FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth
Jun Zhang, … , Julian R. Molina, Peiwen Fei
Jun Zhang, … , Julian R. Molina, Peiwen Fei
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1524-1534. https://doi.org/10.1172/JCI40908.
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Research Article Oncology

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth

Abstract

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.

Authors

Jun Zhang, Deping Zhao, Hwan Ki Park, Hong Wang, Roy B. Dyer, Wanguo Liu, George G. Klee, Mark A. McNiven, Donald J. Tindall, Julian R. Molina, Peiwen Fei

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Figure 7

FAVL elevation initiates growth advantages.

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FAVL elevation initiates growth advantages. (A) Overexpression of FAVL p...
(A) Overexpression of FAVL promotes cell proliferation rate. A growth curve made from average cell number ± SEM, with n = 3, is shown. Cells overexpressing FAVL have a faster growth rate (pink line) than control cells (black line). Elevated FAVL leads to colony formation in soft agar. There was not a single colony (>50 cells) that could be scored from dishes plated with U2OS control cells carrying empty vector. Ten fields per one culture dish were viewed under a light microscope, at an original magnification of ×40. A pair of typical views was shown. (B) U2OS cells overexpressing FAVL form xenograft tumors in nude mice. The left side of the mouse was injected with U2OS cells, which had been pool selected and overexpressed FAVL, and the right side of the same mouse was injected with control U2OS cells, containing empty vector that had been subjected to the same selection process. One of four mice in the group is shown here, and the other mice and growth curves of xenograft tumors are shown in Supplemental Figure 7A. (C) U2OS xenograft tumors expressing high levels of FAVL are high-grade, poorly differentiated osteosarcomas. H&E images show a high number of mitotic figures (red arrows) and large areas of coagulative tumor cell necrosis (marked with yellow lines) and nuclear polymorphism. Morphologic differentiation is shown in Supplemental Figure 7C. Original magnification, ×400.