Shijie Sheng, Ph.D.

Associate Professor

Contact Info Biographical Information Research Publication Job Opportunities

Contact Info

Department of Pathology website

Wayne State University School of Medicine
540 East Canfield Avenue
Detroit, MI 48201 campus map

Office Telephone: 313-993-8197
Fax: 313-993-4112
E-mail: ssheng@med.wayne.edu

Biographical Information

Dr. Shijie Sheng earned her Ph.D. in biochemistry and molecular biology at the University of Florida in 1993 for her work with Dr. Sheldon M. Schuster on the enzyme kinetics of human asparagines synthetase. Dr. Sheng then focused on the identification and functional characterization of a novel tumor suppressive serpin named maspin as a Research Associate jointly with Dr. Arthur B. Pardee and the late Dr. Ruth Sager at the Dana-Farber Cancer Institute of Harvard Medical School. She subsequently joined the faculty here in 1997. Currently, Dr. Sheng serves also as a faculty member of the Cancer Biology Program of Wayne State University School of Medicine, an associate member of the Karmanos Cancer Institute, and the organizing member of the Michigan Prostate Cancer Colloquium.

Research

Key words
A Brief Review of Maspin
Recent Advance
Past News Release

Key words:

maspin, prostate cancer, breast cancer, tumor suppressor genes, tumor invasion and metastasis, cell motility, cell-matrix interaction, ECM remodeling, and apoptosis

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An Introduction of the Maspin Gene

Cancer mortality is primarily caused by metastasis, a complex process caused by multiple genetic and epigenetic changes. In search for tumor suppressor genes by applying expression genetics, the maspin gene was identified by subtractive hybridization on the basis of its expression at the mRNA level in normal but not in tumor-derived human mammary epithelial cells. The cloned and sequenced cDNA encodes a 42 kDa protein with an overall sequence homology to serine protease inhibitors, or serpins.

Maspin expression correlates with normality, and pre-malignant and/or less invasive lesions. In human breast tissues, maspin expression is progressively lost from ductal carcinoma in situ (DCIS) to invasive carcinoma. Maspin is absent in lymph nodes, distant metastases of breast cancer and invasive prostate carcinoma. In the case of oral squamous cell carcinoma, high maspin expression is associated with improved survival. In vitro studies suggest that the down-regulation of maspin expression in prostate tumor progression may occur at the transcriptional level, resulting either from the loss (or mutation) of the transactivating p53, or from the activation of the repressive HRE site in the maspin promoter.

In culture, maspin is expressed in normal mammary epithelial cells and weakly in primary breast tumor cell lines. Its expression is absent in breast carcinoma cell lines of metastatic origin, albeit maspin DNA remains grossly intact in these cells. Further studies showed that maspin is expressed in normal immortalized prostate epithelial cell lines, but down-regulated, to various extents, in several prostate carcinoma cell lines. In vitro studies suggest that the down-regulation of maspin expression in prostate tumor progression may occur at the transcriptional level, resulting either from the loss (or mutation) of the transactivating p53, or from the activation of the repressive HRE site in the maspin promoter.

Maspin has tumor suppressive activity. Orthotopic explants of mammary carcinoma cells transfected with maspin coding cDNA are inhibited in tumor growth and metastasis in nude mice. These maspin transfectants are significantly inhibited in in vitro invasion and motility assays. Consistently, induced re-expression of maspin by g-linolenic acid has been shown to correlate with a marked reduction of the spreading and migration of four different breast tumor cell lines in vitro.

Three forms of recombinant human maspin proteins produced in different expression systems all exhibit potent inhibitory activities on the invasion and motility of an array of human mammary and prostatic carcinoma cell lines in vitro. Treatment of human mammary carcinoma cells with maspin leads to a partial restoration of benign epithelial morphology and an increased cell adhesion to fibronectin. Further studies demonstrate that maspin acts on the cell surface, and induces an increased cell surface expression of _5_1 integrin. Recently, it was shown that recombinant mouse maspin, highly homologous to human maspin, inhibits the growth and metastasis of orthotopical human prostate tumor in nude mice.

Maspin may exert suppressive effects on multiple steps of tumor metastasis. Recombinant mouse maspin is also shown to inhibit prostate tumor induced angiogenesis in nude mice. In addition, several lines of recent evidence suggest a link between maspin expression and cell apoptosis. The transcription of maspin gene can be directly activated by tumor suppressor p53. Furthermore, transgenic mice that overexpress mouse maspin under the control of the WAP promoter have curtailed mammary development accompanied by an increased mammary epithelial cell apoptosis.

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Recent Advances in Dr. Sheng's Laboratory:

We are particularly interested in the role of maspin in the progression of human prostate cancer and breast cancer. To explore the potential therapeutic application of maspin, it is key importance to understand the molecular mode of maspin action. Accumulated biological evidence suggests that the tumor suppressive activity of maspin may depend on its inhibitory interaction with a serine protease target. To this end, In vitro biochemical studies showed that tPA-associated with fibrinogen is specifically inhibited by maspin. We also showed that purified recombinant maspin specifically binds to the surface of prostate carcinoma cells DU145, and inhibits the motility of DU145 cells. Using cell-based biochemical assays, we showed that maspin acts as a competitive inhibitor of DU145 cell surface-mediated plasminogen activation with an apparent Ki value of 20 nM. Recently, we showed that endogenous expression of maspin in DU145 cells specifically inhibited cell surface-mediated plasmingen activation. Furthermore, the interaction of maspin with cell surface associated uPA stimulates the internalization of the uPA/uPAR complex. Our data demonstrate an important role of the epithelial cell surface in regulating the inhibitory interaction between maspin and uPA, and further support the hypothesis that maspin blocks cell motility and invasion, at least in part, by inhibiting the tumor cell-mediated localized plasminogen activation.

Meanwhile, emerging evidence also suggests that the anti-metastasis function of maspin may not be limited to the steps of tumor cell invasion and migration. Recently, we reported the first evidence that endogenous maspin expression in mammary carcinoma cells MDA-MB-435 enhanced staurosporine (STS)-induced apoptosis as judged by the increased fragmentation of DNA, increased proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP), as well as the increased activation of caspase-8 and caspase-3. Consistent with this result, maspin expressing normal mammary epithelial cells underwent more rapid STS-induced apoptosis as compared to breast carcinoma cells. Interestingly, neither purified maspin protein added from outside nor endogenous maspin secreted to the cell culture media sensitized cells to STS-induced apoptosis. To investigate the structural determinants of maspin in its apoptosis-sensitizing effect, MDA-MB-435 cells were also transfected with maspin/PAI-1 and PAI-1/maspin chimeric constructs resulting from swapping the N-terminal and the C-terminal domains between maspin and PAI-1 (plasminogen activator inhibitor type 1). Interestingly, however, expression of both maspin/PAI-1 and PAI-1/maspin in MDA-MB-435 cells failed to sensitize these cells to STS-induced apoptosis. The sensitizing effect of maspin on apoptosis is to be contrasted by the pro-survival effect of several other serpins.

To further investigate the clinical relevance of maspin in tumor progression, we investigated the expression of maspin in prostate tumor progression. We used immunohistochemistry and in-situ hybridization to detect maspin protein and mRNA, respectively, in radical prostatectomy specimens as well as autopsy prostate glands. We showed that maspin expression in prostate epithelial cells was differentially regulated during carcinogenesis. Surprisingly, the highest level of maspin expression, albeit heterogeneous, was found in HGPIN. Furthermore, maspin expression in HGPIN positively correlated with that in adjacent PC. To our knowledge, this is the first evidence that, prior to its loss of expression in PC, maspin expression is up-regulated in premalignant prostate epithelia. Thus, maspin may play an important role in regulating premalignant changes in PC progression.

Genetically modified animal models may provide a powerful tool for maspin study. In a recent study, we examined maspin expression in MMTV/TGF-

α

transgenic mice. Histopathological examinations of MMTV/TGF-

α

transgenic mice revealed TGF-

α

expression leading to hyperproliferation, hyperplasia, and carcinoma in mammary gland. Immunohistochemistry analysis of maspin expression in the breast tissues of TGF-

α

transgenic mice showed a direct correlation between down-regulation of maspin expression and tumor progression. The loss of maspin expression was concomitant with the critical transition from carcinoma in situ to invasive carcinoma. Subsequent in-situ hybridization analyses suggest that the down-regulation of maspin expression is primarily a transcriptional event. This data is consistent with the tumor suppressive role of maspin. Furthermore, our data suggests that MMTV/TGF-

α

transgenic mouse model is advantageous for in vivo evaluation of both the expression and the biological function of maspin during the slow mutli-stage carcinogenesis of mammary gland.

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Past News Release:

• Natures own approach to cancer protection - The University of Chicago Magazine August 1994
• The Molecular Mechanism of Tumor Suppressive Maspin -Inside the Institute by Dana-Farber Cancer Institute, 1997
• Maspin both marks and prevents cancer - Scribe Wayne State University School of Medicine Winter 2000, 11 (1): 4

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pubPublication

1. Ning Jiang, Yonghong Meng, Suliang Zhang, Edith Mensah-Osman, and Shijie Sheng, 2002, Intracellular Maspin Sensitizes Breast Carcinoma Cells to Induced Apoptosis Oncogene 21: 4089-98. (Medline)

2. Christopher R. Pierson, Richard McGowen, David Grignon, Wael Sakr, Jyotirmoy Dey, and Shijie Sheng, 2002, Maspin Expression Is Up-regulated in Premalignant Prostate Epithelia, Prostate 20:287-96.

3. Shijie Sheng., 2002 The Urokinase-type Plasminogen Activator System in Prostate Cancer Metastasis, Cancer and Metastasis Reveiws (in press).

4. Shijie Sheng., Zhang, M. Pardee, AB, and Sager, R. Maspin. 2002, In The Encyclopedia of Molecular Medicine, John Wiley & Son, Inc., New York, NY, Volume 5, pp 2010-3.

5. Zhang, M., Shijie Sheng. and Pardee, A. B. 2002, Maspin Research in Sager Laboratory, In Maspin, Ed. Hendrix, M. J. C. Landes Bioscience Medical Handbook Publisher, Georgetown, TX, pp 57-67

6. Shijie Sheng. and Hector, B. Jr., 2002, Maspin and pericellular plasminogen activation In cell-matrix interaction, in Maspin, Ed. Hendrix, M. J. C. Landes Bioscience Medical Handbook Publisher, Georgetown, TX (in press)

7. Biliran H. Jr. and Shijie Sheng. 2001, Pleiotrophic Inhibition of Pericellular Urokinase-type Plasminogen Activator System by Endogenous Tumor Suppressive Maspin, Cancer Res. 61: 8676-8682. (Medline)

8. Reddy, K. B., McGowen, R., Schuger, L., Visscher, D., and Shijie Sheng., 2001, Maspin Expression Inversely Correlates with Breast Tumor Progression in MMTV/TGF-alpha Transgenic Mice. Oncogene, 20: 6538-6543. (Medline)

9. Shijie Sheng., 2001, The tumor cell surface-associated urokinase type plasminogen activator as a maspin target, Cancer Res. Alert 2: 90-92. (Medline)

10. McGowen, R., Biliran, H., Sager, R., and Shijie Sheng. 2000, The Surface of Prostate Carcinoma Cells DU145 Mediates the Inhibition of uPA by Maspin, Cancer Res. 60:4771-4778.[Medline]

11. Xia, W., Lau, Y. K., Hu, M. C., Li, L, Johnston, D. A, Shijie Sheng., El-Naggar, A., Hung, M. C., 2000, High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma. Oncogene 19: 2398-2403.[Medline]

12. Deng, Y., Jiang, T. Y., Shijie Sheng., Tianasoa-Ramamonjy, M. and Snyder, J. K. 1999, Remangilones A-C, new cytotoxic triterpenes from physena madagascariensis. J. Nat. Prod., 62: 471-476. [Medline]

13. Shijie Sheng., Truong, B., Frederickson, D., Wu, R., Pardee, A. B., and Sager, R., 1998 , Tissue-type Plasminogen Activator (tPA) is a Target of the Tumor Suppressor Gene Maspin, Proc. Natl. Acad. Sci. U.S.A. 95: 499-504. [Medline]

14. Seftor, R. E. B., Seftor, E. A., Shijie Sheng., Pemberton, P. A., Sager, R., and Hendrix, M. J. C., 1998, Maspin Suppresses the Invasive Phenotype of Human Breast Carcinoma, Cancer Res. 58: 5681-5685. [Medline]

15. Zhang, M., Martin, K. J., Shijie Sheng., Sager, R., 1998, Expression genetics: a different approach to cancer diagnosis and prognosis, Trends Biotechnol 16(2): 66-71. (Medline)

16. Biswas, D. K., Averboukh, L., Shijie Sheng., Martin, K., Ewaniuk, D. S., Jawde, T. F., Wang, F., and Pardee, A. B., 1998, Classification of Breast Cancer Cells on the Basis of a Functional Assay for Estrogen Receptor, Mol. Med. 4: 454-467. [Medline]

17. Sager, R., Shijie Sheng., Pemberton, P., Hendrix, M. J. C., 1997, Maspin. A tumor suppressing serpin, Adv. Exp. Med. Biol., 425: 77-88. [Medline]

18. Zhang, M., Shijie Sheng., Mass, N., and Sager R., 1997, mMaspin, the mouse homolog of a human tumor suppressor gene, inhibits tumor invasion and motility, Mol. Med., 3: 49-59. [Medline]

19. Wang, M., Liu, Y. E., Shijie Sheng., Fuchs, A., and Shi, Y. E., 1997, TIMP-4 Inhibits Growth of Human Breast Cancer Cells in the Mammary Fad Pads of Nude Mice, Oncogene 14(23): 2767-74. (Medline)

20. Liu, Y. E., Wang, M., Greene, J., SU, J., Ullrich, S., Li, H., Shijie Sheng., Alexander, P., Sang, Q. A., Shi, E. Y., 1997, Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4), J. Biol. Chem., 272(33): 20479-83. [Medline]

21. Shijie Sheng., Carey, J., Seftor, E., Dias, L., Hendrix, M. J. C., and Sager, R., 1996, Maspin Acts on the Cell Membrane to Inhibit Invasion and Motility of Mammary and Prostate Cancer Cells. Proc. Natl. Acad. Sci. U.S.A., 93: 11669-11674. [Medline]

22. Sager, R., Shijie Sheng., Pemberton, P., and Hendrix, M. J. C., 1995, Maspin, A Tumor Suppressing Serpin, in Current Topics in Microbiology and Immunology, volume on Attempts to Understand Metastasis Formation I, Eds: Gunthert, U., Schlag, P. M., and Birchmeier, W., Springer Verlag, Berlin, Herdelberg-New York-Tokyo, pp. 51-64. (Medline)

23. Shijie Sheng., Pemberton, P., and Sager, R., 1994, Production, Purification and Characterization of Recombinant Maspin Proteins, J. Biol. Chem., 269: 30988-30993. [Medline]

24. Sager, R., Shijie Sheng., Anisowicz, A., Sotiropoulou, G., Zou, Z., Stemman, G., Swisshelm, K., Chen, Z., Hendrix, M. J. C., Pemberton, P., Rafidi, K., and Ryan, K., 1994, RNA Genetics of Breast Cancer: Maspin as a Paradigm, in Cold Spring Harbor Symposium on Quantitative Biology, Vol. LIX, pp. 537-546. [Medline]

25. Zou, Z., Anisowicz, A., Hendrix, M. J. C., Thor, A., Neveu, M., Shijie Sheng., Rafidi, K., Seftor, E., and Sager, R., 1994, Maspin, a Serpin with Tumor Suppressing Activity in Human Mammary Epithelial Cells. Science, 263: 526-529. [Medline]

26. Shijie Sheng., and Schuster, S. M., 1993, Purification and Characterization of Saccharamyces cerevisiae DNA Damage Responsive Protein 48 (DDRP48), J. Biol. Chem., 268: 4752-4758. [Medline]

27. Shijie Sheng., Moraga, D. A., Allison, R. D., and Schuster, S. M., 1993 Glutamine Inhibits the Ammonia-dependent Activities of Two Cys-1 Mutants of Human Asparagine Synthetase by Forming an Abortive Complex, J. Biol. Chem., 268: 16771-16780. [Medline]

28. Shijie Sheng., Kraft, J. J., and Schuster, S. M., 1993, A Simple Quantitative Colorimetric Assay for L-asparagine, J. Anal. Biochem., 211: 242-249. (Medline)

29. Shijie Sheng., and Schuster, S. M., 1992, Simple Modifications of a Protein Immunoblotting Protocol to Reduce Nonspecific Background, BioTech., 13: 704-708. [Medline]

30. Shijie Sheng., Moraga, D. A., Van Heeke, G., and Schuster, S. M., 1992, High Level of Expression of Human Asparagine Synthetase and Production of Monoclonal Antibodies for Enzyme Purification, Protein Expression and Purification, 3: 337-346. [Medline]

Job Opportunities

A Research Associate is needed to carry out in vivo and in vitro biological studies. Qualified candidates must have a Ph.D. degree in biomedical fields with extensive training in cancer research. Hands-on experience with mouse model of cancer is preferred. Additional desirable skills include: organ culture, northern/western blotting, proteolysis analyses, and in situ hybridization/immunohistochemical staining.

A Research Assistant or Associate is needed to carry out independent studies on the biological and biochemical activities of tumor suppressive proteins. Candidates must have a BS or MS or Ph.D. degree in biomedical sciences and extensive training in protein purification, biochemistry and cell biology.

A Research Assistant/Laboratory Manager is needed. Essential Functions include: managing the laboratory maintenance, assist the PI in key experiments, tissue culture, optimizing procedure protocols, and prepare data for publication. Qualified candidates must have a BS or MS degree in biological sciences with experience in tissue culture and molecular biology.

Salary and rank will be commensurate with experience. Please send curriculum vitae and names of three references to:

Dr. Shijie Sheng
Department of Pathology
Wayne State University School of Medicine
540 East Canfield Avenue
Detroit, MI 48201
ssheng@med.wayne.edu