TY - JOUR
T1 - Activation of the hedgehog pathway in human hepatocellular carcinomas
AU - Huang, Shuhong
AU - He, Jing
AU - Zhang, Xiaoli
AU - Bian, Yuehong
AU - Yang, Ling
AU - Xie, Guorui
AU - Zhang, Kefei
AU - Tang, Wendell
AU - Stelter, Arwen A.
AU - Wang, Qian
AU - Zhang, Hongwei
AU - Xie, Jingwu
N1 - Funding Information:
This research was supported by grants from the NIH (R01-CA94160), Department of Defense (DOD-PC030429), The NIEHS (ES06676) and National Science Foundation of China (30228031). We thank Drs Chiaho Shih, Tien Ko and Kui Li for providing cell lines for this study and Huiping Guo for technical support in real-time PCR analysis and Karen Martin for help with the manuscript. Funding to pay the Open Access publication charges for this article was provided by National Cancer Institute (R01-CA94160).
PY - 2006/7
Y1 - 2006/7
N2 - Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here, we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% of HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.
AB - Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here, we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% of HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.
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U2 - 10.1093/carcin/bgi378
DO - 10.1093/carcin/bgi378
M3 - Article
C2 - 16501253
AN - SCOPUS:33745634379
SN - 0143-3334
VL - 27
SP - 1334
EP - 1340
JO - Carcinogenesis
JF - Carcinogenesis
IS - 7
ER -