Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Tumor Immunology: New Perspectives
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhao, X.
Right arrow Articles by Gu, J.-r.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhao, X.
Right arrow Articles by Gu, J.-r.
[Cancer Research 61, 7383-7387, October 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

A Novel Growth Suppressor Gene on Chromosome 17p13.3 with a High Frequency of Mutation in Human Hepatocellular Carcinoma1

Xintai Zhao, Jinjun Li, Yinghua He, Fei Lan, Lili Fu, Jianying Guo, Ruijiao Zhao, Yun Ye, Mei He, Wenming Chong, Jianguo Chen, Lisheng Zhang, Nanwu Yang, Binghua Xu, Mengchao Wu, Dafang Wan and Jian-ren Gu2

National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai 200032 [X. Z., J. L., Y. H., F. L., L. F., J. G., R. Z., D. W., J. G.]; Shanghai GeneCore Bio Technologies Co., Ltd., Shanghai 200233 [Y. Y., M. H.]; Shanghai Research Center of Life Sciences, Shanghai 200031 [X. Z.]; Eastern Hepatobiliary Surgery Hospital, Shanghai 200433 [W. C., M. W.]; Qidong Liver Cancer Institute, Qidong 226200 [J. C., B. X.]; and Guangxi Cancer Institute, Guangxi 530021 [L. Z., N. Y.], China


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89–93, 1991; H. Nagai et al., Oncogene, 14: 2927–2933, 1997; V. Boige et al., Cancer Res., 57: 1986–1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29–33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177–1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full-length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Previous studies have shown that there is a high frequency of LOH3 on chromosome 17p13.3 in hepatocellular carcinoma (1, 2, 3, 4, 5) . Our previous study (5) has demonstrated that chromosome 17p13.3 is the highest region of LOH in HCC by using combined genome-wide genotyping and comparative genomic hybridization. The minimum common deleted lesion was defined in a ~0.5-Mb region between D17S643 and D17S1574. Contig construction and sequencing covering this region of BAC and PAC clones have been accomplished. In particular, PAC clone P579 containing D17S926 with the highest score of LOH has been completely sequenced. The gene annotation demonstrates that 1 known gene (Gemin4; Ref. 6 ) and 13 novel putative genes were clustered within this 0.5-Mb region. Four of these novel genes have been identified by cDNA isolation using screening cDNA libraries with the insert of P579 clone as a probe.4 In this report, we describe the characterization of one of these novel genes, HCCS1.5 HCCS1 had a high frequency of mutations and a significantly lower level of expression in the HCC samples than in noncancerous liver tissues. HCCS1 remarkably reduced the efficiency of colony formation in vitro and inhibited tumor growth in vivo.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Lines and Tissues.
We obtained human hepatic cancer cell lines SMMC-7721 and NIH/3T3 from the Cell Bank of Shanghai Institute of Cell Biology, Academia Sinica. Qi Dong Liver Cancer Institute, Eastern Hepatobiliary Surgery Hospital (Shanghai, China), and Guangxi Cancer Institute (Guangxi, China) provided HCC samples and noncancerous liver tissues.

Construction of Contigs and Sequencing of Genomic Clones.
We screened human PAC and BAC libraries by using STS markers as shown at the top of Fig. 1Citation . The contig construction was based on the PCR reaction of seven individual STS markers with each PAC or BAC genomic clone. The STS-positive genomic clones were then sequenced by shotgun strategy on an ABI 377 automated sequencer. The sequences were assembled into contigs and analyzed using the InnerPeace and Underdog software packages (Axys Pharmaceutics, Inc.).



View larger version (12K):
[in this window]
[in a new window]
  		Fig. 1. Contig of genomic clones covering HCCS1 and the gene structure of HCCS1. Markers used in genomic clone screening and contig construction are shown at the top. The contig of genomic clones covering HCCS1 is shown in the middle. The exons of HCCS1 are shown at the bottom.

 
cDNA Isolation.
Normal human liver cDNA library (Clontech) was screened with recovered insert from P579 as probe in the presence of Cot-1 DNA in prehybridization and hybridization buffer.

RT-PCR and Mutation Screening.
We amplified two overlapping fragments covering HCCS1 by using RT-PCR in HCC and matched noncancerous tissues (for the 5' half fragment of HCCS1, we used external primer sequences 5'-CGGGTGGCGGAATGATG-3' and 5'-TTGGTAGATGGGGGTGGAG-3' and internal primer sequences 5'-GGTGGCGGAATGATGGAG-3' and 5'-GCCGGAGAAGCGTTTTG-3'; for the 3' half fragment of HCCS1, we used external primer sequences 5'-TGCATGGCTGAGAGGATTG-3' and 5'-GGAAGCCAGGTTGT-3' and internal primer sequences 5'-TGCGTACCAGAGCGAAGGA-3' and 5'-ATGGGGACGTTCTGCTTGATGTGCAG-3'). PCR conditions were 95°C for 1 min, 60°C for 1 min, and 72°C for 2 min for 35 cycles. Mutations were detected by sequencing of PCR products.

Immunohistochemistry Assays.
HCC and noncancerous tissues were fixed in 10% formalin in 10 mM PBS (pH 7.2). The paraffin sections (4 µm) were mounted onto poly-L-lysine-coated glass slides and dried overnight at 50°C. Mouse anti-HCCS1 polyclonal antibody (prepared by DNA immunization in our laboratory) was diluted 1:200 in PBS containing 5% normal goat serum and incubated for 30 min at room temperature. After being rinsed in PBS three times for 5 min each, the sections were covered with DAKO EnVision + System, horseradish peroxidase (3,3'-diaminobenzidine), Mouse Ready-to-use Detection System (DAKO, Carpinteria, CA) for 30 min at room temperature. The sections were developed in substrate-chromogen solution (3,3'-diaminobenzidine), counterstained with Mayer’s hematoxylin, and mounted.

Cell Growth Assays.
We made the construct of the HCCS1 cDNA in the pcDNA3.1/V5-His vector (Invitrogen), and transfected it into SMMC-7721 human hepatic carcinoma cells (3 x 104) by using LipofectAMINE (Life Technologies, Inc.) in triplicate according to the manufacturer’s protocols. Empty vector was transfected with the same protocol as a control. After G418 (800 mg/ml) selection for 14 days, the colonies were stained and counted.

Tumor Growth in Nude Mice.
Cells harboring pEGFP-N1-HCCS1 or empty vector were collected and resuspended in PBS. Cells (200 µl; 3.7 x 106) were inoculated s.c. into the right flank of 5- to 6-week-old male BALB/c nude mice. Experimental and control groups had six mice each. After 5 weeks, mice were sacrificed, and the tumors were dissected and weighed.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Isolation and Characterization of a Novel Gene, HCCS1.
A contig was constructed by screening human PAC and BAC libraries using STS markers. It consisted of PAC clone P579 and BAC clones 1127L24, 2189L10, 411G7, and 1029F21 (see the middle of Fig. 1Citation ). A cDNA clone designated HCCS1 was obtained by using cDNA library screening. Its full length was 2075 bp, containing the entire coding sequence of 671 amino acids. The exon/intron structure of the gene was defined by comparing the cDNA sequences with its genomic sequences. HCCS1 had 18 exons, spanning a genomic sequence of about 200 kb (Fig. 1)Citation . The amino acid sequence analysis showed that HCCS1 shared 35%, 23%, and 22% identity with the hypothetical Mr 90,400 protein T05G5.8 in Caenorhabditis elegans, the hypothetical Mr 87,000 protein C3A12.15 in Schizosaccharomyces pombe, and the hypothetical Mr 95,400 protein in the MAD2-RNR2 intergenic region of Saccharomyces cerevisiae, respectively (Fig. 2)Citation . To identify the subcellular localization of the HCCS1 protein product, we constructed the HCCS1-GFP fused gene in pEGFP-N1 vector and transfected the HCCS1-GFP plasmid DNA into both human HCC cell line SMMC-7721 and mouse NIH/3T3 fibroblasts. The fluorescence image of GFP revealed the punctate distribution of the HCCS1 gene product in the cytoplasm of both types of cells (Fig. 3ACitation ; SMMC-7721 data not shown). Overlay of the fluorescence image of GFP and an anti-mitochondria monoclonal antibody, 113-1 (NeoMarkers, Fremont, CA), strongly suggested that HCCS1 fusion protein was located in mitochondria.



View larger version (71K):
[in this window]
[in a new window]
  		Fig. 2. Alignment of HCCS1 protein with putative C. elegans protein T05G5.8, S. pombe protein C3A12.15, and S. cerevisiae hypothetical Mr 95,400 protein in the MAD2-RNR2 intergenic region, respectively. HCCS1_Human, human HCCS1 protein; YNP8_CAEEL, C. elegans protein T05G5.8; YDLF_SCHPO, S. pombe protein C3A12.15; YJC9_YEAST, S. cerevisiae hypothetical Mr 95,400 protein in the MAD2-RNR2 intergenic region. The amino acid sequence of HCCS1 was compared with that of three other proteins using Boxshade software. The black boxes indicate the identical amino acids, and the gray boxes indicate the positive amino acids in these proteins.

 


View larger version (63K):
[in this window]
[in a new window]
  		Fig. 3. A, locations of the products of HCCS1 in cells. a, fluorescence of NIH/3T3 cells transfected with pEGFP-HCCS1. b, immunofluorescence staining with anti-mitochondria antibody of cells shown in a. c, overlay image of a and b indicates the localization of HCCS1 at mitochondria. B, mutation detection of HCCS1 in HCC samples. a, an adenosine deletion in HCC sample T8 was present, as compared with its paired noncancerous tissue, N8. b, a nucleotide acid fragment deletion was identified in HCC sample T12. Compared with its matched noncancerous tissues, T12 displayed a different sequence after TTCTTCTAG. c, there was also a nucleotide acid fragment deletion in HCC sample T7. Possibly because of the presence of noncancerous tissues in T7, two patterns of sequencing after TGGGCTC are displayed. C, immunoperoxidase staining of formalin-fixed, paraffin-embedded section of human HCC and surrounding noncancerous tissues. The antibody used was mouse polyclonal anti-HCCS1, which was prepared in this laboratory. HC, hepatocytes.

 
Detection of the Alterations in HCCS1.
To screen the genetic alteration in HCC, we isolated mRNA from samples of HCC and paired noncancerous liver tissues from the same patients. By direct sequencing of the RT-PCR products of these RNA samples, a high frequency of genetic aberration was observed. Eleven cases were screened for alteration over the whole cDNA region, and 26 cases were analyzed for alteration over only half of the cDNA region. As illustrated in Fig. 3BCitation and Table 1Citation , four types of alteration were identified. Type 1 is a single nucleotide deletion resulting in frameshift mutation (sample T8). Type 2 is a microdeletion lesion causing frameshift mutation (samples T7, T9, T10, T11, and T12). Type 3 is a missense point mutation from C to T resulting in an alteration of amino acid Arg to Cys (sample T6). Type 4 is a deletion of exon 5 (29 amino acids; samples T2, T3, T4, T5, and T6), implicating some aberrant splicing events of HCCS1 in HCC.


View this table:
[in this window]
[in a new window]
  		Table 1 Mutations and allele loss of HCCS1 in HCC

 
In these cases, we proved that one allele of HCCS1 had a high percentage of mutation in HCC samples. We must ask whether or not some genetic alteration occurred in the other allele in these HCC cells. Our results indicated that LOH at D17S926 was present in six of seven informative HCC samples in which one allele had genetic alteration (Table 1)Citation . These results imply that genetic lesions of HCCS1 were present in both alleles in these HCC tissues.

Detection of the Expression of HCCS1.
Because the mRNA transcription level was extremely low, we decided to detect the protein instead of mRNA when addressing the status of expression of the HCCS1 gene product in HCC and noncancerous liver tissues. Polyclonal antibody was prepared, and immunohistochemical analysis of the protein expression was carried out. Thirty-five paired HCC samples and their noncancerous liver tissues were examined. As demonstrated in Fig. 3CCitation and Table 2Citation , the expression level in cancer cells was significantly lower than that in noncancerous liver cells in 33 of 35 cases. No expression of HCCS1 in HCC was observed in 14 cases. In contrast, HCCS1 was expressed in all of the noncancerous liver tissues we have examined thus far. These results provided further evidence of the profound genetic alteration of HCCS1 in HCC.


View this table:
[in this window]
[in a new window]
  		Table 2 Immunohistochemical detection of anti-HCCS1 antibody in HCC

 
Colony Formation Assay and Tumor Growth in Nude Mice.
To further explore the possible biological role of HCCS1, we transfected the HCCS1 cDNA constructed in mammalian expression vector pcDNA3.1/V5-His into human HCC SMMC-7721 cells. Colony formation assay indicated that the number of G418-resistant colonies in HCCS1-transfected cells was reduced to approximately one-sixth of the vector control (Fig. 4)Citation . The pEGFP-N1-HCCS1-transfected cells (3.7 x 106) were inoculated s.c. into nude mice, with the vector-transfected cells as a control. Results indicated that tumorigenicity was significantly reduced in HCCS1-transfected cells compared with the control (Fig. 5)Citation . These data implied that HCCS1 had a biological role to suppress the growth potential of cancer cells.



View larger version (37K):
[in this window]
[in a new window]
  		Fig. 4. Effect of HCCS1 expression on cell growth. a, colony formation of SMMC-7721 cells transfected with vector pcDNA3.1/V5-His. b, colony formation of SMMC-7721 cells transfected with vector containing HCCS1 cDNA. c, diagram of colony formation assay in triplicate. *, P < 0.01 in comparison with the vector group.

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 5. Tumor formation in nude mice. SMMC-7721 cells transfected with vector pEGFP-N1 and vector containing HCCS1 cDNA were inoculated into BALB/c nude mice. Tumor weight was measured 5 weeks after sacrifice of animals. *, P < 0.01 in comparison with GFP vector control group.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In detecting the alterations of HCCS1 cDNA in HCC, we screened the entire cDNA region in 11 cases and only half of the cDNA region in 26 cases. We found that genetic alterations were present in 13 of 37 HCC samples. If the 26 cases could be screened over their entire cDNA regions, the genetic alterations would be much more than this proportion (13 of 37). Because we used the direct sequencing technique instead of sequencing selected clones from RT-PCR products, it seems unlikely that these observations could be partially attributed to the nucleotide error during PCR amplification. Moreover, because such alterations have been seen exclusively in HCC samples and not in noncancerous liver tissue obtained from the same patients by the same methods, it was strongly indicated that these genetic lesions were instinctively related to hepatic carcinogenesis or progression of HCC. The PCR amplification and mutation detection of the HCCS1 genomic sequence of HCC samples and noncancerous liver tissues were in progress.

HCC tissues, in most cases, contained normal or noncancerous cell constituents such as stromal cells, vascular endothelial and smooth muscle cells, infiltrated lymphocytes, and others, and these cells could seriously interfere with the results, particularly by direct sequencing for mutation analysis. In the sequencing result of HCCS1 cDNA in case 7, there were two patterns of peaks after TGGGCTC in the sequencing map of the cancerous liver tissue (Fig. 3B)Citation . These data may be due to contamination by noncancerous cells in the HCC tissue of case 7.

We originally attempted to detect the presence of LOH in these HCC samples using conventional restriction enzyme cleavage and Southern blotting analysis. Unfortunately, no appropriate restriction enzymes were found to demonstrate a reasonable percentage of polymorphism, indicating the presence of heterozygosity. Therefore, we decided to use STS D17S926 as the marker for LOH analysis by PCR amplification. Because D17S926 was located at a site very close to the 5'-untranslated region of HCCS1, the LOH status could implicate the presence of deletion of HCCS1.

The results of Tables 1Citation and 2Citation were derived from samples of different HCC cases. Because of the small size of the surgical specimens obtained from the hospital, we could not perform both the mutation analysis and immunohistochemical study using the same samples. We will extend these surveys by using both assays with samples from the same HCC cases in the future.

As a tumor suppressor gene candidate, the gene of interest should meet the requirements of three principal criteria: (a) the genetic alteration of both alleles; (b) deletion of one allele or mutation of the other allele; or (c) both alleles deleted or mutated in cancer, reduced expression in cancer, and the potential to suppress the growth of cancer cells (7) . In our case, HCCS1 had a high frequency of mutation in one allele and loss of the other allele in six of seven HCC samples, whereas no such alteration occurred in the noncancerous liver tissues, thus strongly implicating a profound genetic aberration present in cancer cells. Second, the protein expression level was reduced in cancer cells, whereas protein expression was present in all of the noncancerous liver samples. Third, after transfection into human hepatoma cells, HCCS1 could significantly reduce the efficiency of colony formation of cancer cells in vitro and suppress their tumorigenicity in nude mice in vivo. Therefore, these data provided evidence for to support that HCCS1 could be a candidate tumor suppressor gene for HCC. Although HCCS1 shared a partial identity with putative genes in C. elegans and yeast, the biological function of this gene in humans, including its role in pathways of signal transduction, cell cycle, or DNA replication, remains to be further elucidated. These studies are now in progress.


   ACKNOWLEDGMENTS
 
We thank Ming Yao (Department of Experimental Pathology, Shanghai Cancer Institute, Shanghai, China) for help with animal experiments.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by grants from the Chinese High Tech Program (863-Z19-12-01-01), National Key Grant of Basic Research (G1998051004), and National Natural Science Foundation (39780023 and 39870426). Back

2 To whom requests for reprints should addressed, at National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Ln2200/25 Xie Tu Road, Shanghai 200032, China. Phone: 021-64177401; Fax: 86-21-64177401; E-mail: nlorg{at}public.sta.net.cn Back

3 The abbreviations used are: LOH, loss of heterozygosity; HCC, hepatocellular carcinoma; HCCS1, HCC suppressor 1; BAC, bacteria artificial chromosome; PAC, P1 artificial chromosome; STS, sequence-tagged sites; RT-PCR, reverse transcription-PCR; GFP, green fluorescent protein. Back

4 X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human hepatocellular carcinoma with densely clustered genes identified, submitted for publication. Back

5 HCCS1, GenBank accession number AF246287. Back

Received 6/25/01. Accepted 8/27/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Fujimori M., Tokino T., Hino O., Kitagawa T., Imamura T., Okamoto E., Mitsunobu M., Ishikawa T., Nakagama H., Harada H. Allelotype study of primary hepatocellular carcinoma. Cancer Res., 51: 89-93, 1991.[Abstract/Free Full Text]
  2. Nagai H., Pineau P., Tiollais P., Buendia M. A., Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene, 14: 2927-2933, 1997.[Medline]
  3. Boige V., Laurent-Puig P., Fouchet P., Flejou J. F., Monges G., Bedossa P., Bioulac-Sage P., Capron F., Schmitz A., Olschwang S., Thomas G. Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res., 57: 1986-1990, 1997.[Abstract/Free Full Text]
  4. Piao Z., Park C., Park J. H., Kim H. Allelotype analysis of hepatocellular carcinoma. Int. J. Cancer, 75: 29-33, 1998.[Medline]
  5. Charroux B., Shevchenko A., Mann M., Dreyfuss G. Gemin4, a novel component of the SMN complex that is found in both gems and nucleoli. J. Cell Biol., 148: 1177-1186, 2000.[Abstract/Free Full Text]
  6. Wang G., Zhao Y., Liu X., Wang L., Wu C., Zhang W., Liu W., Zhang P., Cong W., Zhu Y., Zhang L., Chen S., Wan D., Zhao X., Huang W., Gu J. Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma. Genes Chromosomes Cancer, 31: 221-227, 2001.[Medline]
  7. Haber D., Harlow E. Tumor-suppressor genes: evolving definitions in the genomic age. Nat. Genet., 16: 320-322, 1997.[Medline]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
C. Klebig, S. Seitz, W. Arnold, N. Deutschmann, M. Pacyna-Gengelbach, S. Scherneck, and I. Petersen
Characterization of {gamma}-Aminobutyric Acid Type A Receptor-Associated Protein, a Novel Tumor Suppressor, Showing Reduced Expression in Breast Cancer
Cancer Res., January 15, 2005; 65(2): 394 - 400.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. Wan, Y. Gong, W. Qin, P. Zhang, J. Li, L. Wei, X. Zhou, H. Li, X. Qiu, F. Zhong, et al.
Large-scale cDNA transfection screening for genes related to cancer development and progression
PNAS, November 2, 2004; 101(44): 15724 - 15729.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y.-S. Jou, C.-S. Lee, Y.-H. Chang, C.-F. Hsiao, C.-F. Chen, C.-C. Chao, L. S.H. Wu, S.-H. Yeh, D.-S. Chen, and P.-J. Chen
Clustering of Minimal Deleted Regions Reveals Distinct Genetic Pathways of Human Hepatocellular Carcinoma
Cancer Res., May 1, 2004; 64(9): 3030 - 3036.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
Y. Di, J. Li, Y. Zhang, X. He, H. Lu, D. Xu, J. Ling, K. Huo, D. Wan, Y.-Y. Li, et al.
HCC-Associated Protein HCAP1, a Variant of GEMIN4, Interacts with Zinc-Finger Proteins
J. Biochem., June 1, 2003; 133(6): 713 - 718.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Farrand, B. Delahunt, X.-l. Wang, B. McIver, I. D. Hay, J. R. Goellner, N. L. Eberhardt, and S. K. G. Grebe
High Resolution Loss of Heterozygosity Mapping of 17p13 in Thyroid Cancer: Hurthle Cell Carcinomas Exhibit a Small 411-Kilobase Common Region of Allelic Imbalance, Probably Containing a Novel Tumor Suppressor Gene
J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4715 - 4721.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhao, X.
Right arrow Articles by Gu, J.-r.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhao, X.
Right arrow Articles by Gu, J.-r.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online