Oxidative Stress & Signaling Research Highlights

Title: Hedgehog (Hh) Signaling Pathway and Cancer
    Background and Advances
    Implications & Public Health Impact
    Center Contribution
    Key Researchers
    Publication(s)
    Grant Support
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Title: Hedgehog (Hh) Signaling Pathway and Cancer

Background and Advances: The hedgehog (Hh) pathway plays a critical role during development of embryos and cancer. Dr. Xie investigates the molecular basis by which hedgehog signaling promotes carcinogenesis. Dr. Xie’s laboratory is one of the first groups to discover that the hedgehog pathway is activated in several major human cancers, including basal cell carcinomas (BCCs), medulloblastomas, prostate, lung, liver, pancreatic, gastric and esophageal cancers. These are significant findings as many of these cancers have a strong link to environmental causes. For example, solar UV irradiation is the major risk factor for BCC whereas lung cancer is strongly associated with smoking and air pollution. Furthermore, amounting evidence indicates that oxidative stress is an important factor for cancer development, and investigation of the role of oxidative stress during hedgehog-driven carcinogenesis is another important focus of his laboratory. Dr. Xie’s recent study, funded by National Cancer Institute and Department of Defense, demonstrated a novel regulatory mechanism for hedgehog signaling in mammalian cells (J. Biol. Chem., Vol. 281, Issue 1, 9-12, January 6, 2006).

Implications and Public Health Impact: Cancer is a major public health burden. For the first time in history, cancer has surpassed heart diseases as the leading cause of death in US (American Cancer Society Cancer fact 2005). The findings from Dr. Xie’s laboratory and others indicate that hedgehog pathway plays an important role in most BCCs and in about 30% of extracutaneous tumors. Thus, understanding the molecular basis of hedgehog signaling could potentially lead to new medical diagnoses and treatments for cancer. At present, Dr. Xie is investigating the potential use of hedgehog pathway components as cancer diagnosis and prognosis markers. In addition, inhibitors of the hedgehog pathway have been tested for therapeutics of BCCs (clinical trial phase I). Dr. Xie is also actively collaborating with his colleagues to identify novel hedgehog pathway inhibitors for cancer therapy.

Center Contribution: Dr. Xie is an active user of all the UTMB NIEHS-funded service cores. The instrumentations and technical expertise provided by these service cores allow him to conduct his research projects in an efficient and cost-effective manner. In addition, the intellectual stimulations gained from interactions with other center members are critical for the success of his studies. Dr. Xie has closely interacted with several members of the NIEHS Center at UTMB, including Drs. James Lee, Xiaodong Cheng, Paul Boor and Jonathan Ward, Jr. For example, through the monthly Oxidative Stress and Signaling Core research meetings, Dr. Xie established a close collaboration with Dr. James Lee, whose academic mentoring and expertise in physical biochemistry proved to be invaluable for Dr. Xie’s recent successful publication in JBC (Vol. 281, Issue 1, 9-12, January 6, 2006).

Key Researchers:
Jingwu Xie, Oxidative Stress and Signaling Research Core, Department of Pharmacology and Toxicology.

Paul Boor, Oxidative Stress and Signaling Research Core, Department of Pathology.

Xiaodong Cheng, Oxidative Stress and Signaling Research Core, Department of Pharmacology and Toxicology.

James C. Lee: Oxidative Stress and Signaling Research Core, Department of Biochemistry and Molecular Biology.

Jonathan Ward, Jr., Administrative Core, DNA Repair and Mutagenesis Research Core, Community Outreach and Education Core, Department of Preventive Medicine and Community Health.

Publication(s):
He N., Li C-X, Zhang X., Sheng T, Chi S, Chen K, Wang Q, Vertrees R, Logrono R. and Xie, J. Regulation of lung cancer cell invasion by beta TRCP. Molecular Carcinogenesis 42: 18-28, 2005.

Ma, X.L., Chen, K., Huang S.H., Sheng, T., Zhang, X., Evers, B.M., Adegygoga, P., Zhang H.W. and Xie J. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis 26(10):1698-1705, 2005.

Vertrees RA, Das GC, Coscio AM, Xie J, Zwischenberger JB, Boor PJ. A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells. Mol Carcinog. 44(2):111-21, 2005.

Ma, X.L., Sheng, T., Zhang, Y.X., Huang S.H., He, J., Chen, K., Zhang, X., Zhang H.W. and Xie J. Hedgehog signaling is activated in subsets of esophageal cancers International Journal of Cancer 118(1): 139-148, 2006.

Wickliffe JK, Galbert LA, Ammenheuser MM, Herring SM, Xie J, Masters III OE, Friedberg EC, Lloyd RS and Ward JB Jr. 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice. Environ Mol Mutagen. 47(1):67-70, 2006.

Sheng T, Chi S, Zhang X and Xie J, Regulation of Gli1 localization by the cAMP/ PKA signaling axis through a site near the nuclear localization signal. J. Biological Chemistry 2006 281: 9-12, 2006.

Huang, S-H, Chi, S., Li, C-X, Zhang, X., Haque, A.K., Zwischenberger, J., Tyring, S.K., Logrono, R., Bhutani, M., Zhang, H-W and Xie, J (2006). Expression of sonic hedgehog and its target genes in lung cancers Cancer Letters (accepted).

Grant Support:
NIH/NCI 1R01CA094160
Molecular basis of hedgehog signaling in carcinogenesis

DOD PC 030429
The role of the sonic hedgehog pathway in prostate cancer progression

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