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Pancreatic Neoplasms: HELP
Articles by Courtney W. Houchen
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Courtney W. Houchen wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Cancer stem cells: a novel paradigm for cancer prevention and treatment. 2010

Subramaniam, Dharmalingam / Ramalingam, Satish / Houchen, Courtney W / Anant, Shrikant. ·Medicine and Cell Biology, University of Oklahoma Health Sciences Center, 920 Stanton L. Young Boulevard, WP1345, Oklahoma City, OK 73104, USA. ·Mini Rev Med Chem · Pubmed #20370703.

ABSTRACT: Cancer is the second leading cause for mortality in US only after heart disease and lacks a good or effective therapeutic paradigm. Despite the emergence of new, targeted agents and the use of various therapeutic combinations, none of the treatment options available is curative in patients with advanced cancer. A growing body of evidence is supporting the idea that human cancers can be considered as a stem cell disease. Malignancies are believed to originate from a fraction of cancer cells that show self renewal and pluripotency and are capable of initiating and sustaining tumor growth. The cancer-initiating cells or cancer stem cells were originally identified in hematological malignancies but is now being recognized in several solid tumors. The hypothesis of stem cell-driven tumorigenesis raises questions as to whether the current treatments, most of which require rapidly dividing cells are able to efficiently target these slow cycling tumorigenic cells. Recent characterization of cancer stem cells should lead to the identification of key signaling pathways that may make cancer stem cells vulnerable to therapeutic interventions that target drug-effluxing capabilities, anti-apoptotic mechanisms, and induction of differentiation. Dietary phytochemicals possess anti-cancer properties and represent a promising approach for the prevention and treatment of many cancers.

2 Article ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells. 2020

Liu, Mingyang / Zhang, Yuqing / Yang, Jingxuan / Cui, Xiaobo / Zhou, Zhijun / Zhan, Hanxiang / Ding, Kai / Tian, Xiang / Yang, Zhibo / Fung, Kar-Ming A / Edil, Barish H / Postier, Russell G / Bronze, Michael S / Fernandez-Zapico, Martin E / Stemmler, Marc P / Brabletz, Thomas / Li, Yi-Ping / Houchen, Courtney W / Li, Min. ·Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Chemistry and Biochemistry, The University of Oklahoma, Norman, Oklahoma. · Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Oncology, Mayo Clinic, Rochester, Minnesota; Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany. · Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Min-Li@ouhsc.edu. ·Gastroenterology · Pubmed #31711924.

ABSTRACT: BACKGROUND & AIMS: Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. METHODS: We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. RESULTS: In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3β1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. CONCLUSIONS: In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3β1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

3 Article ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells. 2019

Yang, Jingxuan / Zhang, Zicheng / Zhang, Yuqing / Ni, Xiaoling / Zhang, Guohua / Cui, Xiaobo / Liu, Mingyang / Xu, Can / Zhang, Qiang / Zhu, Huiyun / Yan, Jie / Zhu, Vivian F / Luo, Yusheng / Hagan, John P / Li, Zhaoshen / Fang, Jing / Jatoi, Aminah / Fernandez-Zapico, Martin E / Zheng, Lei / Edil, Barish H / Bronze, Michael S / Houchen, Courtney W / Li, Yi-Ping / Li, Min. ·Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas. · Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of General Surgery, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. · The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of Gastroenterology, Changhai Hospital, Shanghai, China. · The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Gastroenterology, Changhai Hospital, Shanghai, China. · Department of Gastroenterology, Changhai Hospital, Shanghai, China. · The Key Lab of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China. · Department of Oncology, Mayo Clinic, Rochester, Minnesota. · Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: Yi-Ping.Li@uth.tmc.edu. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: Min-Li@ouhsc.edu. ·Gastroenterology · Pubmed #30342032.

ABSTRACT: BACKGROUND & AIMS: Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK). METHODS: We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS: Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS: ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.

4 Article ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism. 2018

Liu, Mingyang / Yang, Jingxuan / Zhang, Yuqing / Zhou, Zhijun / Cui, Xiaobo / Zhang, Liyang / Fung, Kar-Ming / Zheng, Wei / Allard, Felicia D / Yee, Eric U / Ding, Kai / Wu, Huanwen / Liang, Zhiyong / Zheng, Lei / Fernandez-Zapico, Martin E / Li, Yi-Ping / Bronze, Michael S / Morris, Katherine T / Postier, Russell G / Houchen, Courtney W / Yang, Jing / Li, Min. ·Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Pathology, Peking Union Hospital, Peking Union Medical College, Beijing, China. · The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, Mayo Clinic, Rochester, Minnesota. · Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · Department of Integrative Biology and Pharmacology, the University of Texas Medical School at Houston, Houston, Texas. · Department of Pharmacology and Pediatrics, University of California at San Diego, La Jolla, California. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Min-Li@ouhsc.edu. ·Clin Cancer Res · Pubmed #29615456.

ABSTRACT:

5 Article Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. 2016

Westphalen, C Benedikt / Takemoto, Yoshihiro / Tanaka, Takayuki / Macchini, Marina / Jiang, Zhengyu / Renz, Bernhard W / Chen, Xiaowei / Ormanns, Steffen / Nagar, Karan / Tailor, Yagnesh / May, Randal / Cho, Youngjin / Asfaha, Samuel / Worthley, Daniel L / Hayakawa, Yoku / Urbanska, Aleksandra M / Quante, Michael / Reichert, Maximilian / Broyde, Joshua / Subramaniam, Prem S / Remotti, Helen / Su, Gloria H / Rustgi, Anil K / Friedman, Richard A / Honig, Barry / Califano, Andrea / Houchen, Courtney W / Olive, Kenneth P / Wang, Timothy C. ·Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany. · Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA. · Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cell Stem Cell · Pubmed #27058937.

ABSTRACT: The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

6 Article Serum CA125 is a novel predictive marker for pancreatic cancer metastasis and correlates with the metastasis-associated burden. 2016

Liu, Liang / Xu, Hua-Xiang / Wang, Wen-Quan / Wu, Chun-Tao / Xiang, Jin-Feng / Liu, Chen / Long, Jiang / Xu, Jin / Fu, De Liang / Ni, Quan-Xing / Houchen, Courtney W / Postier, Russell G / Li, Min / Yu, Xian-Jun. ·Department of Pancreatic Surgery, Fudan University, Shanghai Cancer Center, Shanghai 20032, P.R. China. · Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China. · Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. · Department of Pancreatic Surgery, Huashan Hospital, Shanghai 200040, P.R. China. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. ·Oncotarget · Pubmed #26745601.

ABSTRACT: This study evaluated potential of serum tumor markers to predict the incidence and intensity of pancreatic cancer metastasis as well as patient survival. Retrospective records from 905 patients and prospective data from 142 patients were collected from two high-volume institutions. The levels of eight serum tumor markers (CA19-9, CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) commonly used in gastroenterological cancer were analyzed in all stages of pancreatic cancer. Serum CA125 levels were the most strongly associated with pancreatic cancer metastasis and were higher in patients with metastatic disease than those without. CA125 levels increased with increasing metastasis to lymph nodes and distant organs, especially the liver. High baseline CA125 levels predicted early distant metastasis after pancreatectomy and were associated with the presence of occult metastasis before surgery. An optimal CA125 cut-off value of 18.4 U/mL was identified; patients with baseline CA125 levels of 18.4 U/mL or higher had poor surgical outcomes. In addition, high serum CA125 levels coincided with the expression of a metastasis-associated gene signature and with alterations in "driver" gene expression involved in pancreatic cancer metastasis. CA125 may therefore be a promising, noninvasive, metastasis-associated biomarker for monitoring pancreatic cancer prognosis.

7 Article ZIP4 silencing improves bone loss in pancreatic cancer. 2015

Zhang, Qiang / Sun, Xiaotian / Yang, Jingxuan / Ding, Hao / LeBrun, Drake / Ding, Kai / Houchen, Courtney W / Postier, Russell G / Ambrose, Catherine G / Li, Zhaoshen / Bi, Xiaohong / Li, Min. ·Department of Orthopedics, General Hospital of The Jinan Military Command, Jinan, Shandong 250031, China. · The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA. · Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Department of Nanomedicine and Biomedical Engineering, The University of Texas Medical School at Houston, Houston, TX 77030, USA. · Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Department of Orthopedic Surgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA. ·Oncotarget · Pubmed #26305676.

ABSTRACT: Metabolic bone disorders are associated with several types of human cancers. Pancreatic cancer patients usually suffer from severe nutrition deficiency, muscle wasting, and loss of bone mass. We have previously found that silencing of a zinc transporter ZIP4 prolongs the survival and reduces the severity of the cachexia in vivo. However, the role of ZIP4 in the pancreatic cancer related bone loss remains unknown. In this study we investigated the effect of ZIP4 knockdown on the bone structure, composition and mechanical properties of femurs in an orthotopic xenograft mouse model. Our data showed that silencing of ZIP4 resulted in increased bone tissue mineral density, decreased bone crystallinity and restoration of bone strength through the RANK/RANKL pathway. The results further support the impact of ZIP4 on the progression of pancreatic cancer, and suggest its potential significance as a therapeutic target for treating patients with such devastating disease and cancer related disorders.

8 Article Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression. 2015

Mohammed, Altaf / Janakiram, Naveena B / Madka, Venkateshwar / Brewer, Misty / Ritchie, Rebekah L / Lightfoot, Stan / Kumar, Gaurav / Sadeghi, Michael / Patlolla, Jagan Mohan R / Yamada, Hiroshi Y / Cruz-Monserrate, Zobeida / May, Randal / Houchen, Courtney W / Steele, Vernon E / Rao, Chinthalapally V. ·Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. · Digestive Diseases Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, MD, USA. ·Oncotarget · Pubmed #25906749.

ABSTRACT: Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients.

9 Article Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells. 2015

Qu, Dongfeng / Johnson, Jeremy / Chandrakesan, Parthasarathy / Weygant, Nathaniel / May, Randal / Aiello, Nicole / Rhim, Andrew / Zhao, Lichao / Zheng, Wei / Lightfoot, Stanley / Pant, Shubham / Irvan, Jeremy / Postier, Russell / Hocker, James / Hanas, Jay S / Ali, Naushad / Sureban, Sripathi M / An, Guangyu / Schlosser, Michael J / Stanger, Ben / Houchen, Courtney W. ·Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America. · Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America. · Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States of America. · Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Oncology, Beijing Chaoyang Hospital, Capital Medicinal University, Beijing, China. · COARE Biotechnology Inc., Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America; COARE Biotechnology Inc., Oklahoma City, OK, United States of America. ·PLoS One · Pubmed #25723399.

ABSTRACT: Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance.

10 Article XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism. 2014

Sureban, Sripathi M / May, Randal / Weygant, Nathaniel / Qu, Dongfeng / Chandrakesan, Parthasarathy / Bannerman-Menson, Eddie / Ali, Naushad / Pantazis, Panayotis / Westphalen, Christoph B / Wang, Timothy C / Houchen, Courtney W. ·Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States. · COARE Biotechnology Inc., Oklahoma City, OK 73104, United States. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States. · Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States. · Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States. Electronic address: courtney-houchen@ouhsc.edu. ·Cancer Lett · Pubmed #24880079.

ABSTRACT: XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC.

11 Article DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer. 2013

Sureban, Sripathi M / May, Randal / Qu, Dongfeng / Weygant, Nathaniel / Chandrakesan, Parthasarathy / Ali, Naushad / Lightfoot, Stan A / Pantazis, Panayotis / Rao, Chinthalapally V / Postier, Russell G / Houchen, Courtney W. ·Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America ; Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, United States of America ; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, Oklahoma, United States of America. ·PLoS One · Pubmed #24040120.

ABSTRACT: Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and many other aggressive cancers. The dysregulation of these processes is believed to play key roles in tumor initiation, progression, and metastasis, and is contributory to PDAC being the fourth leading cause of cancer-related deaths in the US. The tumor suppressor miRNA miR-145 downregulates critical pluripotency factors and oncogenes and results in repressed metastatic potential in PDAC. Additionally, the miR-200 family regulates several angiogenic factors which have been linked to metastasis in many solid tumors. We have previously demonstrated that downregulation of DCLK1 can upregulate critical miRNAs in both in vitro and in vivo cancer models and results in downregulation of c-MYC, KRAS, NOTCH1 and EMT-related transcription factors. A recent report has also shown that Dclk1 can distinguish between normal and tumor stem cells in Apc (min/+) mice and that ablation of Dclk1(+) cells resulted in regression of intestinal polyps without affecting homeostasis. Here we demonstrate that the knockdown of DCLK1 using poly(lactide-co-glycolide)-encapsulated-DCLK1-siRNA results in AsPC1 tumor growth arrest. Examination of xenograft tumors revealed, (a) increased miR-145 which results in decreased pluripotency maintenance factors OCT4, SOX2, NANOG, KLF4 as well as KRAS and RREB1; (b) increased let-7a which results in decreased pluripotency factor LIN28B; and (c) increased miR-200 which results in decreased VEGFR1, VEGFR2 and EMT-related transcription factors ZEB1, ZEB2, SNAIL and SLUG. Specificity of DCLK1 post-transcriptional regulation of the downstream targets of miR-145, miR-200 and let-7a was accomplished utilizing a luciferase-based reporter assay. We conclude that DCLK1 plays a significant master regulatory role in pancreatic tumorigenesis through the regulation of multiple tumor suppressor miRNAs and their downstream pro-tumorigenic pathways. This novel concept of targeting DCLK1 alone has several advantages over targeting single pathway or miRNA-based therapies for PDAC.

12 Article RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. 2011

Subramaniam, Dharmalingam / Ramalingam, Satish / Linehan, David C / Dieckgraefe, Brian K / Postier, Russell G / Houchen, Courtney W / Jensen, Roy A / Anant, Shrikant. ·Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America. dsubramaniam@kumc.edu ·PLoS One · Pubmed #21347286.

ABSTRACT: BACKGROUND: Curcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; however, the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. Here, we have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that curcumin treated tumor xenografts have a significant reduction in tumor volume and angiogenesis. Curcumin inhibited the proliferation, while inducing G2-M arrest and apoptosis resulting in mitotic catastrophe of various pancreatic cancer cells. This was further confirmed by increased phosphorylation of checkpoint kinase 2 (Chk2) protein coupled with higher levels of nuclear cyclin B1 and Cdc-2. Curcumin increased the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) mRNA, but protein levels were lower. Furthermore, curcumin increased the expression of RNA binding proteins CUGBP2/CELF2 and TIA-1. CUGBP2 binding to COX-2 and VEGF mRNA was also enhanced, thereby increasing mRNA stability, the half-life changing from 30 min to 8 h. On the other hand, silencer-mediated knockdown of CUGBP2 partially restored the expression of COX-2 and VEGF even with curcumin treatment. COX-2 and VEGF mRNA levels were reduced to control levels, while proteins levels were higher. CONCLUSION/SIGNIFICANCE: Curcumin inhibits pancreatic tumor growth through mitotic catastrophe by increasing the expression of RNA binding protein CUGBP2, thereby inhibiting the translation of COX-2 and VEGF mRNA. These data suggest that translation inhibition is a novel mechanism of action for curcumin during the therapeutic intervention of pancreatic cancers.

13 Article DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. 2011

Sureban, Sripathi M / May, Randal / Lightfoot, Stan A / Hoskins, Aimee B / Lerner, Megan / Brackett, Daniel J / Postier, Russell G / Ramanujam, Rama / Mohammed, Altaf / Rao, Chinthalapally V / Wyche, James H / Anant, Shrikant / Houchen, Courtney W. ·Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. ·Cancer Res · Pubmed #21285251.

ABSTRACT: Pancreatic cancer is an exceptionally aggressive disease in great need of more effective therapeutic options. Epithelial-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis, and there is a gain of stem cell properties during EMT. Here we report increased expression of the putative pancreatic stem cell marker DCAMKL-1 in an established KRAS transgenic mouse model of pancreatic cancer and in human pancreatic adenocarcinoma. Colocalization of DCAMKL-1 with vimentin, a marker of mesenchymal lineage, along with 14-3-3 σ was observed within premalignant PanIN lesions that arise in the mouse model. siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with downregulation of EMT-associated transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism. These findings illustrate direct regulatory links between DCAMKL-1, microRNAs, and EMT in pancreatic cancer. Moreover, they demonstrate a functional role for DCAMKL-1 in pancreatic cancer. Together, our results rationalize DCAMKL-1 as a therapeutic target for eradicating pancreatic cancers.