Abstract
Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited. Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome. Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice. Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy.
| Original language | English |
|---|---|
| Pages (from-to) | 2518-2528 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 16 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2010 May 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. / Satow, Reiko; Shitashige, Miki; Kanai, Yae; Takeshita, Fumitaka; Ojima, Hidenori; Jigami, Takafumi; Honda, Kazufumi; Kosuge, Tomoo; Ochiya, Takahiro; Hirohashi, Setsuo; Yamada, Tesshi.
In: Clinical Cancer Research, Vol. 16, No. 9, 01.05.2010, p. 2518-2528.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Combined functional genome survey of therapeutic targets for hepatocellular carcinoma
AU - Satow, Reiko
AU - Shitashige, Miki
AU - Kanai, Yae
AU - Takeshita, Fumitaka
AU - Ojima, Hidenori
AU - Jigami, Takafumi
AU - Honda, Kazufumi
AU - Kosuge, Tomoo
AU - Ochiya, Takahiro
AU - Hirohashi, Setsuo
AU - Yamada, Tesshi
PY - 2010/5/1
Y1 - 2010/5/1
N2 - Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited. Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome. Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice. Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy.
AB - Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited. Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome. Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice. Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy.
UR - http://www.scopus.com/inward/record.url?scp=77951721529&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951721529&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-09-2214
DO - 10.1158/1078-0432.CCR-09-2214
M3 - Article
C2 - 20388846
AN - SCOPUS:77951721529
VL - 16
SP - 2518
EP - 2528
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 9
ER -