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Role of viral-derived genes in lung cancer

Institution: Sidney Kimmel Cancer Center
Investigator(s): Francoise Mathieu-Daude, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6KT-0272 Award: $375,800
Subject Area: Cancer
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
The genetic material of every human being contains the remnants of 50,000 or more fragments of viral genetic information that integrated into the genes of our ancestors. Some of these ancient virus fragments can move around within the human genetic material and disturb the normal function of various tissues and organs. Activated by the stress caused by smoking, these viral-derived genes could contribute to uncontrolled cell proliferation in lung tissues, resulting in cancer. This phenomenon could also contribute to an increase in the severity of existing cancers. Studying the movement of these viral-derived genes, as well as their role and significance in the triggering and evolution of pulmonary carcinogenesis, could lead to the development of new treatments. It may be possible to reduce the progression of lung cancer by inhibiting the movement and the function of these viral-derived genes

Final Report
The goal of this project was to investigate the involvement of viral derived sequences in lung carcinogenesis. The genome of every human being contains the remnants of viral genetic information that integrated into the genome of our ancestors. Although most of these ancient virus fragments, called human endogenous retroviruses (HERVs), are defective and inactive, some of them are active and can move around in the human genome. Activity of these HERVs has been reported in various normal and diseased tissues and in many cancer cell lines but their implication in pathophysiological process remains to be proved and elucidated. The stress caused by cigarette smoke components can activate the movement of these viral-derived genes that might contribute to changes in human genes or in their expression and perturb the normal function of cells and tissues. If such changes occur in genes responsible for the control of cell cycle and growth they will be particularly harmful by disrupting the normal growth control mechanisms. Thus, exposure to cigarette smoke may contribute, through the activation of HERV sequences, to uncontrolled cell proliferation in lung tissues, resulting in cancer.

We investigated whether there was an increase in viral-derived gene activity in lung cancer cell lines and in lung cancer tissues, and whether the movement of some of these genes was involved in the development of the disease in a subset of lung cancers. HERV activity was measured through a viral enzyme, the reverse transcriptase, and through viral expression profiles. Our findings indicated a retroviral reverse transcriptase activity in all the cell lines and lung tissues. A subset of lung cancer cell lines showed an increase in the retroviral activity corresponding to different members of the two main HERV families. Interestingly, an increase in activity was also evident in some lung cancer tissues relative to the matching normal tissues. These cancer cell lines and tissues, that were more likely to have movement of retroviral sequences in their genome, were being tested for new viral integration sites. We developed two approaches to detect these sites, but the integration event seemed not to be frequent enough to be sampled. We designed a new strategy to screen for human/viral-chimerical transcripts. Such transcripts represent the products of human genes which functions have been altered by the integration and the expression of viral genes. All these transcripts are currently being analysed to check if they represent ancient or recent integration of HERV sequences in human genes and how those integrations might contribute to tumorigenesis. Understanding the role and the significance of viral-derived genes in the triggering and evolution of pulmonary carcinogenesis could lead to the development of new treatments.
Publications

Differentially expressed genes in the trypanosoma brucei life cycle identified by RNA fingerprinting
Periodical: Molecular and Biochemical Parasitology Index Medicus:
Authors: Mathieu-Daude F, Welsh J, Davis C, McClelland M ART
Yr: 1998 Vol: 92 Nbr: Abs: Pg: 15-28

Non-stoichiometric reduced complexity probes for cDNA arrays
Periodical: Nucleic Acids Research Index Medicus:
Authors: Trenkle T, Welsh J, Jung B, Mathieu-Daude F, McClelland M ART
Yr: 1999 Vol: 26 Nbr: Abs: Pg: 3883-3891

Estrogen-responsive RING finger mRNA induction in gastrointestinal carcinoma cells following bile acid treatment
Periodical: Carcinogenesis Index Medicus:
Authors: Jung B, Vogt T, Mathieu-Daude F, et al ART
Yr: 1998 Vol: 19 Nbr: Abs: Pg: 1901-1906