Abdul Qader Omer Al-aidaroos1, Hiu Fung Yuen1, Ke Guo1, Shu Dong Zhang2, Tae-Hoon Chung4, Wee Joo Chng3,4, Qi Zeng1,5,*.
1 - Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore.
2 - Center for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, United Kingdom.
3 - Haematological Malignancy Genomics Lab, Cancer Science Institute of Singapore, National University of Singapore, Singapore.
4 - Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, Singapore.
5 - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
* Corresponding author: Zeng QI's lab, please click here.
Published online in the Journal of Clinical Investigation, Vol. 123 (8), on 8 July 2013.
To read the paper, please click here.
For press release, please click here.
Also featured on August cover of the JCI.
Metastasis-associated PRL-3 has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of the EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, pro-migratory character, and tumorigenicity. Importantly, PRL-3 induced cellular addiction to EGFR signaling as evidenced by the pronounced reversion in these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically-approved anti-EGFR antibody, cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose elevated PRL-3 expression as an important clinical predictive biomarker for favorable anti-EGFR cancer therapy outcome.
(Proposed model of PRL-3-induced oncogenic addiction to hyperactivated EGFR. (A-B) Compared to non-PRL-3-overexpressing cells (A), PRL-3 overexpression (B) induces the constitutive hyperactivation of the EGFR primarily via the downregulation of PTP1B, thereby promoting the growth of ‘EGFR-addicted’ cancer cells. (C-D) Compared to non-PRL-3-overexpressing cells (C), such ‘EGFR-addicted’ PRL-3-overexpressing cells (D) are hypersensitive to EGFR inhibition