Gastric cancer (GC) patients with hedgehog pathway activation: PTCH1 and GLI2 as independent prognostic factors.
Activation of sonic hedgehog (HH) signaling pathway has been implicated in aggressiveness and progression of gastrointestinal tumors. We planned this study to identify a subgroup of gastric cancer (GC) patients with HH activation and to assess the effect of a HH inhibitor in HH activated GC in vitro. We surveyed HH pathway activation among 512 GC specimens for protein expression of various target genes involved in HH pathway: Indian hedgehog (IHH), patched-1 (PTCH1), smoothened (SMO), GLI2, and FOXA2. We analyzed the correlations between the expression of these factors and clinicopathological features and prognosis. In vitro, ten gastric cancer cell lines were screened for anti-tumoractivity of an HH inhibitor, GDC-0449. Among the 512 specimens, 105 (20.0 %), 83 (16.3 %), 130 (25.5 %), 61 (12.0 %), and 206 (40.8 %) were positive for IHH, PTCH1, GLI2, SMO, and FOXA2 expression, respectively. PTCH1 expression was more frequently observed in well- or moderately differentiated tubular adenocarcinoma, intestinal type and low stage GC. GLI2 was correlated with lymphovascular invasion and intestinal type GC. A high-stage and negative PTCH1 staining were identified as unfavorable independent risk factors for overall survival in multivariate analysis (P < 0.001, 0.045, respectively). For IHH, SMO, and FOXA2, there was no statistical difference in clinicopathologic variables and survival outcome. An HH inhibitor had particularly potent effects on GC cell lines with SMO mRNA overexpression. This is the largest report to analyze the hedgehog pathway in GC. PTCH1 overexpression was an independent prognostic factor for survival and SMO overexpression which was found in 12.0 % of GC patients might be the potential predictive marker of HH inhibitor.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul, 135-710, South Korea.
Su Jin
SJ
Lee
In-Gu
IG
Do
Jeeyun
J
Lee
Kyoung-Mee
KM
Kim
Jiryeon
J
Jang
Insuk
I
Sohn
Won Ki
WK
Kang
D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000075746:Zinc Finger Protein Gli2
C496502:FOXA2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; D051542:Hepatocyte Nuclear Factor 3-beta