Molecular Mechanisms of Cancer
Members in the Molecular Mechanisms of Cancer Program use a global approach to improve the understanding of how genetic and cell-signaling alterations contribute to the development of cancer. Program members continue to make important scientific discoveries that have a positive impact on cancer prevention, diagnosis, and treatment. In 2012, they published nearly 80 peer-reviewed publications—many of them in high-impact journals. Thirty-six percent of publications were interprogrammatic, and 11% were intraprogrammatic collaborations, which demonstrate the interactive nature of the program.
MKK4 suppresses prostate cancer metastasis
Many cancers, including prostate cancer, spread to metastatic sites early during the course of the disease and remain undetected for extended periods of time. In previous studies, Carrie Rinker-Schaeffer, PhD, identified the MKK4 signal transduction protein as a metastasis suppressor in an experimental model of ovarian cancer metastasis. Dr. Rinker-Schaeffer with her colleagues, Drs. Kay Macleod and Russell Szmulewitz (Pharmacogenomics and Experimental Therapeutics Program), demonstrated that MKK4 also suppressed prostate cancer metastases and significantly improved survival in a preclinical model by suppressing cell cycle progression. This study has significant implications for the design of new therapies aimed at controlling cancer metastases. (Szmulewitz et al., Int J Cancer 130:509-20, 2012)
This work was supported by grant number W81XWH-09-1-0415 from the National Institutes of Health and the Department of Defense.
Miz1 represses TNF-α-induced JNK activation
TNF-a is a cytokine that regulates many cellular events, including inflammation, immune responses, and carcinogenesis. Previous studies have demonstrated that the transcription factor zinc-finger protein Miz1 represses TNF-α stimulation. Anning Lin, PhD, Yingming Zhao, PhD, and colleagues revealed that this activity is accomplished by the interference of Miz1 with the ubiquitin conjugating enzyme Ubc13, which subsequently suppresses TNF-a-induced activation of JNK, a downstream signaling protein. Furthermore, ubiquination of Miz1 reverses this activity, which may account for regulation of this pathway. These findings shed light on the regulatory mechanisms of TNF-α-signaling and contribute to our understanding of how this pathway may influence cancer development. (Liu et al., Proc Natl Acad Sci 109:191-6, 2012)
This work was supported in part by grant numbers CA100460, ES015868, and GM081603 from the National Institutes of Health and in part by the National Basic Research Program of China and the National Natural Science Foundation of China.
Tumor suppressor inhibits skin cancer
Researchers have found a tumor suppressor that inhibits the development of ultraviolet B (UVB) radiation-induced skin cancer. UVB radiation in sunlight is a major risk factor for non-melanoma skin cancer, the most common type of cancer in the United States. Yu-Ying He, PhD, and colleagues found that 5’-AMP-activated protein kinase (AMPK), an energy-sensing enzyme, was inhibited in human and mouse skin cancer tissue, and that activators of AMPK (AICAR and metformin, a widely used antidiabetic drug) enhanced the repair of UVB-induced DNA damage. Using a mouse model, the researchers demonstrated that topical application of AMPK activators delayed the development of UVB-induced skin cancer and suppressed the growth of existing tumors. These findings suggest that AMPK functions as a tumor suppressor, and that AMPK activators potentially may be used as chemopreventive agents for skin cancer.
(Wu et al., Oncogene published online ahead of print, July 2012)
This work was supported by grant numbers ES016936, P30 CA014599, and UL1 RR024999 from the National Institutes of Health. Additional funds were provided by UC Friends of Dermatology Research Funds.
New network of genes is associated with prostate cancer
A recent study identifies a group of genes that play a role in prostate cancer development and progression, explaining why cancer develops primarily in prostate, but not seminal vesicle, tissue. Led by Donald Vander Griend, PhD, UCCCC researchers and colleagues performed gene expression analyses and identified unique gene signatures between prostate and seminal vesicle tissues. Using computational methods, they identified signatures that were associated with cancer-related genes and evaluated their usefulness in predicting prostate cancer recurrence and survival. Analyses revealed that a network of genes, including MEIS1, MEIS2, PBX1, and HOXA9, detected differences in survival and recurrence following prostatectomy, as well as distinguished between normal, primary, and metastatic disease. MEIS1, MEIS2, and PBX1 gene expression was decreased in tumors with poor prognosis. These data indicate that genes in the network may potentially serve as therapeutic targets and biomarkers for prostate cancer. (Chen et al., Clin Cancer Res 18:4291-302, 2012)
This work was supported by grant number P50 CA090386 from the National Cancer Institute and UL1 RR024999 from the University of Chicago Clinical and Translational Science Awards Program funded by the National Center for Advancing Translational Sciences of the National Institutes of Health, the Brinson Foundation, the Alvin Baum Family Fund, and the University of Chicago Cancer Research Foundation Women’s Board.