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author:("hiyama, S")
1.  Stratifin accelerates progression of lung adenocarcinoma at an early stage 
Molecular Cancer  2015;14:142.
Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in initiation and progression of lung adenocarcinoma.
Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN+/−) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN+/− mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK. Interestingly, several Tg-SPC-SFN+/− mice developed tumors without NNK. These tumor cells showed high hSFN expression.
These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0414-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4518688
Stratifin; Tg-SPC-SFN+/−; Lung adenocarcinoma; Malignant progression; NNK
2.  Fucosylated TGF-β receptors transduces a signal for epithelial–mesenchymal transition in colorectal cancer cells 
British Journal of Cancer  2013;110(1):156-163.
Transforming growth factor-β (TGF-β) is a major inducer of epithelial–mesenchymal transition (EMT) in different cell types. TGF-β-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-β is unclear.
Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-β downstream molecules were analysed by western blot. Fucosylation of TGF-β receptor (TβR) was examined by lectin blot analysis.
Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I TβR and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT.
Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-β-mediated EMT.
PMCID: PMC3887298  PMID: 24253505
colorectal cancer; fucosyltransferase; TGF-β; EMT
3.  CSB interacts with SNM1A and promotes DNA interstrand crosslink processing 
Nucleic Acids Research  2014;43(1):247-258.
Cockayne syndrome (CS) is a premature aging disorder characterized by photosensitivity, impaired development and multisystem progressive degeneration, and consists of two strict complementation groups, A and B. Using a yeast two-hybrid approach, we identified the 5′-3′ exonuclease SNM1A as one of four strong interacting partners of CSB. This direct interaction was confirmed using purified recombinant proteins—with CSB able to modulate the exonuclease activity of SNM1A on oligonucleotide substrates in vitro—and the two proteins were shown to exist in a common complex in human cell extracts. CSB and SNM1A were also found, using fluorescently tagged proteins in combination with confocal microscopy and laser microirradiation, to be recruited to localized trioxsalen-induced ICL damage in human cells, with accumulation being suppressed by transcription inhibition. Moreover, SNM1A recruitment was significantly reduced in CSB-deficient cells, suggesting coordination between the two proteins in vivo. CSB-deficient neural cells exhibited increased sensitivity to DNA crosslinking agents, particularly, in a non-cycling, differentiated state, as well as delayed ICL processing as revealed by a modified Comet assay and γ-H2AX foci persistence. The results indicate that CSB coordinates the resolution of ICLs, possibly in a transcription-associated repair mechanism involving SNM1A, and that defects in the process could contribute to the post-mitotic degenerative pathologies associated with CS.
PMCID: PMC4288174  PMID: 25505141
4.  Identification of a novel gene (Apq1) from the indica rice cultivar ‘Habataki’ that improves the quality of grains produced under high temperature stress 
Breeding Science  2014;64(4):273-281.
The appearance of brown rice grown under high temperature conditions is an important characteristic for improvement in Japanese rice breeding programs. We performed a QTL analysis of the appearance quality of brown rice using chromosome segment substitution lines of the indica cultivar ‘Habataki’ in the ‘Koshihikari’ genetic background. A line carrying a ‘Habataki’ segment on chromosome 7 showed a high percentage of perfect grains produced under high temperature conditions during the ripening period. To verify the role of this segment, and to narrow down the region containing the useful allele, substitution mapping was performed using multiple paired lines. As a result, the chromosomal location of a gene that we named Appearance quality of brown rice 1 (Apq1) was delimited to a 48-kb region. In addition, we developed an Apq1-near isogenic line (NIL) to evaluate the effect of Apq1 on various agronomic traits. Under high temperature conditions during the ripening period, the Apq1-NIL produced significantly higher percentages of perfect grains than ‘Koshihikari’. Other agronomic traits, including yield and palatability, were similar between the Apq1-NIL and ‘Koshihikari’. Therefore, the ‘Habataki’ allele of Apq1 will be useful in breeding programs aimed at improving the quality of grains ripened under high temperature conditions.
PMCID: PMC4267301  PMID: 25914581
Apq1; appearance quality; grain; ‘Habataki’; ‘Koshihikari’; mapping; rice (Oryza sativa L.)
5.  Single-breath-hold whole-heart coronary MRA in healthy volunteers at 3.0-T MRI 
SpringerPlus  2014;3:667.
The purpose of this study was to investigate the feasibility of single-breath-hold whole-heart MRA with a 3-T system. Ten healthy male volunteers underwent single-breath-hold whole-heart coronary MRA at 3 T. We assessed acquisition time, scores of image quality of coronary artery (RCA: proximal, middle and distal, LAD: main, proximal, middle and distal, LCX: proximal and distal) and the visualized vessel length of RCA, LAD and LCX.
Mean acquisition time was 37.7 ± 5.2 sec. Coronary branch was successfully depicted in 67/80 branches (84%) in the 10 healthy volunteers with diagnostic image quality. And, the average visible RCA, LAD and LCX vessel length were 83.4 ± 22 mm and 59.6 ± 24 mm.
3-T MRI with single-breath-hold 3D whole-heart coronary MRA can yield adequate image quality. Further study is needed to evaluate the clinical benefit of this technique.
PMCID: PMC4236310  PMID: 25485202
Single-breath-hold whole-heart MRA; Imaging; 3-T MRI
6.  Efficacy of Enteral Supplementation Enriched with Glutamine, Fiber, and Oligosaccharide on Mucosal Injury following Hematopoietic Stem Cell Transplantation 
Case Reports in Oncology  2014;7(3):692-699.
The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3–4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days); the same was true for days of mucositis grade 3–4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p < 0.001 and p = 0.0014, respectively). Although not significant, less gut bacterial translocation with Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.
PMCID: PMC4255989  PMID: 25493082
Glutamine; Fiber; Oligosaccharide; GFO; Mucosal injury; Hematopoietic stem cell transplantation
7.  Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study 
British Journal of Cancer  2013;109(6):1537-1542.
Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances.
We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors.
Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5+). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies.
Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.
PMCID: PMC3777011  PMID: 24002591
ethinylestradiol; endocrine therapy; metastatic breast cancer; aromatase inhibitor resistance
8.  Radiation-Induced Leiomyosarcoma of the Prostate after Brachytherapy for Prostatic Adenocarcinoma 
Case Reports in Oncology  2014;7(2):565-570.
Radiation therapy (RTx) has been employed as a curative therapy for prostatic adenocarcinoma. RTx-induced sarcomas (RISs) are rare, late adverse events, representing less than 0.2% of all irradiated patients. RISs are more aggressive tumors than prostatic adenocarcinomas. Herein, we present a case with RTx-induced prostatic leiomyosarcoma after permanent brachytherapy for prostatic adenocarcinoma. A 69-year-old male presented with dysuria and gross hematuria. Six years previously, he had been diagnosed with localized prostate cancer and was treated by permanent brachytherapy. Urethroscopy showed stenosis by a tumor at the prostate. Transurethral prostatectomy was performed for a diagnosis. Based on pathological findings, the diagnosis was leiomyosarcoma of the prostate. He was treated with three cycles of neoadjuvant chemotherapy (CTx) that consisted of doxorubicin and ifosfamide (AI), followed by a prostatocystectomy with intrapelvic lymphadenectomy. The tumor extended from the prostate and infiltrated the bladder wall and serosa with lymphatic and venous invasion. The surgical margin was negative, and no residual prostatic adenocarcinoma was observed. The proportion of necrotic tumor cells by neoadjuvant CTx was around 50%. Subsequently, adjuvant CTx was offered, but the patient chose a follow-up without CTx. Local recurrence and lung metastasis were detected by computed tomography 3 months after the surgery. He was treated again with AI. However, CTx was not effective and he died 6 months after the operation. In conclusion, an effective treatment strategy for prostatic sarcoma should be developed in the near future, although the clinical feature of prostatic sarcoma remains unclear due to its rare incidence.
PMCID: PMC4164087  PMID: 25232328
Radiation-induced sarcoma; Brachytherapy; Leiomyosarcoma; Prostatic sarcoma; p53
9.  DNA repair mechanisms in dividing and non-dividing cells 
DNA repair  2013;12(8):620-636.
DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye towards how these pathways may regulate the development of neurological disease.
PMCID: PMC3720834  PMID: 23684800
DNA repair; Neural cells; Neurological disorder; Dividing and non-dividing; Endogenous DNA damage
10.  EZH2 Is Associated with Malignant Behavior in Pancreatic IPMN via p27Kip1 Downregulation 
PLoS ONE  2014;9(8):e100904.
The epigenetic mechanism of tumorigenesis in pancreatic intraductal papillary mucinous neoplasm (IPMN) remains largely unknown. The aim of this study is to examine the role of enhancer of zeste homologue 2 (EZH2) alteration in pancreatic IPMN progression.
Fifty-four surgically resected pancreatic IPMN specimens, including a total of 181 lesions (normal duct in 48, adenoma in 50, borderline atypia in 53, carcinoma in situ (CIS) in 19, and invasive carcinoma in 11) were analyzed by immunohistochemical staining (EZH2, Ki-67, p27Kip1). Using paraffin embedded sections, total RNA was successfully extracted from 20 IPMN lesions (borderline IPMN in 9, CIS in 6, invasive carcinoma in 5) and 7 pancreatic normal ducts, and then levels of EZH2 and p27Kip1 mRNA were analyzed by real time PCR.
In immunohistochemical analysis, cell proliferative activity revealed by Ki-67 positive nuclei was increased during IPMN progression (normal duct
EZH2 is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the downregulation of p27Kip1.
PMCID: PMC4118850  PMID: 25084021
Breeding Science  2014;64(2):134-141.
Rice (Oryza sativa L.) can produce black grains as well as white. In black rice, the pericarp of the grain accumulates anthocyanin, which has antioxidant activity and is beneficial to human health. We developed a black rice introgression line in the genetic background of Oryza sativa L. ‘Koshihikari’, which is a leading variety in Japan. We used Oryza sativa L. ‘Hong Xie Nuo’ as the donor parent and backcrossed with ‘Koshihikari’ four times, resulting in a near isogenic line (NIL) for black grains. A whole genome survey of the introgression line using DNA markers suggested that three regions, on chromosomes 1, 3 and 4 are associated with black pigmentation. The locus on chromosome 3 has not been identified previously. A mapping analysis with 546 F2 plants derived from a cross between the black rice NIL and ‘Koshihikari’ was evaluated. The results indicated that all three loci are essential for black pigmentation. We named these loci Kala1, Kala3 and Kala4. The black rice NIL was evaluated for eating quality and general agronomic traits. The eating quality was greatly superior to that of ‘Okunomurasaki’, an existing black rice variety. The isogenicity of the black rice NIL to ‘Koshihikari’ was very high.
PMCID: PMC4065320  PMID: 24987299
black rice; Kala; ‘Koshihikari’; ‘Hong Xie Nuo’; mapping; near isogenic line; Oryza sativa L.
Case Reports in Oncology  2014;7(2):316-322.
Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.
PMCID: PMC4049016  PMID: 24932174
Therapy-related leukemia; Colorectal cancer; Oxaliplatin; Azacitidine; Cetuximab
Blood Cancer Journal  2014;4(2):e180-.
Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.
PMCID: PMC3944660  PMID: 24510029
CD19; liposome; rapamycin; Burkitt's lymphoma
PLoS ONE  2013;8(11):e80552.
Pax transactivation domain interacting protein (PTIP) associated protein 1, PA1, was a newly found protein participating in the modulation of transactivity of nuclear receptor super family members such as estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR). Breast cancer is one of the most life threatening diseases for women and has tight association with estrogen and ER. This study was performed to understand the function of PA1 in breast cancer. The expression of PA1 had been evaluated in a total of 344 primary invasive breast cancer samples and examined the relationship with clinical output, relapse free survival (RFS), breast cancer-specific survival (BCSS). PA1 expression was observed in both nucleus and cytoplasm, however, appeared mainly in nuclear. PA1 nuclear expression was correlated with postmenopausal (P = 0.0097), smaller tumor size (P = 0.0025), negative Ki67 (P = 0.02), positive AR (P = 0.049) and positive ERβ (P = 0.0020). Kaplan–Meier analysis demonstrated PA1 nuclear positive cases seemed to have a longer survival than negative ones for RFS (P = 0.023) but not for BCSS (P = 0.23). In the Cox hazards model, PA1 nuclear protein expression proved to be a significant prognostic univariate parameter for RFS (P = 0.03), but not for BCSS (P = 0.20). In addition, for those patients without lymphnode metastasis PA1 was found to be an independent prognostic factor for RFS (P = 0.025), which was verified by univariate and multivariate analyses. These investigations suggested PA1 expression could be a potential prognostic indicator for RFS in breast cancer.
PMCID: PMC3832393  PMID: 24260416
Journal of Cellular Physiology  2012;227(6):2622-2631.
CD73 is a GPI-anchored cell surface protein with ecto-5′-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73−/−) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A2A receptors (A2AAR) and A2B receptors (A2BAR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A2BAR antagonist but not with an A2AAR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A2BAR signaling.
PMCID: PMC3237726  PMID: 21882189
CD73; adenosine; osteoblasts; bone; mouse
Case Reports in Oncology  2013;6(2):256-262.
Metastatic cancers of the pancreas are rare, accounting for approximately 2–4% of all pancreatic malignancies. Renal cell carcinoma is the most common solid tumor that metastasizes to the pancreas. Here, we present a case of uterine cervical carcinoma metastasizing to the pancreas and review the literature regarding this rare event. A 44-year-old woman with a uterine cervical tumor had undergone radical hysterectomy and had been diagnosed pathologically with stage Ib mixed adenoneuroendocrine carcinoma in 2004. She underwent concurrent radiotherapy and chemotherapy postoperatively. Pulmonary metastases subsequently appeared in 2008 and 2011, and she underwent complete resection of the lung tumors by video-assisted thoracic surgery. Although she was followed up without any treatment and with no other recurrences, positron emission tomography revealed an area of abnormal uptake within the pancreatic body in 2012. Enhanced computed tomography demonstrated a 20-mm lesion in the pancreatic body and upstream pancreatic duct dilatation. Endoscopic ultrasonography-guided fine needle aspiration was performed and pathological examination suggested neuroendocrine carcinoma (NEC). On the basis of these results and the patient's oncological background, lesions in the pancreatic body were diagnosed as secondary metastasis from the cervical carcinoma that had been treated 8 years earlier. No other distant metastases were visualized, and the patient subsequently underwent middle pancreatectomy. Pathological examination showed NEC consistent with pancreatic metastasis from the uterine cervical carcinoma. The patient has survived 7 months since the middle pancreatectomy without any signs of local recurrence or other metastatic lesions.
PMCID: PMC3670638  PMID: 23741220
Pancreatic metastasis; Uterine cervical mixed adenoneuroendocrine carcinoma; Endoscopic ultrasonography-guided fine needle aspiration; Middle pancreatectomy
British Journal of Cancer  2012;106(5):876-882.
The mammalian target of rapamycin (mTOR) protein is important for cellular growth and homeostasis. The presence and prognostic significance of inappropriate mTOR activation have been reported for several cancers. Mammalian target of rapamycin inhibitors, such as everolimus (RAD001), are in development and show promise as anti-cancer drugs; however, the therapeutic effect of everolimus on oesophageal squamous cell carcinoma (OSCC) remains unknown.
Phosphorylation of mTOR (p-mTOR) was evaluated in 167 resected OSCC tumours and 5 OSCC cell lines. The effects of everolimus on the OSCC cell lines TE4 and TE11 in vitro and alone or in combination with cisplatin on tumour growth in vivo were evaluated.
Mammalian target of rapamycin phosphorylation was detected in 116 tumours (69.5%) and all the 5 OSCC cell lines. Everolimus suppressed p-mTOR downstream pathways, inhibited proliferation and invasion, and induced apoptosis in both TE4 and TE11 cells. In a mouse xenograft model established with TE4 and TE11 cells, everolimus alone or in combination with cisplatin inhibited tumour growth.
The mTOR pathway was aberrantly activated in most OSCC tumours. Everolimus had a therapeutic effect both as a single agent and in combination with cisplatin. Everolimus could be a useful anti-cancer drug for patients with OSCC.
PMCID: PMC3305959  PMID: 22333597
everolimus; RAD001; mTOR; oesophageal squamous cell carcinoma; proliferation
Disruptions in FOXP2, a transcription factor, are the only known monogenic cause of speech and language impairment. We report clinical findings for two new individuals with a submicroscopic deletion of FOXP2: a boy with severe apraxia of speech and his currently moderately affected mother. A 1.57 Mb deletion on chromosome 7q31 was detected by array Comparative Genomic Hybridization (aCGH). In addition to FOXP2, the patients’ deletion involves two other genes, MDFIC and PPP1R3A, neither of which has been associated with speech or language disorders. Thus, findings for these two family members provide informative phenotypic information on FOXP2 haploinsufficiency. Evaluation by a clinical geneticist indicated no major congenital anomalies or dysmorphic features. Evaluations by a clinical psychologist and occupational therapist indicated cognitive-linguistic processing and sensorimotor control deficits, but did not support a diagnosis of autism spectrum disorder. Evaluation by clinical and research speech pathologists confirmed that both patients’ speech deficits met contemporary criteria for apraxia of speech. Notably, the patients were not able to laugh, cough, or sneeze spontaneously, replicating findings reported for two other FOXP2 cases and a potential diagnostic sign of nonsyndromic apraxia of speech. Speech severity findings for the boy were not consistent with the hypothesis that loss of maternal FOXP2 should be relatively benign. Better understanding of the behavioral phenotype of FOXP2 disruptions will aid identification of patients, toward an eventual understanding of the pathophysiology of syndromic and nonsyndromic apraxia of speech.
PMCID: PMC3319495  PMID: 22106036
aCGH; apraxia of speech; autism; dyspraxia; speech sound disorder
Case Reports in Gastroenterology  2012;6(3):590-595.
We report a rare case of primary hepatic gastrinoma. A 77-year-old woman exhibited continuous watery diarrhea for 8 months and weight loss. Bacterial cultures of the stools were negative and colonoscopy revealed no abnormalities. Esophagogastroduodenoscopy showed severe reflux esophagitis and multiple duodenal erosions. Computed tomography and magnetic resonance imaging detected two solid masses measuring <2 cm in diameter in the right lobe of the non-cirrhotic liver. Microscopically, the tumor was consistent with neuroendocrine tumor (grade 2) with abundant gastrin-immunoreactive cells. Endoscopic ultrasound detected no other alternative primary source of an endocrine tumor. The serum gastrin levels exceeded 40,000 pg/ml in the absence of H2 receptor antagonist and proton pump inhibitor administrations. Based on an arterial stimulation and venous sampling test, the patient was diagnosed as primary gastrinoma of the liver. Our findings demonstrated the presence of Zollinger-Ellison syndrome in a patient who was subsequently cured by surgical resection of the liver tumors.
PMCID: PMC3529581  PMID: 23271988
Gastrinoma; Zollinger-Ellison syndrome; Arterial stimulation and venous sampling test
Blood Cancer Journal  2012;2(9):e87-.
Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34+ cells, CD34+ blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34+ acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO+ leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO+ leukemic cell proliferation. The demethylating agent, 5-aza-2′-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.
PMCID: PMC3461706  PMID: 22961059
acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); human hedgehog-interacting protein (HHIP); stromal cells
PLoS ONE  2012;7(7):e39545.
Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.
PMCID: PMC3394772  PMID: 22808043
International Journal of Oncology  2012;41(3):876-884.
CD138 expression is a hallmark of plasma cells and multiple myeloma cells. However, decreased expression of CD138 is frequently observed in plasma cells of myeloma patients, although the clinical significance of this is unclear. To evaluate the significance of low expression of CD138 in MM, we examined the phenotypes of MM cells expressing low levels of CD138. Flow cytometric analysis of primary MM cells revealed a significant decrease in CD138 expression in patients with relapsed/progressive disease compared with untreated MM patients. Patients with low levels of CD138 had a worse overall survival compared with patients with high levels of CD138, in newly diagnosed patients and patients receiving high-dose chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines, KYMM-1 (CD138− low) and KYMM-2 (CD138− high), were established from a single MM patient with decreased CD138 expression. High expression of BCL6 and PAX5, and downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2 cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib was observed. KYMM-2 cells were further divided in CD138+ and CD138− fractions using anti-CD138-coated magnetic beads. CD138− cells sorted from the KYMM-2 cell line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide compared with CD138+ cells. Our observations suggest that low CD138 expression relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity to lenalidomide. The observed distinct characteristics of CD138 low MM cells, suggest this should be recognized as a new clinical entity. Establishment of a treatment strategy for MM cells expressing low levels of CD138 is needed to improve their poor outcome.
PMCID: PMC3582943  PMID: 22766978
multiple myeloma; CD138; IRF4; lenalidomide
Solid-pseudopapillary tumors of the pancreas (SPTs) are comparatively rare and have low malignancy, with a predilection for young women. Diagnosis is difficult when a SPT develops in a boundary region with other organs. Here, we report a 42-year old woman with a SPT of the pancreas mimicking a submucosal tumor of the stomach on imaging. She was admitted to our hospital complaining of abdominal pain. We suspected a submucosal tumor of the stomach from the findings of endoscopy, endoscopic ultrasonography and abdominal computed tomography. However, angiography showed that some of the tumor vessels arose from the pancreas. Intraoperative findings revealed the tumor originated from the pancreas. Therefore, distal pancreatectomy was performed. The pathological diagnosis was SPT of the pancreas.
PMCID: PMC3251744  PMID: 22224175
Solid pseudopapillary tumor; Submucosal tumor; Gastrointestinal stromal tumors; endoscopic ultrasonography; Fine needle aspiration; Cluster of differentiation; Somatostatin receptor
Case Reports in Gastroenterology  2011;5(3):583-589.
Metastasis of gastrointestinal stromal tumor (GIST) into the central nervous system is extremely rare. We report a patient with synchronous GIST and brain metastasis. At disease onset, there was left hemiplegia and ptosis of the right eyelids. Resection cytology of the brain tumor was reported as metastasis of GIST. After positron emission tomography examination, another tumor in the small bowel was discovered, which suggested a small bowel GIST associated with intracranial metastasis. Immunohistochemical analysis of the intestinal tumor specimen obtained by double balloon endoscopy showed a pattern similar to the brain tumor, with the tumors subsequently identified as intracranial metastases of jejunal GIST. After surgical resection of one brain tumor, the patient underwent whole brain radiation therapy followed by treatment with imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland). Mutational analysis of the original intestinal tumor revealed there were no gene alterations in KIT or PDGFRα. Since the results indicated the treatment had no apparent effect on either of the tumors, and because ileus developed due to an intestinal primary tumor, the patient underwent surgical resection of the intestinal lesion. However, the patient's condition gradually worsen and she subsequently died 4 months after the initial treatment.
PMCID: PMC3219482  PMID: 22110419
Gastrointestinal stromal tumor; Brain metastasis; Mutational analysis
BMJ Case Reports  2009;2009:bcr10.2008.1137.
Primary squamous cell cancer of the thyroid gland (SCT) is a rare malignant tumour and is associated with a high mortality. A female patient who suffered from primary SCT is described in this report. The cancer was identified with acute painful swelling of the thyroid gland, when the patient was under periodical observation for her chronic thyroiditis at our outpatient’s clinic. In spite of the highly malignant potential of the cancer as indicated by histological examinations, including p53 and MIB-1 index analyses, the patient has been successfully treated so far with surgery and radiation therapy, surviving for more than 34 months with no sign of recurrence or metastasis. Early diagnosis and prompt treatment might have been essential for the successful management of this patient. Further observations and investigations are necessary to clarify the mechanisms of the long survival and to find a better treatment for the disease.
PMCID: PMC3029573  PMID: 21686450

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