Brain tumor biology and prognosis, cancer evolution and PAX6, cancer therapy and EFEMP1
1995.1-1996.12, Postdoctoral researcher (mentor Wen-Hsuing Li, PhD), Human Genetics Center, University of Texas Health Science Center, Houston, TX
1997.1-2000.5, Postdoctoral researcher (mentor Grady F. Saunders, PhD), Department of Biological Chemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX
2000.5-2000.8, Postdoctoral researcher (mentor W.K. Alfred Yung, MD), Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
2000.9-2002.6, Instructor, Department of Neuro-Oncology, M.D. Anderson Cancer Center, TX
2003.7-2006.7 Assistant Professor (non-Tenure track), Departments of Neurobiology (Primary), Neurological Surgery (secondary), and Radiation Oncology (secondary), University of Arkansas for Medical Sciences, AR
2006.8 - present Assistant Professor (Tenure track), Departments of Neurological Surgery (primary) and Biological Chemistry (Joint), University of California, Irvine, CA
We are the first discovered tumor suppressive function of PAX6 in malignant glioma cell lines and favorable prognostic value of PAX6 for patients with WHO grade IV glioblatoma multiforme (median survival 0.9 to 1 year). We also revealed PAX6’s unfavorable prognostic value for patients with WHO grade II and III gliomas (median survival 4 to 7 years). We have been seeking an answer to PAX6’s conflicting role in different glioma types. Our current research data suggest a content-dependent function of PAX6 in glioma development and the role of PAX6 in brain tumor neural stem-like cells and GBM heterogeneity maintenance. Our recently published paper revealed tumor suppressive and therapeutic effect of an extracellular matrix protein EFEMP1, which is encoded by a target gene of PAX6. We are studying EFEMP1 in inhibiting EGFR/PTK2/AKT signaling pathways and developing tumor-suppressive extracellular signaling peptide out of EFEMP1 as a novel therapeutic agent to still the malignant behavior of cancer, thus to achieve therapeutic improvement of survival for patients with advance cancers. We have been studying glioma prognosis for a decade, focusing on developing multivariate models to improve outcome prediction, identify potential new therapeutic targets and uncover potential biomarkers for disease severity and/or progression in glioma patients.
1. Zhou Y-H and Wang S-J (1989) Isolation and cultivation of protoplasts of Caloglossa leprieurii (Mont.) J. Ag. Chinese Journal of Biotechnology (in English) 5(4): 297-302.
2. Zhou Y-H (1991) Ultrastructure of red alga Caloglossa leprieurii (Mont.) J. Ag. in Study on Ultrastructure of Economic Seaweeds in China (Wang SJ et al.), Hang Zhou Sci. and Tech. press, pp 166-169.
3. Wang S-J, Zhou Y-H (1989) Isolation of protoplast from four Gracilaria. Agricultural Biotechology in China pp. 108-112.
4. Zhou YH, Ragan MA (1993) cDNA cloning and characterization of the nuclear gene encoding chloroplast glyceraldehyde-3-phosphate dehydrogenase from the marine red alga Gracilaria verrucosa. Current Genetics 23: 483-489.
5. Zhou YH, Ragan MA (1994) Gene cloning and characterization of the nuclear gene encoding chloroplast glyceraldehyde-3-phosphate dehydrogenase from the marine red alga Gracilaria verrucosa. Current Genetics 26: 79-86.
6. Zhou YH, Ragan MA (1995) Cloning and characterization of cDNA and the nuclear gene encoding triosephosphate isomerase from the marine red alga Gracilaria verrucosa. Current Genetics 28: 317-323.
7. Zhou YH, Ragan MA (1995) The nuclear gene and cDNAs encoding cytosolic glyceraldehyde-3-phosphate dehydrogenase from the marine red alga Gracilaria verrucosa: cloning, characterization and phylogenetic analysis. Current Genetics 28: 324-332.
8. Zhou YH, Ragan MA (1995) Characterization of the nuclear gene encoding mitochondrial aconitase in the marine red alga Gracilaria verrucosa. Plant Mol. Biol. 28: 635-646.
9. Zhou YH, Ragan MA (1995) Characterization of the polyubiquitin gene in the marine red alga Gracilaria verrucosa. Biochem. Biophy. Acta 1261: 215-222.
10. Zhou YH, Ragan MA (1996) Nuclear-encoded protein-coding genes of the agarophyte Gracilaria verrucosa (Gracilariales, Rhodophyta). Hydrobiologia 326/327, S.C. Lindstom & D.J. Chapman (eds), Fifteenth International Seaweed Symposium, Kluwer Academic Publishers, pp. 429-436.
11. Zhou YH, Li WH (1996) Gene conversion and natural selection in the evolution of X-linked color vision genes in higher primates. Mol. Biol. Evol 13: 780-783.
12. Zhou YH, Hewett-Emmett D, Ward JP, Li WH (1997) Unexpected conservation of the X-linked color vision gene in nocturnal prosimians: Evidence from two bush babies. J. Mol. Evol. 45: 610-618.
13. Boissinot, S, Zhou YH, Qiu Li, Dulai KS, Neiswanger K, Schneider H, Sampaio I, Hunt DM, Hewett-Emmett D, and Li WH (1997) Origin and molecular evolution of the X-linked color vision genes in howler monkeys. Zool. Studies 36:360-369.
14. Sun HM, Rodin A, Zhou YH, Dickinson DP, Harper DE, Hewett-Emmett D, Li WH (1997) Evolution of paired domains: Isolation and sequencing of jellyfish and hydra Pax genes related to Pax-5 and Pax6. Proc. Natl. Acad. Sci. USA. 94:5156-5161.
15. Zhou YH (corresponding author), Zheng JB, Gu X, Li WH, Saunders GF (2000) A novel Pax-6 binding site in rodent B1 repetitive elements: coevolution between developmental regulation and repeated elements? Gene 245:319-328.
16. Wu CF, Nakamura H, Chan AP, Zhou YH, Cao T, Kuang J, Gong SG, He G, Etkin LD (2001) Tumorhead, a Xenopus gene product that inhibits neural differentiation through regulation of proliferation. Development 128:3381-3393.
17. Zheng JB, Zhou YH, Maity T, Liao WS-L, Saunders GF (2001) Transcription factors SEF and Sp1 activate the human PAX6 through the exon 1 enhancer. Nucleic Acids Res. 29:4070-4078.
18. Zhou YH (corresponding author), Zheng JB, Gu X, Saunders GF, Yung WKA (2002) Novel PAX6 binding sites in human genome and the role of repetitive elements in evolution of gene regulation. Genome Res. 12:1716-1722.
19. Zhou YH, Tan F, Hess KR, Yung WKA (2003). The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin. Cancer Res. 9:3369-3375.
20. Wang H, Wang H, Shen W, Huang H, Hu L, Ramdas L, Zhou YH, Liao WS-L, Fuller GN, Zhang W (2003) Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 63:4315-4321.
21. Zhou YH (corresponding author), Wu X, Tan F, Shi YX, Glass T, Liu TJ, Wathen K, Hess KR, Gumin J, Lang F, Yung WKA (2005). PAX6 suppresses growth of human glioblastoma cells. J. Neuro-Oncology, 71:223-229.
22. Zhou YH (corresponding author), Hess KR, Longjian Liu, Linskey ME, Yung WKA (2005). Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables. Neuro-Oncology, 7(4):485-94.
23. Iruthayanathan M, Zhou YH, Childs GV (2005). Dehydroepiandrosterone restoration of growth hormone gene expression in aging female rats, in vivo and in vitro: evidence for actions via estrogen receptors. Endocrinology 146(12):5176-87.
24. Mayes DA, Hu Y, Teng Y, Siegel E, Wu X, Panda K, Tan F, Yung WKA, Zhou YH (corresponding author) (2006). PAX6 suppresses the invasiveness of glioblastoma cells and the expression of the matrix metalloproteinase 2 gene. Cancer Res. 66 (20): 9809-17.
25. Akhter N, Johnson BW, Crane C, Iruthayanathan M, Zhou YH, Kudo A, Childs GV (2007). Anterior Pituitary Leptin Expression Changes in Different Reproductive States: Stimulation, in vitro, by Gonadotropin Releasing Hormone (GnRH). J Histochem Cytochem. 55(2):151-66.
26. Heister D, Hayar A, Charlesworth A, Yates C, Zhou YH, Garcia-Rill E (2007). Evidence for electrical coupling in the SubCoeruleus (SubC) nucleus. J Neurophysiology. 97(4):3142-7
27. Chang J, Hu Y, Siegel E, Stanley L, and Zhou YH (corresponding author) (2007). PAX6 Increases Glioma Cell Susceptibility to Detachment and Oxidative Stress. J Neurooncol. 84(1):9-19.
28. Crane C, Akhter N, Johnson BW, Iruthayanathan M, Syed F, Kudo A, Zhou YH, Childs GV (2007). Fasting and glucose effects on pituitary leptin expression. Is leptin a local signal for nutrient status? Journal of Histochemistry and Cytochemistry. 55(10):1059-73
29. Wang-Gillam A, Siegel E , Mayes DA, Hutchins LF, , Zhou YH (corresponding author) (2007). Anti-tumor effect of doxycycline on glioblastoma cells. Journal of Cancer Molecules. 3: 147-153.
30. Zhou YH (2009). A structured review on: PAX6 (11p13), the Atlas of Genetics and Cytogenetics in Oncology and Haematology Atlas Genet Cytogenet Oncol Haematol. August, 2009.
31. Zhou YH (corresponding author), Hu Y, Mayes D, Siegel E, Kim JG, Mathews MS, Hsu N, Eskander D, Yu O, Tromberg BJ, Linskey ME (2010). PAX6 suppression of glioma angiogenesis and the expression of vascular endothelial growth factor A. J Neurooncol. 2010. 96(2): p. 191-200.
32. Zhou Y, Hofstetter WL, He Y, Hu W, Pataer A, Wang L, Wang J, Zhou YH, Yu L, Fang B, Swisher SG (2010) KLF4 inhibition of lung cancer cell invasion by suppression of SPARC expression. Cancer Biology & Therapy 9:7, 507-513.
33. Zhou YH (corresponding author), Vinay RR, Siegel E, Yu L (2010) Standardization of gene expression quantification by absolute real-time qRT-PCR system using a single standard for marker and reference genes. Biomarker Insights. 5: 79–85
34. Hoa N, Ge L, Kuznetsov Y, McPherson A, Cornforth AN, Pham JT, Myers MP, Ahmed N, Salsman VS, Lamb LS, Jr., Bowersock JE, Hu Y, Zhou YH, Jadus MR (2010) Glioma cells display complex cell surface topographies that resist the actions of cytolytic effector lymphocytes. J Immunol 185:4793-4803.
35. Zhou YH (corresponding author), Hess KR, Vinay RR, Yu L, Liu L, Yung WKA, Linskey ME (2010). Establishment of Prognostic Models for Astrocytic and Oligodendroglial Tumors with Standardized Quantification of Marker Gene Expression and Clinical Variables. Biomarker Insights. 2010:5 153–168
36. Hu Y, Pioli PD, Siegel E, Zhang Q, Nelson J, Chaturbedi A, Mathews MS, Ro DI, Alkafeef S, Hsu N, Hamamura M, Yu L, Hess KR, Tromberg BJ, Linskey ME, Zhou YH (2011). EFEMP1 is a tumor suppressor functioning in extracellular compartment of high grade gliomas. Mol Cancer. 2011 Sep 28;10(1):123. PMID: 21955618
37. He Y, Correa AM, Raso MG, Hofstetter WL, Fang B, Behrens C, Roth JA, Zhou YH, Yu L, Wistuba II, Swisher SG, Pataer A (2011) The role of PKR/eIF2a signaling pathway in prognosis of non-small cell lung cancer. PLoS ONE November 2011 | Volume 6 | Issue 11 | e24855
38. Chaturbedi A, Yu L, Linskey ME, Zhou YH (corresponding author) (2012). Detection of 1p19q deletion by real-time comparative quantitative PCR. Biomarker Insights. 7 9–17
Musella Foundation For Brain Tumor Research & Information, Inc (2/1/2012 – 1/31/2013),
Title: Development of a tumor suppressive extracellular signaling peptide to treat GBM, Role: PI;
UC CRCC (7/1/2011 – 6/30/2012), Title: Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 to treat malignant gliomas, Role: PI;
UC Irvine, CORCL Single Investigator Innovation Grant #SIIG 13-2009-2010 (7/1/2010- 6/30/2011),
Title: Modeling prognosis for GBM patients with standardized qualification of gene expression for a select set of genes,
UC, Irvine Foundation Philanthropy Gift (1/1/10 – 12/31/10),
Title: Operationalizing the PAX6 signaling pathway to identify new targets and create new therapies for patients with malignant glioma,
Chao Family Comprehensive Cancer Center Seed Grant (7/1/08 – 6/30/10),
Title: to establishing a more accurate and comprehensive prognostic model for patients with malignant gliomas through a combination of molecular and clinical variables,
University of California Irvine, School of Medicine Committee on Research Award (3/1/07 – 11/30/07),
Title: to characterization of downstream pathways of PAX6 on suppression of glioblastoma,
The Norwegian Radium Hospital Research Foundation (4/1/07-12/30/09)
Title: Treatment of malignant brain tumors using viral and non-viral PAX6 gene therapy and photochemical internalization,
Arkansas Cancer Research Center Tobacco Settlement Fund (7/1/03-6/30/06)
Title: Advancing the ACRC Neuro-Oncology Research Program
University of Arkansas for Medical Science, Center for Translational Neuroscience Pilot Grant (12/04 – 9/05)
Title: Prognostic Model for Patients with Glioblastoma,
American Society of Cancer IRG-91-021-11 (7/1/04 – 12/30/05)
Title: A Pathway of Tumor Suppression in GBMs,
University of Arkansas for Medical Science COM Pilot Fund (1/01/04 – 12/30/04)
Title: PAX6 function in medulloblastomas,
National Brain Tumor Foundation Pediatric Brain Tumor Grant (7/1/02-6/30/03)
Title: PAX6 Function in Medulloblastoma
NIH National Research Service Award 1F32 EY06949-01, 5 F32 EY06949-02 (10/1/98-09/30/00)
Title: PAX6 Target Genes and Eye Development,
2000-present, Active member, The American Society for Cancer Resear
2000-present, Active member, The Society for Neuro-Oncology
2004-present Adjunct member, Section on Tumors, American Association of Neurological Surgeons and Congress of Neurological Surgeons