRPE regulates androgen receptor (AR) mRNA expression in PC cells. Knockdown of SNRPE expression by siRNA resulted in the marked suppression of AR and its downstream target genes at the mRNA level. We suggest that the regulation of AR expression by SNRPE is essential for cell proliferation and progression of high-grade PC and that it may be a novel molecular target for cancer drugs.
Oncology letters 02/2012; 3(2):264-268. · 0.11 Impact Factor
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ABSTRACT: The purpose of the present study was to examine the pathobiological properties of a matrix metalloproteinase, MMP-11 (also known as stromelysin-3), in the carcinogenesis of lobular carcinoma of the breast. Immunohistochemical staining demonstrated immunoreactivity with specific antibody to MMP-11 in 16 of 30 lobular carcinoma cells, but not in the non-cancerous terminal duct lobular unit. In positive cases, both noninvasive and invasive cancer cells exhibited immunoreactivity with anti-MMP-11 antibody; however, the staining patterns in noninvasive and invasive foci were distinct. In the noninvasive foci, immunoreactivity was observed in the cytoplasm beneath the plasma membrane, whereas immunoreactivity was found in all of the cytoplasm of infiltrating lobular carcinoma cells. Enforced expression of MMP-11 in the cultured lobular carcinoma MDA-MB-330 cells did not affect cell growth or Matrigel invasion activity. By contrast, overexpression of MMP-11 significantly increased resistance to anoikis, a programmed cell death triggered by a lack of proper cell matrix interaction, as evidenced by decrease in annexin V-positive cells and apoptotic DNA ladders. The present findings indicate that MMP-11 is overexpressed in many lobular carcinoma cells and that it may play a role in lobular carcinogenesis through increasing resistance to anoikis.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 07/2011; 459(3):291-7. · 2.49 Impact Factor
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Keiji Inoue,
Hideo Fukuhara,
Tsutomu Shimamoto,
Masayuki Kamada,
Tatsuo Iiyama,
Mitsuhiko Miyamura,
Atsushi Kurabayashi, Mutsuo Furihata,
Masanobu Tanimura,
Hironobu Watanabe,
Taro Shuin
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ABSTRACT: This study was undertaken to evaluate the clinical value of photodynamic diagnosis (PDD) with intravesical and oral instillation of 5-aminolevulinic acid (ALA) (ALA-PDD), and transurethral resection of bladder tumor (TURBT) guided by ALA-PDD (PDD-TURBT) for nonmuscle invasive bladder cancer.
Of all 210 cases, 75 underwent PDD with intravesically applied ALA, and 135 cases underwent PDD with orally applied ALA. Diagnostic accuracy was evaluated by comparing the level on images of ALA-induced fluorescence with the pathological result. PDD-TURBT was performed in 99 completely resectable cases corresponding to 210 ALA-PDD cases. To evaluate the abilities of PDD-TURBT, survival analysis regarding intravesical recurrence was retrospectively compared with the historical control cases that underwent conventional TURBT.
The diagnostic accuracy and capability of ALA-PDD were significantly superior to those of conventional endoscopic examination. Moreover, 72.1% of flat lesions, including dysplasia and carcinoma in situ, could be detected only by ALA-PDD. The recurrence-free survival rate in the cases that underwent PDD-TURBT was significantly higher than that of conventional TURBT. Moreover, multivariate analysis revealed that the only independent factor contributing to improving prognosis was PDD-TURBT (hazard ratio, 0.578; P = .012). Regardless of the ALA administration route, there was no significant difference in diagnostic accuracy, ability of PDD, or recurrence-free survival. All procedures were well tolerated by all patients without any severe adverse events.
This multicenter study is likely to be biased, because it is limited by the retrospective analysis. This study suggests that regardless of the ALA administration route, ALA-PDD and PDD-TURBT are remarkably helpful in detection and intraoperative navigation programs.
Cancer 07/2011; 118(4):1062-74. · 4.77 Impact Factor
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ABSTRACT: To investigate the feasibility of intraoperative photodynamic diagnosis (PDD) by 5-aminolevulinic acid (ALA) for the identification of positive surgical margins (PSM) during retropubic radical prostatectomy (RRP) in patients with prostate cancer (PCa).
Intraoperative PDD was carried out in 16 patients with pathologically confirmed PCa by biopsy of the apex, or carrying >25% of probability of extraprostatic extension as defined by Japan PC Table. Before operation, 1.0 g of ALA was given orally. During open RRP, the resection margins inside the body were examined by PDD system with a fluorescence laparoscope. After their removal, 12 harvested prostates were divided and also investigated by PDD. Red fluorescent-positive lesions were biopsied and compared with the pathological result.
All 16 patients were fluorescence-negative inside the body, and negative margins were pathologically confirmed during PDD. Among the 43 specimens of 12 cases obtained by biopsy under PDD, 11 specimens (25.6%) were pathologically diagnosed as malignant tissue (adenocarcinoma, 10 specimens; high grade prostatic intraepithelial neoplasia, 1 specimen) and 19 specimens (44.2%) were evaluated as positive fluorescence by PDD with a sensitivity of 81.8%, a specificity of 68.8% and a predictive accuracy of 72.1%. No side-effects were observed and the procedures were well tolerated.
PDD mediated by ALA during RRP might be a feasible and safe modality for detection of surgical margins. Further prospective randomized studies with larger populations are required.
International Journal of Urology 06/2011; 18(8):585-91. · 1.75 Impact Factor
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ABSTRACT: We have reported that tubular epithelial cell injury caused by renal ischemia-reperfusion is attenuated in conditional VHL knockout (VHL-KO) mice and also that induction of hypoxia-inducible factor (HIF) suppresses angiotensin II-accelerated Habu snake venom (HV) glomerulonephropathy in rats. However, it remains unknown whether VHL knockdown protects glomerular endothelial cells from endothelium-targeted glomerulonephritis.
VHL-KO mice with HV glomerulonephropathy (HV GN) had fewer injured glomeruli, a lower mesangiolysis score and reduced blood urea nitrogen levels. Immunoreactivity of vascular endothelial growth factor (VEGF) in the glomerular capillaries was enhanced by VHL knockdown and was conserved even in VHL-KO mice with HV GN, despite HV-attenuating endothelial VEGF expression in vitro. VHL-KO mice showed enhanced nitric oxide (NO) production in glomerular endothelial cells and tubular cells, associated with activated VEGF expression in the kidney (i.e. an activated NO-VEGF axis). The levels of NO in glomeruli and tubules were conserved even in mice with HV GN. In contrast, suppressing NO production in glomerular endothelial cells by an NO synthase inhibitor, N(ϖ)-nitro-L-arginase, completely blunted the protection of VHL-KO from HV GN. The activated NO-VEGF axis in the kidney of VHL-KO mice was also associated with an elevation in Flk-1 phosphorylation and increased levels of IL-10 and IP-10.
Conditional VHL knockdown may enhance the NO-VEGF axis and protect glomerular endothelial cells from HV GN, thereby providing resistance to injury of tubular epithelial cells and glomerular endothelial cells.
Nephrology Dialysis Transplantation 04/2011; 26(12):4023-31. · 3.40 Impact Factor
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ABSTRACT: Our study determined if Janus kinase 2 (JAK2) was activated in acute myelogenous leukemia (AML; n = 77, excluding acute promyelocytic leukemia) by immunohistochemistry (IHC) using a phosphor-specific antibody against JAK2. p-JAK2 was detectable in all cases, although its levels varied between patient samples (high levels, n = 31; low levels, n = 46). The quantification of levels of p-JAK2 by IHC was well correlated with that assessed by Western blot analyses and fluorescence-activated cell sorting (FACS). Levels of p-JAK2 were directly correlated with high white blood cell count (52.3 × 10(3) /L in patients with high p-JAK2 vs. 28.3 × 10(3) /L in patients with low p-JAK2, p < 0.01) and were inversely correlated with complete remission rates (45% in patients with high p-JAK2 vs. 78% in patients with low p-JAK2, p < 0.003). In addition, multivariate analysis confirmed that high levels of p-JAK2 remained a significant factor for overall survival (hazard ratio = 2.213; 95% confidence interval, 1.212-4.041, p = 0.023). Moreover, we found that AZ960, a novel and specific inhibitor of the JAK2 kinase, potently inhibited the clonogenic growth and induced apoptosis of freshly isolated AML cells from patients in association with cleavage of caspase 3 and downregulation of anti-apoptotic Bcl-xL proteins. Taken together, JAK2 may be a promising molecular target for treatment of AML.
International Journal of Cancer 01/2011; 129(10):2512-21. · 5.44 Impact Factor
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ABSTRACT: Lobular pregnancy-like hyperplasia (PLH) merged with cystic hypersecretory hyperplasia (CHH), designated PLH/CHH, is a rare multicystic breast lesion. A previous report has described the high rate of coexistent ductal carcinoma in situ in PLH/CHH; however, a PLH/CHH study involving a larger number of cases is necessary to unravel the clinical significance of this tumor type.
We describe a unique case of PLH/CHH that coexisted with multifocal lobular neoplasm. Multifocal invasive lobular carcinoma with lobular carcinoma in situ was observed to be adjacent to the PLH/CHH cystic lesions in the left breast of a 70-year-old woman.
The present case documents the previously unreported coexistence of PLH/CHH accompanied by multifocal lobular carcinoma. Extensive examination, including an excisional biopsy, is prudent if a needle core biopsy reveals a PLH/CHH lesion.
Onkologie 01/2011; 34(8-9):448-50. · 0.87 Impact Factor
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ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease in which the Jak2/Stat5 pathway is constitutively activated. This study found that AZ960, a novel inhibitor of Jak2 kinase, effectively induced growth arrest and apoptosis of human T-cell lymphotropic virus type 1, HTLV-1-infected T cells (MT-1 and MT-2) in parallel with downregulation of the phosphorylated forms of Jak2 and Bcl-2 family proteins including Bcl-2 and Mcl-1. Interestingly, AZ960 increased levels of Bcl-xL in MT-1 and MT-2 cells in association with accumulation of cAMP response element-binding protein bound to the Bcl-xL promoter as measured by chromatin immunoprecipitation assay. Importantly, genetic inhibition of Bcl-xL by a small interfering RNA potentiated antiproliferative effects of AZ960 in MT-1 cells. Taken together, Jak2 is an attractive molecular target for treatment of ATL. Concomitant blockade of Jak2 and Bcl-xL may be a promising treatment strategy for this lethal disease.
Molecular Cancer Therapeutics 12/2010; 9(12):3386-95. · 5.23 Impact Factor
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ABSTRACT: The aim of this study was to examine whether Nedd4L (neural precursor cell expressed, developmentally down-regulated 4-like) participated in gallbladder carcinogenesis. We first immunohistochemically examined the expression of Nedd4L in various gallbladder tissue specimens. Weak immunoreactivity to Nedd4L-specific antibody was observed in normal or dysplastic epithelial cells. Cancer cells in non-invasive regions exhibited little immunoreactivity, whereas strong immunostaining was found in cytoplasm of many invasive cancers, especially at cancer invasive front with desmoplastic reaction. Notably, siRNA-mediated silencing of the Nedd4L gene significantly decreased the Matrigel-invasion activity and collagen invasion activity of cultured gallbladder cancer cells, without affecting the cell growth. The subtractive mRNA hybridization followed by RT-PCR and immunoblotting revealed that down-regulation of Nedd4L significantly decreased the expression of collagenases, matrix metalloproteinase (MMP)-1 and -13, in gallbladder cancer cells. Finally, immunohistochemical staining showed that many Nedd4L-expressing invasive gallbladder cancer cells co-expressed MMP-1 and MMP-13. These results indicated that over-expression of Nedd4L might lead to gallbladder cancer invasion by regulating the transcription of the MMP-1 and MMP-13 genes.
International Journal of Experimental Pathology 10/2010; 92(2):79-86. · 2.57 Impact Factor
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Motohide Uemura,
Seijiro Honma,
Suyoun Chung,
Ryo Takata, Mutsuo Furihata,
Kazuo Nishimura,
Norio Nonomura,
Yasutomo Nasu,
Tsuneharu Miki,
Taro Shuin,
Tomoaki Fujioka,
Akihiko Okuyama,
Yusuke Nakamura,
Hidewaki Nakagawa
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ABSTRACT: Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.
Cancer Science 08/2010; 101(8):1897-904. · 3.33 Impact Factor
