Int J Biochem Mol Biol 2012;3(1):46-57
Original Article
Hedgehog signaling activation in the development of squamous cell carcinoma and
adenocarcinoma of esophagus
Ling Yang, Li-Shu Wang, Xiaoxin (Luke) Chen, Zoran Gatalica, Suimin Qiu, Zhihua Liu, Gary Stoner, Hongwei Zhang, Heidi Weiss, Jingwu Xie
Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis, Indiana 46202;
Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, P.R. China; Clinical Research Center of
Affiliated Hospital, Inner Mongolian Medical College, Hohhot, Inner Mongolia, China; Department of Medicine, Medical College of Wisconsin,
Milwaukee, WI 53226; Cancer Research Program, Julius L. Chambers Biomedical/ Biotechnology Research Institute, North Carolina Central
University, 700 George Street, Durham, NC 27707; Department of Pathology, Creighton University Medical Center, Omaha, NE 68131, USA;
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1048, USA; National Laboratory of Molecular Oncology,
Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China; University of Kentucky
Markey Cancer Center, Lexington, KY 40536, USA.
Received January 10, 2012; accepted January 27, 2012; Epub February 10, 2012; Published March 30, 2012
Abstract: Hedgehog (Hh) signaling is frequently activated in human cancer, including esophageal cancer. Most esophageal cancers are
diagnosed in the advanced stages, therefore, identifying the very alterations that drive esophageal carcinogenesis may help designing novel
strategies to diagnose and treat the disease. Analysis of Hh signaling in precancerous lesions is a critical first step in determining the
significance of this pathway for carcinogenesis. Here we report our data on Hh target gene expression in 174 human esophageal specimens
[28 esophageal adenocarcinomas (EAC), 19 Barrett’s esophagus, 103 cases of esophageal squamous cell carcinoma (ESCC), and 24 of
squamous dysplastic lesions], and in two rat models of esophageal cancer. We found that 96% of human EAC express Hh target genes. We
showed that PTCH1 expression is the most reliable biomarker. In contrast to EAC, only 38% of ESCC express Hh target genes. We found
activation of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees (21% and 58% respectively). Expression of Hh
target genes is frequently detected in severe squamous dysplasia/ carcinoma in situ (p=0.04) and Barrett’s esophagus (p=0.01). Unlike EAC,
sonic hedgehog (Shh) expression was rare in ESCCs. Consistent with the human specimen data, we found a high percentage of Hh signaling
activation in precancerous lesions in rat models. These data indicate that Hh signaling activation is an early molecular event in the
development of esophageal cancer, particularly EAC. (IJBMB1201004).
Keywords: Esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), hedgehog (Hh), patched-1 (PTCH1 for
humans and Ptch1 for animals), Gli2, sFRP-1, human homologue of hedgehog-interaction protein (HHIP), rat model, Barrett’s esophagus (BE)
Address all correspondence to:
Dr. Jingwu Xie, Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis,
Indiana 46202 E-mail: jinxie@iupui.edu.
Dr. Ling Yang, Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis,
Indiana 46202; Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, P.R. China; Clinical Research
Center of Affiliated Hospital, Inner Mongolian Medical College, Hohhot, Inner Mongolia, China E-mail: lingorangefan@gmail.com
Original Article
Hedgehog signaling activation in the development of squamous cell carcinoma and
adenocarcinoma of esophagus
Ling Yang, Li-Shu Wang, Xiaoxin (Luke) Chen, Zoran Gatalica, Suimin Qiu, Zhihua Liu, Gary Stoner, Hongwei Zhang, Heidi Weiss, Jingwu Xie
Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis, Indiana 46202;
Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, P.R. China; Clinical Research Center of
Affiliated Hospital, Inner Mongolian Medical College, Hohhot, Inner Mongolia, China; Department of Medicine, Medical College of Wisconsin,
Milwaukee, WI 53226; Cancer Research Program, Julius L. Chambers Biomedical/ Biotechnology Research Institute, North Carolina Central
University, 700 George Street, Durham, NC 27707; Department of Pathology, Creighton University Medical Center, Omaha, NE 68131, USA;
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1048, USA; National Laboratory of Molecular Oncology,
Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China; University of Kentucky
Markey Cancer Center, Lexington, KY 40536, USA.
Received January 10, 2012; accepted January 27, 2012; Epub February 10, 2012; Published March 30, 2012
Abstract: Hedgehog (Hh) signaling is frequently activated in human cancer, including esophageal cancer. Most esophageal cancers are
diagnosed in the advanced stages, therefore, identifying the very alterations that drive esophageal carcinogenesis may help designing novel
strategies to diagnose and treat the disease. Analysis of Hh signaling in precancerous lesions is a critical first step in determining the
significance of this pathway for carcinogenesis. Here we report our data on Hh target gene expression in 174 human esophageal specimens
[28 esophageal adenocarcinomas (EAC), 19 Barrett’s esophagus, 103 cases of esophageal squamous cell carcinoma (ESCC), and 24 of
squamous dysplastic lesions], and in two rat models of esophageal cancer. We found that 96% of human EAC express Hh target genes. We
showed that PTCH1 expression is the most reliable biomarker. In contrast to EAC, only 38% of ESCC express Hh target genes. We found
activation of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees (21% and 58% respectively). Expression of Hh
target genes is frequently detected in severe squamous dysplasia/ carcinoma in situ (p=0.04) and Barrett’s esophagus (p=0.01). Unlike EAC,
sonic hedgehog (Shh) expression was rare in ESCCs. Consistent with the human specimen data, we found a high percentage of Hh signaling
activation in precancerous lesions in rat models. These data indicate that Hh signaling activation is an early molecular event in the
development of esophageal cancer, particularly EAC. (IJBMB1201004).
Keywords: Esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), hedgehog (Hh), patched-1 (PTCH1 for
humans and Ptch1 for animals), Gli2, sFRP-1, human homologue of hedgehog-interaction protein (HHIP), rat model, Barrett’s esophagus (BE)
Address all correspondence to:
Dr. Jingwu Xie, Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis,
Indiana 46202 E-mail: jinxie@iupui.edu.
Dr. Ling Yang, Wells Center for Pediatric Research, Department of Pediatrics and the Simon Cancer Center, Indiana University, Indianapolis,
Indiana 46202; Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, P.R. China; Clinical Research
Center of Affiliated Hospital, Inner Mongolian Medical College, Hohhot, Inner Mongolia, China E-mail: lingorangefan@gmail.com
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