Factor’s Role In Head and Neck Cancer Studied

October 1, 2007

Jialiang Wang, Ph.D., and colleagues are studying a protein that may function as a tumor suppressoby Leigh MacMillan

Wendell Yarbrough, M.D., and colleagues “went fishing” for new molecules involved in tumor formation, and they may have brought home a trophy catch.

In the September issue of Cancer Cell, they report that the protein LZAP has activities that suggest it functions as a “tumor suppressor” — a molecule that puts the brakes on tumor formation. They also found that LZAP is lost in one-third of head and neck squamous cell carcinomas, providing new clues about tumorigenesis in these cancers.

“If loss of LZAP is a mechanism that enables head and neck cancer formation or tumor growth, understanding how it works will, in the long run, help us to better treat these tumors,” said Yarbrough, associate professor of Otolaryngology and Cancer Biology.

The investigators were looking for proteins that regulate the tumor suppressor ARF. Jialiang Wang, Ph.D., screened for proteins that bind to ARF and found LZAP. The new protein had the interesting ability to inhibit cell growth.

In the current study, the researchers demonstrated that cells with reduced LZAP expression grew in soft agar and invaded a matrix barrier, measures of “tumor-like” growth qualities. In a mouse model for tumor growth, cells with reduced levels of LZAP grew into tumors more quickly, and the tumors were larger with more blood vessels compared to tumors that grew from cells with normal LZAP levels.

“All of these activities are consistent with LZAP functioning as a tumor suppressor,” Yarbrough said, adding that LZAP still has some tests to pass before it can be considered a tumor suppressor. One of these tests is to delete the LZAP gene in mice and watch for spontaneous or carcinogen-induced tumor formation, experiments that are underway in the Yarbrough laboratory.

A new tumor suppressor gene doesn’t come along every day, making the findings very exciting, Yarbrough said.

The investigators linked LZAP activity to NF-kappa-B, a family of transcription factors that regulates genes involved in inflammatory and immune responses and that has been implicated in tumorigenesis.

The current paper reports that LZAP inhibits NF-kappa-B, and that when LZAP is lost, NF-kappa-B activity increases.

“NF-kappa-B is important in tumorigenesis,” Yarbrough said. “Especially in head and neck cancers, we know that NF-kappa-B is activated in a large portion of these tumors, but we don’t know why. Could loss of LZAP be part of the explanation for NF-kappa-B activation in these tumors? Maybe so.”

In the human primary head and neck tumor samples, the investigators found that decreased LZAP expression correlated with increased expression of two NF-kappa-B-regulated genes, supporting the hypothesis that loss of LZAP activates NF-kappa-B.

The team demonstrated that LZAP binds directly to an NF-kappa-B component, impairs a modification required for activation, and increases association with HDACs, molecules that inhibit NF-kappa-B.

“Mechanistically, we found that LZAP works in the nucleus on NF-kappa-B and probably turns it from a transcriptional activator (turns genes “on”) to a transcriptional repressor (turns genes “off”),” Yarbrough said.

“It remains to be seen whether loss of LZAP is broadly important in human tumorigenesis.”

Other authors of the Cancer Cell paper include Hanbing An, Ph.D., at Vanderbilt, Marty Mayo, Ph.D., at the University of Virginia, and Albert Baldwin, Ph.D., at the University of North Carolina, Chapel Hill.

The research was supported by the National Institutes of Health, the Barry Baker Laboratory for Head and Neck Oncology at Vanderbilt, the Vanderbilt-Ingram Cancer Center and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation.

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