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Hiroshi Nakagawa, M.D., Ph.D.

Research Associate Professor of Medicine
Department: Medicine
Graduate Group Affiliations

Contact information
Division of Gastroenterology
421 Curie Boulevard
956 Biomedical Research Building
Philadelphia, PA 19104
Office: 215-573-1867
Fax: 215-573-2024
Okayama University, Okayama, Japan, 1989.
Okayama University (Medical Science) Okayama, Japan, 1993.
Post-Graduate Training
Resident in Medicine , Okayama University Hospital, Okayama, Japan, 1989-1990.
Clinical Fellow in Gastroenterology and Hepatology, The First Department of Internal Medicine, Okayama University Medical School, Okayama, Japan, 1990-1993.
Postdoctoral Research Fellow, Massachusetts General Hospital, Gastrointestinal Unit, Harvard Medical School, Boston, Mass, 1993-1996.
Postdoctoral Research Fellow, The First Department of Internal Medicine, Okayama University Medical School, Okayama, Japan, 1997-1998.
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Description of Research Expertise

A major goal of my laboratory is to understand the molecular mechanisms by which the tumor microenvironment fosters esophageal tumor initiation and progression. Currently, I investigate how factors such as hypoxia and transforming growth factor (TGF)-β induce epithelial-to-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) cells. In addition, I have been exploring the roles of the Notch signaling in esophageal epithelial homeostasis, malignant transformation and cancer stem cells. Notch signaling and TGF-β regulate cooperatively EMT and foster resistance to conventional chemotherapy. I have a broad background in gastrointestinal epithelial biology, tumor biology, and molecular and cellular biology with specific training and expertise in key research areas.

As a postdoctoral fellow at the Massachusetts General Hospital, I worked on fundamental cell cycle regulation and gene transcription in esophageal squamous epithelial cell model systems, using both in vitro and in vivo approaches. I investigated the transcriptional regulation of viral and cellular promoters that are active in the esophageal epithelium, with the identification of cis-regulatory elements and trans-activating factors, cross-regulating the Epstein-Barr virus ED-L2 promoter and keratin promoters. I used this as a platform for utilizing the EBV ED-L2 promoter to target genes (e.g. cyclin D1) in transgenic mice.

As faculty member at the Gastroenterology Division of the University of Pennsylvania, I expanded my research to include epidermal growth factor receptor (EGFR) oncogene. As PI of several previous university, private (American Gastroenterological Association Research Scholar Award), and NIH-funded grants (K01, K26, R21 and R01), I have developed primary and immortalized human and mouse esophageal epithelial cell culture systems, human tissue engineering in organotypic 3D culture, a form of human tissue engineering, and xenograft transplantation and genetically engineered mouse models coupled with in vivo molecular imaging.

I successfully administered the projects (e.g. staffing, research protections, budget), collaborated with other researchers, and produced several peer-reviewed publications from each project. I have mentored a visiting faculty member, nine postdoctoral research fellows, including young clinician-scientists, and graduate and undergraduate students.

In addition, I serve as Associate Director of Cell Culture Core at the University of Pennsylvania Perelman School of Medicine. We provide a centralized repository of human and mouse-derived normal and engineered as well as cancer cell lines including numerous esophageal and head and neck squamous cell carcinoma cell lines. We also produce retroviruses and lentiviruses for gene transduction experiments, and preparation of organotypic 3D culture substrates (fibroblasts-matrix) and required media.

Selected Publications

Kagawa S, Natsuizaka M, Whelan K A, Facompre N, Naganuma S, Ohashi S, Kinugasa H, Egloff A M, Basu D, Gimotty P A, Klein-Szanto A J, Bass A J, Wong K-K, Diehl J A, Rustgi A K, Nakagawa H: Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities. Oncogene Jun 2014.

Kita Yoshiaki, Nishizono Yuka, Okumura Hiroshi, Uchikado Yasuto, Sasaki Ken, Matsumoto Masataka, Setoyama Tetsuro, Tanoue Kiyonori, Omoto Itaru, Mori Shinichiro, Owaki Tetsuhiro, Ishigami Sumiya, Nakagawa Hiroshi, Tanaka Fumiaki, Mimori Koshi, Mori Masaki, Natsugoe Shoji: Clinical and biological impact of cyclin-dependent kinase subunit 2 in esophageal squamous cell carcinoma. Oncology reports 31(5): 1986-92, May 2014.

Natsuizaka Mitsuteru, Kinugasa Hideaki, Kagawa Shingo, Whelan Kelly A, Naganuma Seiji, Subramanian Harry, Chang Sanders, Nakagawa Kei J, Rustgi Naryan L, Kita Yoshiaki, Natsugoe Shoji, Basu Devraj, Gimotty Phyllis A, Klein-Szanto Andres J, Diehl J Alan, Nakagawa Hiroshi: IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment. American journal of cancer research 4(1): 29-41, 2014.

Basu Devraj, Bewley Arnaud F, Sperry Steven M, Montone Kathleen T, Gimotty Phyllis A, Rasanen Kati, Facompre Nicole D, Weinstein Gregory S, Nakagawa Hiroshi, Diehl J Alan, Rustgi Anil K, Herlyn Meenhard: EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas. Molecular cancer therapeutics 12(10): 2176-86, Oct 2013.

Grugan Katharine D, Vega Maria E, Wong Gabrielle S, Diehl J Alan, Bass Adam J, Wong Kwok K, Nakagawa Hiroshi, Rustgi Anil K: A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion. Cancer biology & therapy 14(9): 853-9, Sep 2013.

Li, K, Jiang M, Lu, Y, Chen H, Sun J, Wu S, Ku WY, Nakagawa H, Kita Y, Natsugoe S, Peters JH, Rustgi AK, Onaitis MW, Kiernan A, Chen X, Que J: Sox2 Cooperates with Inflammation-Mediated Stat3 Activation in the Malignant Transformation of Foregut Basal Progenitor Cells. Cell Stem Cell 12(3): 304-15, March 2013.

Wong Gabrielle S, Habibollahi Peiman, Heidari Pedram, Lee Ju-Seog, Klein-Szanto Andres J, Waldron Todd J, Gimotty Phyllis, Nakagawa Hiroshi, Taylor Philip R, Wang Timothy C, Mahmood Umar, Rustgi Anil K: Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice. Gastroenterology 144(2): 294-7, Feb 2013.

Wong G S, Lee J-S, Park Y-Y, Klein-Szanto A J, Waldron T J, Cukierman E, Herlyn M, Gimotty P, Nakagawa H, Rustgi A K: Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment. Oncogenesis 2: e59, 2013.

Natsuizaka Mitsuteru, Naganuma Seiji, Kagawa Shingo, Ohashi Shinya, Ahmadi Azal, Subramanian Harry, Chang Sanders, Nakagawa Kei J, Ji Xinjun, Liebhaber Stephen A, Klein-Szanto Andres J, Nakagawa Hiroshi: Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Mar 2012.

Kalabis Jiri, Wong Gabrielle S, Vega Maria E, Natsuizaka Mitsuteru, Robertson Erle S, Herlyn Meenhard, Nakagawa Hiroshi, Rustgi Anil K: Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture. Nature protocols 7(2): 235-46, Feb 2012.

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Last updated: 01/27/2015
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