Hsin-Sheng Yang
Assistant Professor

Graduate Center for Toxicology

Phone:
(859) 323-6684

Fax:
(859) 323-1059

e-mail:
hyang3@uky.edu

The interest of my laboratory is to study gene regulation events that occur during multistage carcinogenesis and to target these events for cancer prevention and therapeutics.  Specifically, we focus on studying the molecular action of a novel tumor suppressor Programmed cell death 4 (Pdcd4) in inhibiting tumor promotion and progression. 

The current project in my laboratory is to investigate the molecular mechanism of how Pdcd4 suppresses colon tumor invasion.  Pdcd4 is a highly conserved protein in mammalian cells and expressed in most tissues.  Over-expressing pdcd4 cDNA in invasive colon carcinoma RKO cells significantly and negatively impacted invasion, as evinced by decreased ability to penetrate a Matrigel barrier, reduced cell migration, and diminished extracellular matrix (ECM) proteinase activity when compared to RKO control cells with empty vector.  In addition, over-expression of sense pdcd4 reduces the activation of JNK, c-Jun, and AP-1 in RKO cells.  These findings lead us to hypothesize that Pdcd4 suppressing invasion of colon cancer cells is through inhibition of JNK signaling pathway and AP-1 activation. 

The other research focus in my laboratory is to understand how Pdcd4 is down-regulated during lung tumor progression.  Immunohistochemical analyses of primary lung tumor tissues indicate that the higher stage or grade of lung tumors express lower Pdcd4 protein level when compared to normal lung tissues.  Northern blot and RT-PCR analyses of cultured lung carcinoma cells also showed that Pdcd4 expression is down-regulated in both non-small cell lung carcinomas (NSCLCs) and small cell lung carcinomas (SCLCs).  Likewise, protein expression patterns from the NCI 60 human cancer cell lines show that the more progressed cancer cells have the less Pdcd4 protein.  Most importantly, a higher Pdcd4 protein level correlates with a good prognosis in lung cancer patients. These findings suggest that elevating the expression of Pdcd4 has the potential to suppress lung tumor progression and prolong survival for the lung cancer patient.  It would be of high interest to determine the molecular basis for down regulation of Pdcd4 at gene, mRNA, and protein levels in lung cancer cells.

Research Publications/Presentations

1.            Wang, Q., Z. Sun, and H.-S. Yang. (2007). Down-regulation of tumor suppressor Pdcd4 promotes invasion and activates both b-catenin/Tcf and AP-1 dependent transcription in colon carcinoma cells.  Oncogene (in press).

2.            Hu, J., J. Straub, D. Xiao, S. V. Singh, H.-S. Yang, N. Sonenberg. And J. Vatsyayan. (2007). Phenethyl isothiocyanate, a cancer chemopreventive constituent of cruciferous vegatables, inhibits cap-dependent translation by regulating level and phosphorylation of 4E-BP1. Cancer Res. 67, 3569-3573.

3.            Hwang, S.-K., H. Jin, T. H. Kim, C.-S. Cho, K. H. Lee, M. R. Young, N. H. Colburn, G. R. Beck Jr, H.-S. Yang and M.-H. Cho. (2007). Aerosol delivery of PDCD4 facilitated apoptosis in the lung of AP-1 luciferase reporter mice.  Gene Ther. 14, 1353-1361.

4.            Leupold, J. H., H.-S. Yang, N. H. Colburn, S. Post, and H. Allgayer.  (2007). Tumor suppressor Pdcd4 inhibits invasion and regulates urokinase-receptor (uPAR) gene expression via Sp-transcription factors.  Oncogene  26, 4550-4562.

5.            Yang, H.-S., C. P. Matthews, T. Clair, Q. Wang, A.R. Baker, C.-C. H. Li, T.-H. Tan and N.H. Colburn. (2006). Tumorigenesis suppressor Pdcd4 down-regulates MAP4K1 expression to suppress colon carcinoma cell invasion. Mol. Cell. Biol. 26, 1297-1306.

6.            Jin, H., T. H. Kim, S.-K. Hwang, H. W. Kim, H. K. Anderson, H.-W. Lee, K. H. Lee, N. H. Colburn, H.-S. Yang, M.-H. Cho and C. S. Cho. (2006). Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle and angiogenesis in lungs of K-ras null mice.  Mol. Cancer Ther. 5, 1041-1049.

7.            Zakowicz, H., H.-S. Yang, C. Stark, A. Wlodawer, N Laronde-Leblanc and N. H. Colburn. (2005). Mutational analysis of the DEAD box RNA helicase eIF4AII with respect to its interaction with Pdcd4 and eIF4G. RNA, 11, 261-274.

8.            Yang, H.-S., M.-H. Cho, H. Zakowicz, G. Hegamyer, N. Sonenberg and N. H. Colburn. (2004). A novel function of the MA-3 domain in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol. Cell. Biol., 24, 3894-3906.

9.            Yang, H.-S., J. L. Knies, C. Stark and N. H. Colburn. (2003). Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene, 22, 3712-3720.

10.        Young M., H.-S. Yang and N. H. Colburn. (2003). Promising molecular targets for cancer prevention: AP-1, NF-kB, and Pdcd4. Trends Mol. Med., 9, 36-41.

11.        Yang, H.-S., A. P. Jansen, X. Zheng, W. C. Merrick, S. Costes, S. J. Lockett, N. Sonenberg and N. H. Colburn. (2003). The transformation suppressor Pdcd4 is a novel eIF4A binding protein that inhibits translation. Mol. Cell. Biol., 23, 26-37.