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Pancreatic Neoplasms: HELP
Articles by Hideya Onishi
Based on 16 articles published since 2009
(Why 16 articles?)
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Between 2009 and 2019, Hideya Onishi wrote the following 16 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. 2014

Onishi, Hideya / Katano, Mitsuo. ·Hideya Onishi, Mitsuo Katano, Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·World J Gastroenterol · Pubmed #24605030.

ABSTRACT: Pancreatic cancer is one of the most aggressive and difficult cancers to treat. Despite numerous research efforts, limited success has been achieved in the therapeutic management of patients with this disease. In the current review, we focus on one component of morphogenesis signaling, Hedgehog (Hh), with the aim of developing novel, effective therapies for the treatment of pancreatic cancer. Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells. In addition, we propose a novel concept linking Hh signaling and tumor hypoxic conditions, and discuss the effects of Hh inhibitors in clinical trials. The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.

2 Article RBPJ and MAML3: Potential Therapeutic Targets for Small Cell Lung Cancer. 2018

Onishi, Hideya / Ichimiya, Shu / Yanai, Kosuke / Umebayashi, Masayo / Nakamura, Katsuya / Yamasaki, Akio / Imaizumi, Akira / Nagai, Shuntaro / Murahashi, Mutsunori / Ogata, Hisanobu / Morisaki, Takashi. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ohnishi@surg1.med.kyushu-u.ac.jp. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Fukuoka General Cancer Clinic, Fukuoka, Japan. · Shukoukai Inc., Tokyo, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. ·Anticancer Res · Pubmed #30061220.

ABSTRACT: BACKGROUND/AIM: Small cell lung cancer (SCLC) is still a deadly type of cancer for which there are few effective therapeutic strategies. Development of a new molecule targeting agent is urgently desired. Previously we showed that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) are new therapeutic targets for pancreatic cancer. In the present study, we analyzed whether RBPJ/MAML3 inhibition could also be a new therapeutic strategy for SCLC. MATERIALS AND METHODS: Using silencing of RBPJ/MAML3, proliferation, invasion, migration and chemosensitivity of SBC-5 cells were investigated. RESULTS: RBPJ/MAML3 inhibition reduced Smoothened and HES1 expression, suggesting that RBPJ/MAML3 signaling was through Hedgehog and NOTCH pathways. In the analysis of cell functions, RBPJ/MAML3 inhibition significantly reduced proliferation and invasiveness via reduction of expression of matrix metalloproteinases. On the other hand, RBPJ/MAML3 inhibition also reduced chemosensitivity to cis-diamminedichlo-roplatinum and gemcitabine. CONCLUSION: These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.

3 Article Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer. 2017

Yamasaki, Akio / Nakayama, Kazunori / Imaizumi, Akira / Kawamoto, Makoto / Fujimura, Akiko / Oyama, Yasuhiro / Nagai, Shuntaro / Yanai, Kosuke / Onishi, Hideya. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Shukoukai Inc., Tokyo, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ohnishi@surg1.med.kyushu-u.ac.jp. ·Anticancer Res · Pubmed #29187440.

ABSTRACT: BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. RESULTS: Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. CONCLUSION: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.

4 Article Protein-bound Polysaccharide-K Inhibits Hedgehog Signaling Through Down-regulation of MAML3 and RBPJ Transcription Under Hypoxia, Suppressing the Malignant Phenotype in Pancreatic Cancer. 2016

Yamasaki, Akio / Onishi, Hideya / Imaizumi, Akira / Kawamoto, Makoto / Fujimura, Akiko / Oyama, Yasuhiro / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ohnishi@surg1.med.kyushu-u.ac.jp. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Shukoukai Inc., Tokyo, Japan. ·Anticancer Res · Pubmed #27466498.

ABSTRACT: Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor.

5 Article Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models. 2016

Shinkai, Kentaro / Nakano, Kenji / Cui, Lin / Mizuuchi, Yusuke / Onishi, Hideya / Oda, Yoshinao / Obika, Satoshi / Tanaka, Masao / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. ·Int J Cancer · Pubmed #26939718.

ABSTRACT: The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target.

6 Article Hypoxic Conditions Promote Gemcitabine Sensitivity in a Pancreatic Cancer Stem Cell Line. 2016

Imaizumi, Akira / Onishi, Hideya / Yamasaki, Akio / Kawamoto, Makoto / Umebayashi, Masayo / Morisaki, Takashi / Hasumi, Kenichiro. ·Shukoukai Inc., Tokyo, Japan. · Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ohnishi@surg1.med.kyushu-u.ac.jp. · Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Fukuoka General Cancer Clinic, Fukuoka, Japan. ·Anticancer Res · Pubmed #26851020.

ABSTRACT: Development of an effective therapeutic strategy for refractory pancreatic cancer must consider whether chemosensitivity can be induced in chemoresistant cells. We established a pancreatic cancer stem cell-rich cell line using TIG-1 feeder cells and leukemia inhibitory factor (LIF)-rich SNL76/7 conditioned medium. We generated a cell line, namely YNPC031312-B, following isolation of cells from the malignant ascites of a patient with gemcitabine-resistant pancreatic cancer. A YNPC031312-B-Hypoxia cell line was established by maintaining YNPC031312-B cells under tumor-like hypoxic conditions (1% O2). Both cell lines exhibited a pancreatic cancer stem cell phenotype: YNPC031312-B cells were CD24(+)CD44(-)CD133(+)epithelial cell adhesion molecule (EpCAM)(+)alkaline phosphatase(+)Octamer-binding transcription factor (OCT)3/4+and YNPC031312-B-Hypoxia cells were CD24(+)CD44(+)CD133(+)EpCAM(+). YNPC031312-B-Hypoxia cells were larger, had superior migratory ability, and higher gemcitabine sensitivity compared to YNPC031312-B cells. The use of LIF or other factors with similar bioactivity under hypoxic conditions may contribute to the phenotypic change to gemcitabine sensitivity. Our results may aid development of new therapeutic strategies targeting refractory pancreatic cancer.

7 Article Hypoxia but not normoxia promotes Smoothened transcription through upregulation of RBPJ and Mastermind-like 3 in pancreatic cancer. 2016

Onishi, Hideya / Yamasaki, Akio / Kawamoto, Makoto / Imaizumi, Akira / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: ohnishi@surg1.med.kyushu-u.ac.jp. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Shukoukai Inc., Tokyo, Japan. ·Cancer Lett · Pubmed #26655998.

ABSTRACT: We previously demonstrated that Hedgehog (Hh) signaling is activated under hypoxia through upregulation of transcription of Smoothened (SMO) gene. However, the mechanism of hypoxia-induced activation of SMO transcription remains unclear. In the analysis of altered expressions of genes related to Hh signaling between under normoxia and hypoxia by DNA microarray analysis, we picked up 2 genes, a transcriptional regulator, recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and a transcriptional co-activator, Mastermind-like 3 (MAML3). Expressions of SMO, MAML3 and RBPJ were increased under hypoxia in pancreatic ductal adenocarcinoma cells (PDAC). RBPJ and MAML3 inhibition under hypoxia led to decreased SMO and GLI1 expressions, whereas SMO expression in MAML3-inhibited and RBPJ-inhibited cells under normoxia showed no change. However, overexpression of RBPJ under normoxia led to increased SMO expression. Additionally, cells knocked down for MAML3 and RBPJ inhibition under hypoxia showed decreased invasiveness through matrix metalloproteinase-2 suppression and decreased proliferation. Xenograft mouse models showed that MAML3 and RBPJ knockdown inhibited tumorigenicity and tumor volume. Our results suggest that hypoxia promotes SMO transcription through upregulation of MAML3 and RBPJ to induce proliferation, invasiveness and tumorigenesis in pancreatic cancer.

8 Article An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro. 2014

Umebayashi, Masayo / Kiyota, Akifumi / Koya, Norihiro / Tanaka, Hiroto / Onishi, Hideya / Katano, Mitsuo / Morisaki, Takashi. ·Fukuoka General Cancer Clinic, Fukuoka, Japan. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Fukuoka General Cancer Clinic, Fukuoka, Japan tmorisaki@cancer-clinic.jp. ·Anticancer Res · Pubmed #25075094.

ABSTRACT: Cancer stem-like properties of various types of cancer, including pancreatic cancer, one of the most aggressive types, correlate with metastasis, invasion, and therapeutic resistance. More importantly, chemoresistance in cancer stem-like cells (CSLCs) is a critical problem for eradication of pancreatic cancer. Several cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM), are molecular targets on CSLCs of pancreatic carcinoma. In this study, we investigated whether catumaxomab, a clinical-grade bi-specific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant pancreatic CSLCs in vitro. Firstly, we established a CSLC line (MU-PK1) from human pancreatic carcinoma cells derived from a patient with chemoresistant and disseminated pancreatic cancer. These CSLCs were almost completely resistant to gemcitabine-mediated cytotoxicity up to a concentration of 10 μg/ml. The cells expressed high levels of CSLC markers (CD44 and EpCAM) and had significantly higher capacities for sphere formation, invasion, and aldehyde dehydrogenase-1 expression, which are associated with cancer stemness properties. We found that pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3 activated autologous T-cells eliminated CSLCs during a short incubation period. Moreover, when MU-PK1 cells were cultured under hypoxic conditions, the CSLCs became more aggressive. However, the combination of cytokine-activated killer T-cells with catumaxomab successfully lysed almost all these cells. In conclusion, catumaxomab combined with activated T-cells may be a potent therapeutic modality to eradicate chemoresistant pancreatic CSLCs.

9 Article Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling. 2014

Morifuji, Yoshihiro / Onishi, Hideya / Iwasaki, Hironori / Imaizumi, Akira / Nakano, Kenji / Tanaka, Masao / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Cancer Sci · Pubmed #24397700.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated under hypoxic condition for 3-6 months and reoxygenation experiments were performed using these chronic-hypoxia-resistant PDAC cells in in vivo-mimicking conditions. Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation. A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation. Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9. Moreover, inhibition of Sonic Hh and Smoothened abrogated reoxygenation induced increases in proliferation and invasiveness. These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway. Therefore, the Hh signaling pathway may be a therapeutic target for refractory PDAC in metastatic processes induced by reoxygenation.

10 Article Protein-bound polysaccharide decreases invasiveness and proliferation in pancreatic cancer by inhibition of hedgehog signaling and HIF-1α pathways under hypoxia. 2013

Onishi, Hideya / Morisaki, Takafumi / Nakao, Fumihiko / Odate, Seiichi / Morisaki, Takashi / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ohnishi@surg1.med.kyushu-u.ac.jp ·Cancer Lett · Pubmed #23485726.

ABSTRACT: To develop an effective therapeutic approach to pancreatic ductal adenocarcinoma (PDAC), we focused on the antitumor mechanism of protein-bound polysaccharide (PSK) under hypoxia. PSK decreased proliferation in PDAC cells under hypoxia but not normoxia. PSK also showed anti-tumor effects in vivo, inhibited invasiveness of PDAC cells, and decreased the expression of HIF-1α and hedgehog (Hh) signaling-related molecules under hypoxia. Inhibition of HIF-1α and Hh signaling reduced proliferation and invasiveness in PDAC cells under hypoxia. In conclusion, we found new PSK-related pathways in invasiveness and proliferation in PDAC under hypoxia. PSK may be a promising therapeutic drug to treat refractory PDAC.

11 Article Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer. 2012

Onishi, Hideya / Morifuji, Yoshihiro / Kai, Masaya / Suyama, Kumi / Iwasaki, Hironori / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ohnishi@surg1.med.kyushu-u.ac.jp ·Cancer Sci · Pubmed #22486854.

ABSTRACT: Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.

12 Article Transforming growth factor β1 contributes to the invasiveness of pancreatic ductal adenocarcinoma cells through the regulation of CD24 expression. 2011

Kitaura, Yoshiki / Chikazawa, Nobuhito / Tasaka, Takehiko / Nakano, Kenji / Tanaka, Masao / Onishi, Hideya / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Pancreas · Pubmed #21697762.

ABSTRACT: OBJECTIVES: The aim of this study was to investigate the role of CD24 in the invasiveness of pancreatic ductal adenocarcinoma (PDAC). METHODS: We used 2 human PDAC cell lines containing large numbers of CD24-positive (CD24) cells (>65%; AsPC-1 cells) or few CD24 cells (<20%; CFPAC-1 cells). Invasiveness was estimated using the Matrigel invasion assay. The role of CD24 in invasiveness was evaluated using small interference RNA against CD24 mRNA. RESULTS: The invasive ability of CD24 cells collected by cell sorter was higher than that of CD24-negative (CD24) cells. On the other hand, silencing of CD24 decreased the invasive ability of CD24 cells. Importantly, considerable amount of CD24 cells was converted to CD24 cells within 24 hours under in vitro culture condition. Transforming growth factor β1 significantly inhibited this conversion and consequently maintained the high invasiveness of CD24 cells. CONCLUSIONS: Our data show that CD24 contributes to the invasive ability of PDAC and also suggest that transforming growth factor β1 may contribute to the invasiveness of PDAC by suppressing the conversion from CD24 cells to CD24 cells at the tumor site.

13 Article Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. 2011

Onishi, Hideya / Kai, Masaya / Odate, Seiichi / Iwasaki, Hironori / Morifuji, Yoshihiro / Ogino, Toshitatsu / Morisaki, Takafumi / Nakashima, Yutaka / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ohnishi@surg1.med.kyushu-u.ac.jp ·Cancer Sci · Pubmed #21338440.

ABSTRACT: The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.

14 Article Gamma-secretase complexes regulate the responses of human pancreatic ductal adenocarcinoma cells to taxanes. 2010

Tasaka, Takehiko / Akiyoshi, Takashi / Yamaguchi, Koji / Tanaka, Masao / Onishi, Hideya / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Anticancer Res · Pubmed #21187481.

ABSTRACT: BACKGROUND/AIM: It was previously reported that γ-secretase inhibitors (GSIs) enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. To enable the development of taxane-based chemotherapy for pancreatic ductal adenocarcinoma (PDAC), this study investigated the molecular mechanisms by which γ-secretase (GS) complexes regulate taxane sensitivity. MATERIALS AND METHODS: The effect of GS complexes on taxane-induced apoptosis in PDAC cells was evaluated by a cell cycle analysis. GS complexes were examined with small interference RNAs targeted to GS complex-related genes. RESULTS: GSIs and silencing of presenilin 1 (PS1) did not affect cell proliferation but resulted in enhanced taxane-induced G(2)/M accumulation and apoptosis. Silencing of the Notch gene did not induce these effects. However, PS2-specific silencing suppressed proliferation and taxane-induced apoptosis. CONCLUSION: Data from this study indicate that GS complexes regulate the response of PDAC to taxanes through GS-dependent and GS-independent mechanisms.

15 Article Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh. 2010

Yamasaki, Akio / Kameda, Chizu / Xu, Rui / Tanaka, Haruo / Tasaka, Takehiko / Chikazawa, Nobuhito / Suzuki, Hiroyuki / Morisaki, Takashi / Kubo, Makoto / Onishi, Hideya / Tanaka, Masao / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan. y-akio@surg1.med.kyushu-u.ac.jp ·Cancer Immunol Immunother · Pubmed #19862523.

ABSTRACT: Recently, it was reported that Hh signaling is activated in tumor stromal cells but not in tumor cells themselves and that stromal cells may play a role in the proliferation of cancer cells. This suggests the possibility that stromal cells have an important role in the proliferation of tumor cells that may be mediated through Hh signaling. In this report, we present for the first time that inflammation-stimulated monocytes produce Shh through activation of the NF-kappaB signaling pathway, and that the Shh produced promotes the proliferation of pancreatic cancer cells in a paracrine manner through Hh signaling.

16 Article Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. 2009

Ikebe, Mio / Kitaura, Yoshiki / Nakamura, Masafumi / Tanaka, Haruo / Yamasaki, Akio / Nagai, Shuntaro / Wada, Junji / Yanai, Kosuke / Koga, Kenichiro / Sato, Norihiro / Kubo, Makoto / Tanaka, Masao / Onishi, Hideya / Katano, Mitsuo. ·Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·J Surg Oncol · Pubmed #19722233.

ABSTRACT: BACKGROUND: Inflammation plays a multifaceted role in cancer progression, and NF-kappaB is one of the key factors connecting inflammation with cancer progression. We have shown that lipopolysaccharide (LPS) promotes NF-kappaB activation in colon cancer cells and pancreatic cancer cells. However, it is unclear why inflammatory stimuli can induce NF-kappaB activation in cancer cells. METHODS: We used two human pancreatic cancer cells, Panc-1 and AsPC-1, as target cells. LPS was used as an inflammatory stimulus. To confirm the participation of TLR4/NF-kappaB signaling pathway, we used three different NF-kappaB inhibitors (PDTC, IkappaBalpha mutant, and NF-kappaB decoy ODN) and siRNAs (against TLR4, MyD88, and MMP-9). Effect of LPS on pancreatic cancer cell invasive ability was determined by Matrigel invasion assay. RESULTS: LPS increased the invasive ability of pancreatic cancer cells, while blockade of NF-kappaB pathway decreased the LPS-dependent increased invasive ability. Blockade of TLR4 or MyD88 by siRNA also decreased the LPS-dependent increased invasive ability. CONCLUSION: These results suggest that TLR/MyD88/NF-kappaB signaling pathway plays a significant role in connecting inflammation and cancer invasion and progression.