PRL-3 and Cancer Metastasis


Lab Location: #3-02   Email: mcbzengq@imcb.a-star.edu.sg   Tel: 65869664

Qi Zeng studied her Ph.D in Roswell Park Memorial Institute (RPMI, USA) and IMCB.  She obtained her Ph.D in 1993 from National University of Singapore.  As part of her graduate work, she genetically engineered the first Transgenic Rat in Asia for a San Diego biotech firm to study human diabetes, and her success story appeared in Fortune Magazine (USA, Oct. 1991). She has continued using animal models to study human diseases for decades. Her team demonstrated that PRL-1 and PRL-3 monoclonal antibodies can inhibit experimental metastatic tumors expressing their respective antigens.  In 2009, Exploit Technologies Pte Ltd (ETPL, A*STAR) awarded her group a Flagship grant of $3.1 million for anticancer therapy in mice. (Please click here for more information) In 2011, she proposed a new concept of ‘Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination to treat cancer’.  She is a pioneer in using the unconventional approach of immunotherapy targeting intracellular oncoproteins for blocking tumor growth in cancer mice. Recently, in 2014.  an additional award of $1.5 million Gap fund to work until pre-clinical trials.  She is a leader in the fields of PRL-3 cancer research and unconventional immunotherapy targeting intracellular oncoproteins. She became a Senior Principal Investigator (Associate Professor) in 2010 and Research Director (Professor) in 2015..


PRL-3 and Cancer Metastasis

Dr Zeng’s laboratory works on both Basic and Translational Research:

Basic Research
PRL-3 phosphatase contributes to human cancers

PRL-3 phosphatase was identified in 1998 (Zeng et al., 1998). Professor Bert Vogelstein’s laboratory first found that PRL-3 was upregulated in colorectal cancer metastasis (Saha et al., 2001). PRL-3 was then demonstrated to play a causal role in promoting cancer metastasis in mice (Zeng et al., 2003). Subsequently, many other groups demonstrated that PRL-3 transcript or protein is often overexpressed in various types of human cancer and its expression is associated with poor prognosis. The group has found that PRL-3 could downregulate PTEN expression and signal through PI3K pathway to promote Epithelial-Mesenchymal Transition (EMT) (Wang et al., 2007). They identified PolyC-RNA-binding protein 1 (PCBP1) as an upstream negative regulator of PRL-3 translation and reveals a molecular mechanism responsible for the regulation of PRL-3 expression in cancer. The group has made high-impact contributions to the understanding of the molecular basis underlying PRL-3-induced cancer metastasis. Recently, they showed oncogenic roles of PRL‐3 in FLT3‐ITD induced acute myeloid leukaemia (Park, et al., 2013) and demonstrated that PRL-3 induces EGFR activation and addiction in cancer cells (Al-aidaroos et al., 2013). This study was featured as a cover story of the Journal of Clinical Investigation.

Figure legend: PRL-3 promotes EGFR activation and addiction. Elevated PRL-3 predicted favour response to pharmacological inhibitors of EGFR. This study uncovers a mechanism for PRL-3 in cancer progression. Here, EGF-stimulated human cancer cells are shown, with staining for phospho-tyrosyl activated proteins (red), EGFP-PRL-3 (green), and DNA (blue).

Translational Research: Inhibiting PRL-3 tumors in mice

The group generated specific PRL-1 and PRL-3 monoclonal antibodies (mAbs) (Li et al., 2005) and unexpectedly blocked PRLs-expressing tumors with the PRLs-mAbs in animal models (Guo et al., 2008). In 2011, the group reported a new concept of ‘Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination’ in Science Translational Medicine with Perspective; their findings were highlighted in Science main website on 7 Sept. 2011. ETPL expects her team to generate several humanized PRLs’ antibodies as therapeutic agents to treat human cancers that are associated with overexpression of PRL-phosphatases. Several pharmaceutical and biotech companies have expressed strong interests in the proposed pre-clinical studies using their mouse models.<span xml:lang="EN-US" lang="EN-US">

Figure legend: PRL-3 antibody could block metastatic tumors expressing intracellular PRL-3 oncoprotein. Mice were injected (via tail vein) with 1 x 106 B16F0 cells that express endogenous PRL-3. In treated mice, PRL-3 chimeric antibody was injected (via tail vein), following therapeutic schedule (100ug/dose, twice/week). Organs were harvested, examined, and imaged on ~ day 17. Arrows point at the metastatic tumors formed by B16F0 cells (PRL-3 positive).



Department: Qi ZENG

Name: Abdul Qader AL-AIDAROOS

Designation: Senior Research Fellow

Email: qaderaa@imcb.a-star.edu.sg

Name: Vivian Yujing LIM

Designation: Research Fellow (A-Star NSS Scholar)

Email: limvyj@imcb.a-star.edu.sg

Name: Abhishek GUPTA

Designation: Research Officer

Email: abhishekg@imcb.a-star.edu.sg

Name: Thura MIN

Designation: Senior Research Fellow

Email: mthura@imcb.a-star.edu.sg

Name: Xuan En Joel SNG

Designation: Research Fellow (A-Star NSS Scholar)

Email: sngxej@imcb.a-star.edu.sg

Name: Nicholas Yan Zhi TAN

Designation: Research Officer

Email: tanyz@imcb.a-star.edu.sg

Name: Jie LI

Designation: Research Officer

Email: mcblij@imcb.a-star.edu.sg


Thura, M., Al-Aidaroos, A.Q., Gupta, A., Chee, C.E., Lee, S.C., Hui, K.M., Li, J., Yong, W.P., So, J., Chng, W.J., Ng, C.H., Zhou, J.B., Wong, L.Z., Yuen, S.P., Ho, S.S., Y., S.M., Chiong, E., Choo, S.P., Ngeow, J., Ng, C.H., Chua, C., Yeo, S.A., Tan, B.H., Sng, X.E., Tan, Y.Z.,  Thiery, J.P., Goh, B.C., and Zeng, Q. (2019) PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein.
Nature Communication 10:2484. 

Min Thura, Abdul Qader Omer Al-Aidaroos, Wei Peng Yong ,Koji Kono, Abhishek Gupta, You Bin Lin, Kousaku Mimura, Jean Paul Thiery, Boon Cher Goh, Patrick Tan, Ross Soo, Cheng William Hong, Lingzhi Wang, Suling Joyce Lin, Elya Chen, Sun Young Rha, Hyun Cheol Chung, Jie Li, Sayantani Nandi, Hiu Fung Yuen, Shu-Dong Zhang, Yeoh Khay Guan, Jimmy So and Qi Zeng
JCI Insight1(9):e87607. doi:10.1172/jci.insight.87607

H Wang, B Liu, AQO Al-Aidaroos, H Shi, L Li, K Guo, J Li, BCP Tan, JM Loo, JP Tang, M Thura and Q Zeng (2016)
Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans
Oncogene 35, 3303-3313

Zu Ye, Abdul Qader Omer Al-aidaroos, Jung Eun Park, Hiu Fung Yuen, Shu Dong Zhang, Abhishek Gupta, Youbin Lin, Han-Ming Shen and Qi Zeng (2015)
Scientific Reports, 5:17046 | DOI: 10.1038/srep17046

Yu-Han Huang*, Abdul Qader O Al-aidaroos*, Hiu-Fung Yuen*, Shu-Dong Zhang, Han-Ming Shen, Ewelina Rozycka,Cian M McCrudden, Vinay Tergaonkar, Abhishek Gupta, You Bin Lin, Jean Paul Thiery, James T Murray, and Qi Zeng (2014)
A role of autophagy in PTP4A3-driven cancer progression.
Autophagy 10:10
*equal first authors

Park, J.E., Yuen, H.F., Zhou, J.B., Al-aidaroos, A.Q., Guo, K., Valk, P.J., Zhang, S.D., Chng, W.J.,  Hong, C.W., Mills, K., and Zeng, Q. (2013)
An oncogenic role of PRL-3 in FLT3-ITD Induced Acute Myeloid Leukemia.
EMBO Mol Med

Al-aidaroos, A.Q., Yuen, H.F., Guo, K., Zhang, S.D., Chung, T.H., Chng, W.J., and Zeng, Q. (2013)
PRL-3 induces EGFR activation and addiction in human cancer cells.
Journal of Clinical Investigation

Liu, H., Al-aidaroos, A.Q., Wang, H., Guo, K., Li, J., Zhang, H.F., and Zeng, Q. (2013)
PRL-3 suppresses c-Fos and integrin α2 expression in ovarian cancer cells.
BMC Cancer

Xu, S., Guo, K., Zeng, Q., Huo, J., and Lam, K.P. (2012)
The RNase III enzyme Dicer is essential for germinal center B-cell formation.

Guo, K.*, Tang, J.P.*, Jie, L.*, Al-Aidaroos, A.Q., Hong, C.W., Tan, C.P., Park, J.E., Varghese, L., Feng, Z., Zhou, J., Chng, W.J., and Zeng, Q. (2012)
First Chimeric Antibody in Targeting Intracellular Oncoprotein for Cancer Therapy in Mice.
* equal first authors

Guo, K.*, Li, J.*, Tang, J.P.*, Tan, C.P., Hong, C.W., Al-Aidaroos, A.Q., Varghese, L., Huang, C., Zeng, Q. (2011) Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination.
Science Translational Medicine
3(99):99ra85. (Proposed the new concept of unconventional Immunotherapies to target intracellular oncoproteins)
* equal first authors

Jiang, Y., Liu, X., Rajput, A., Geng, L., Ongchin, M., Zeng,Q., Taylor, G.S., and Wang J. (2011)
Phosphatase PRL-3 is a Direct Regulatory Target of TGFβ in Colon Cancer Metastasis.
Cancer Research 71:234-44.

Zhou J, B.C., Chng, W.J., Cheong, L.L., Liu, S.C., Mahara, S., Tay, K.G., Zeng, Q., Li, J., Guo, K., Tan, C.P., Yu, H., Albert, D.H., and Chen, C.S. (2011)
PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy.
PLoS One.
Wang, H., Vardy, L., Tan, C.P., Loo, J.M., Guo, K., Li, J., Lim, S.G., Zhou, J., Chng, W.J., Ng, S.B., Li, H.X., and Zeng, Q. (2010)
PCBP1 Suppresses the Translation of Metastasis-Associated PRL-3 Phosphatase.
Cancer Cell

Tang, J.P.*, Tan, C.P.*, Li, J.*, Siddique, M.M., Guo, K., Chan, S.W., Park, J.E., Tay, W.N., Huang, Z.Y., Li, W.C., Chen, J., and Zeng, Q. (2010)
VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers.
Molecule Cancer
* equal first authors

Guo, K.*, Li, J.*, Tang, J.P.*, Tan, C.P., Wang, H., and Zeng, Q. (2008)
Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice.
Cancer Biology & Therapy
* equal first authors

Basak, S., Jacobs, S.B., Krieg, A.J., Pathak, N., Zeng, Q., Kaldis, P., Giaccia, A.J., Attardi, L.D.  (2008)
The metastasis-associated gene Prl-3 is a p53 target involved in cell cycle regulation.
Molecular Cell

Wang, H.H., Quah, S.Y., Dong, J.M.,Manser, E., Tang, J.P. and Zeng, Q. (2007)
PRL-3 downregulates PTEN expression and signals through PI3K to promote Epithelial-Mesenchymal Transition.
Cancer Research 67:2922-2926.

Guo, K., Li, J., Wang, H.H., Osato, M., Tang, J.P., Quah, SY., Gan, B.Q., and Zeng Q. (2006)
PRL-3 initiates tumor angiogenesis by recruiting endothelial cells in vitro and in vivo.
Cancer Research

Wang, Y., Foo, L.Y., Guo, K., Gan, B.Q., Zeng, Q., Hong, W., and Tang, B.L. (2005)
Syntaxin 9 is enriched in skin hair follicle epithelium and interacts with the Epidermal Growth Factor Receptor.
Wang, X.Y., Kua, H.Y., Guo, K., Zeng, Q., Wu, Q., Ng, H.H., Karsenty, G., Crombrugghe, B., Yeh, J., and Li B.J. (2005)
P53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis and bone remodeling.
J. Cell Biol. 172:115-125.

Li, J., Guo, K., Koh, V.W.C., Tang, J.P., Gan, B.Q. Shi, H., Li, H.X. and Zeng, Q. (2005)
Generation of PRL-3 and PRL-1 specific monoclonal antibodies as potential diagnostic markers for cancer metastases.
Clinical Cancer Research
11:2195-2204 (Cover). 

Guo, K.*, Li, J.*, Tang, J.P.*, Koh, V., Gan, B.Q., and Zeng, Q. (2004)
Catalytic Domain of PRL-3 Plays an Essential Role in Tumor Metastasis; Formation of PRL-3 tumors inside the blood vessels.
Cancer Biology & Therapy 3:945-951 (Cover with commentary).
* equal first authors

Koh, V., Fu, J.L., Guo, K., Lip, K.M., Li, J., and Zeng, Q. (2003)
PRL-3 as a target for cancer therapy
Gene Ther. Mol. Biol.

*Zeng, Q., Dong, J.M., Guo, K., Li, J., Tan, H.X., Koh, V., Pallen, C.J., Manser, E., and Hong, W. (2003)
PRL-3 and PRL-1 promote cell migration, invasion, and metastasis.
Cancer Research
63:2716-2722 (*Correspondence).

Si, X., Zeng, Q., Ng, C.H., Hong, W., and Pallen, C.J. (2001)
Interaction of Farnesylated PRL-2, a protein Tyrosine Phosphatase, with the Beta Subunit of Geranylgeranyltransferase II.
J. Biol. Chem. 276:32875-32882.

Zeng, Q., Si, X., Horstmann, H., Xu, Y., Tan, Y.H., Hong, W. and Pallen, C.J. (2000)
Prenylation-dependent Association of Protein-tyrosine Phosphatases PRL-1, -2, and -3 with the Plasma Membrane and the Early Endosome.
J. Biol. Chem. 274:21444-21452.

Zeng, Q., Hong, W., and Tan, Y.H. (1998)
Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1.
Biochem. Biophys. Res. Commun. 244:421-7. (Identified PRL-3 for the first time)

Invited reviews:

Hong, C.W. and Zeng Q. (2013)
Targeting Intracellular Oncoproteins with Immunotherapy.
FEBS Lett, Invited review

Hong, C.W. and Zeng Q. (2012)
Awaiting a New Era of Cancer Immunotherapy.
Cancer Research
72: 3715-19.

Al-Aidaroos, A.Q., and Zeng, Q. (2010)
PRL-3 phosphatase and human cancers.
Journal of Cellular Biochemistry
111:1087-98 (Highlighted as Cover).

Zeng, Q., and Hong, W. (2008)
The emerging role of the Hippo pathway in cell contact inhibition, organ size control and cancer development in mammals (mini-review).
Cancer Cell