DMP1 Deletion Cooperates With Oncogenic K-ras In Lung Cancer

Main Category: Lung Cancer
Also Included In: Biology / Biochemistry
Article Date: 16 Oct 2007 - 4:00 PDT

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Scientists have identified the transcription factor DMP1 as a pivotal tumor suppressor for both human and mouse lung cancers, especially in carcinomas that exhibit intact Arf-p53 pathways. The research, published by Cell Press in the October 2007 issue of Cancer Cell, may lead to development of new drug therapies for lung cancer.

Lung cancer is the leading cause of cancer deaths in the world, responsible for 1.3 million deaths each year. Non-small-cell lung cancers (NSCLCs) are the most common type of lung cancer, and scientists have identified distinct patterns of genetic alterations that are associated with this malignancy. Mutations that activate the oncogene K-ras or interfere with the tumor suppressors p53 and Arf are common in human NSCLCs. The mouse model K-rasLA had previously been developed based on this knowledge and is an excellent system for studying human NSCLC.

Dmp1 is a unique tumor suppressor that activates Arf expression and thus induces p53-dependent cell cycle arrest. Mice lacking the gene for Dmp1 commonly develop lung tumors, and Dmp1 has been identified as a regulator of the Arf-p53 pathway in vitro. "In striking contrast to the accumulating information on mouse Dmp1, very little is known about the involvement of human DMP1 (hDMP1) in cancer," says lead author Dr. Kazushi Inoue of Wake Forest University. Dr. Inoue and colleagues conducted a study designed to investigate the collaborative effects of Dmp1 deletion and K-ras activation in the genesis and progression of lung cancer.

Tumorigenesis was significantly accelerated in K-rasLA mice that were lacking one or both copies of Dmp1. The researchers demonstrated that Dmp1 also showed haploid insufficiency, meaning that cancer developed even when one copy of the gene was present, in samples from lung cancer patients with non-small-cell lung cancers. Further, in K-rasLA mice, lung carcinomas were associated with either p53 mutations or deletion of Dmp1 to inactivate the Arf-p53 pathway. Consistent with this finding, human lung carcinomas exhibited loss of hDMP1 in a mostly exclusive fashion with loss of Arf-p53 activation. Importantly, Dmp1 overexpression inhibited growth of human lung cancer cells with K-ras mutation and wild-type Arf and p53.

These findings suggest that DMP1 plays a critical role in the development of lung cancer. "We have demonstrated that the hDMP1 gene is hemizygously deleted in a significant percentage of mouse and human non-small-cell lung carcinomas, especially those which retained the intact Arf-p53 pathway," explains Dr. Inoue. "Since hDMP1 loss-of-heterozygosity lung cancer cells retain one allele of the hDMP1 locus, this gene might be a promising target for future drug development."

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The researchers include Ali Mallakin, Takayuki Sugiyama, Pankaj Taneja, Lauren A. Matise, Donna P. Frazier, Mayur Choudhary, Gregory A. Hawkins, Ralph B. D'Agostino, Jr., Mark C. Willingham, and Kazushi Inoue of Wake Forest University Health Sciences in Winston-Salem.

This work was supported by NIH/NCI 5R01CA106314 (K.I.).

Mallakin et al.: "Mutually Exclusive Inactivation of DMP1 and ARF/p53 in Lung Cancer." Publishing in Cancer Cell 12, 381-394, October 2007. DOI 10.1016/j.ccr.2007.08.034 http://www.cancercell.org/

Source: Cathleen Genova
Cell Press

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