Functional evidence of decreased tumorigenicity associated with monochromosome transfer of chromosome 14 in esophageal cancer and the mapping of tumor‐suppressive regions to 14q32
Josephine Mun Yee KoWing Lung YauPui Ling ChanHong Lok LungLichun YangPaulisally Hau Yi LoJohnny TangGopesh SrivastavaEric J. StanbridgeMaria Li Lung
26
Citation
35
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Despite the abundant evidence of high allelic loss of chromosome arm 14q in human cancers, tumor‐suppressor genes mapped to this chromosome have yet to be identified. To narrow the search for candidate genes, we performed monochromosome transfer of chromosome 14 into an esophageal carcinoma cell line, SLMT‐1 S1. Statistically significant suppression of the tumorigenic potential of microcell hybrids containing the transferred chromosome 14 provided functional evidence that tumor‐suppressive regions of chromosome 14 are essential for esophageal cancer. Tumor segregants emerging in nude mice during the tumorigenicity assay were analyzed by detailed PCR‐microsatellite typing to identify critical nonrandomly eliminated regions (CRs). A 680‐kb CR mapped to 14q32.13 and an ∼2.2‐Mb CR mapped to 14q32.33 were delineated. Dual‐color BAC FISH analysis of microcell hybrids and tumor segregants verified the selective loss of the 14q32.13 region. In contrast, similar transfers of an intact chromosome 11 into SLMT‐1 S1 did not significantly suppress tumor formation. These functional complementation studies showing the correlation of tumorigenic potential with critical regions of chromosome 14 validated the importance of the 14q32 region in tumor suppression in esophageal cancer. The present study also paved the path for further identification of novel tumor‐suppressor genes that are relevant to the molecular pathogenesis of esophageal cancer. © 2005 Wiley‐Liss, Inc.Keywords:
Tumor progression
Cite
Citations (41)
Retinoblastoma
Cre recombinase
Retinoblastoma protein
Cite
Citations (138)
Tumor progression
Cite
Citations (32)
Since the cloning of the first tumor suppressor gene 22 years ago, we have learned a great deal about the role of tumor suppressor pathways in human cancer. One general principle is that some tumor suppressor pathways (e.g., p53 and Rb pathways) are inactivated in virtually every human cancer. Thus, one might predict that inheritance of a genetic lesion in such a pathway would cause the rapid onset of tumors originating from different tissues. However, this is not true for the Rb pathway. Children with a defective copy of the RB1 gene show increased susceptibility to retinoblastoma but not to other developmental tumors of the nervous system. Moreover, after RB1 inactivation, certain retinal cell types are more susceptible to tumorigenesis than others. Our recent studies on the role of the Rb family of genes in retinal development and retinoblastoma have led to a new hypothesis that explains this paradox. We propose that cells that require the Rb family for their cell fate specification and/or differentiation are less susceptible to tumorigenesis than those that do not require the Rb family for these processes. If correct, this hypothesis would allow us to predict which cell types in the developing nervous system are susceptible to tumorigenesis after inactivation of the Rb family and may establish a general principle of tissue- and cell type-specific susceptibility to tumorigenesis. In this perspective, we discuss our recent findings that have changed our views on tumor initiation and progression following Rb family inactivation.
Retinoblastoma
Retinoblastoma protein
Cite
Citations (14)
Southern blot
Cite
Citations (2)
Pavelic ZP, Gluckman JL. The role of p53 tumor suppressor gene in human head and neck tumorigenesis.Molecular genetics has led to new insights into diagnosis and treatment of human cancer. The alterations of tumor suppressor genes like retinoblastoma, p53 and others may have an important role in tumorigenesis. Mutations of p53 have been found in a majority of human malignancies including head and neck cancer. The distribution of p53 is different between types of tumors. suggesting environmental exposure as a cause active factor. The p53 mutation in head and neck tumors is an early event and appears to have a hot spot region at codons 238-248. While mutation and loss of heterozygosity at p53 are important in the genesis of head and neck cancer, other mechanisms such as binding of viral and cellular proteins to p53 are also likely to play a role.
Retinoblastoma
Cite
Citations (14)
Loss of tumor suppressor function clearly contributes to the multistep process of tumorigenesis, as evidenced by the frequent mutation of these genes in human cancer (Marshall 1991; Hinds and Weinberg 1994). Investigation into the mechanisms by which inactivation of tumor suppressors contributes to tumorigenesis is therefore central to understanding cancer. The p53 gene is presently the most frequently mutated tumor suppressor gene in human cancers. Moreover, tumors of many different cell types harbor p53 mutations. Exactly how the disruption of p53 contributes to the genesis of these tumors and whether the contribution is the same or different in cancers of different cell types is not understood.
Cite
Citations (22)
Recent advances in molecular genetics have made it possible to understand the molecular mechanisms of human cancer progression. The results indicate that clinically evident tumor cells already carry multiple genetic alterations and further accumulation of genetic alteration occurs during tumor progression. It is widely accepted that tumor suppressor genes play a central role in the genesis and progression of human cancers, as frequent alterations of tumor suppressor genes have been found in a variety of human cancers. Molecular analyses of various stages of human cancers, from precancerous lesions to advanced or metastatic tumors, indicate that sequential accumulation of genetic alterations correlates with more malignant phenotypes of tumor cells. Furthermore, biological studies of tumor suppressor genes have revealed that a single gene defect is not sufficient for the cells to gain growth advantage and start clonal expansion in vivo. These results are consistent with the concept of human multistage carcinogenesis, indicated by experimental animal models and epidemiological studies. Although it is supposed that there are more than 20 tumor suppressor genes in the human genome, only a few tumor suppressor genes have been identified to date. Thus, further studies should focus on the identification and characterization of novel tumor suppressor genes, and molecular analysis of those genes in human cancer would be of great help in clarifying the multiple steps in the process of human carcinogenesis.—Yokota, J., Sugimura, T. Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes. FASEB J. 7: 920-925; 1993.
Tumor progression
Cite
Citations (117)
TIP30/CC3 was first identified and characterized as a “candidate” tumor-suppressor gene in 1997. Recently, the TIP30 tumor-suppressor status has been fully established since several studies have described that TIP30 protein expression is frequently downregulated in diverse types of human tumors, and the downregulation is often associated with tumor progression. TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. Moreover, TIP30 −/− mice spontaneously develop hepatocellular carcinoma and other tumors at a higher incidence than that of wild-type mice. In this review, we provide an overview of current knowledge concerning the role of TIP30 in tumor development and progression. To our knowledge, this is the first review about the role of novel tumor-suppressor gene TIP30 in tumor development and progression.
Tumor progression
Cite
Citations (11)
Oral cancer provides a unique model system for the study of the multistep nature of cancer. The influence of viruses and tumor suppressor gene inactivation are of major importance in this HPVs are small oncogenic viruses which are implicated in epithelial carcinogenesis, and p53 is a tumor suppressor gene with a central role in the prevention of genomic injury. p53 protein detection is usually a synonym for p53 mutation. This study was designed to determine the immunohistochemical detection of p53 protein in HPV positive oral squamous cell carcinomas and hyperplastic oral lesions. p53 was detected in 50% (5/10) of HPV positive hyperplastic oral lesions and in 59.41% (22/39) of oral squamous cell carcinomas. These results indicate that HPV and p53 protein alterations frequently coexist in the lesions of our study and suggest that p53 mutation may be an early genetic event in oral carcinogenesis. Moreover, this coexistance reveals that other environmental carcinogens have a more prominent role in oral carcinogenesis, one that overrides the action of HPV.
P53 protein
Cite
Citations (8)