Secreted PEBP4 promotes colorectal cancer progression via regulation of the TGF-β signaling pathway

Phosphatidylethanolamine binding protein 4 (PEBP4) is a multifunctional protein. The role of intracellular PEBP4 in cancer is well established. However, as a secreted protein, its extracellular functions have yet to be elucidated. Thus, the present study attempted to decipher the functions of the secreted PEBP4. Here, we demonstrated that PEBP4 was upregulated in colorectal cancer (CRC) specimens and was also elevated in the serum of CRC patients. Our results revealed that the secreted PEBP4 (sPEBP4) stimulated the proliferation and migration of colon cancer cells, an event that was prevented by treatment with antibodies against PEBP4 or by mutating the N-glycosylation site (N169 to Q). Our studies indicated that the action of sPEBP4 was different from that of its cellular counterpart. Further, co-injection of the sPEBP4 with colon cancer cells promoted tumorigenesis and lung metastasis in vivo. Mechanistically, sPEBP4 increased phosphorylation of Smad2/3 and Akt/mTOR, which was blocked by the TGFβRⅠ inhibitor SB525334, siRNA or a dominant-negative mutant of TGFβRI, but not by knockdown of IGF-1R or EGFR. In vitro surface plasmon resonance assay revealed that sPEBP4 directly associated with TGFβRs. Finally, sPEBP4 enhanced the stability of TGFβRI by upregulating USP4 through a mechanism similar to TGF-β. Collectively, our study for the first time demonstrates that sPEBP4 activates the TGF-β signaling pathway to promote CRC progression in a TGFβ-independent manner. This would prompt further studies to explore if sPEBP4 could serve as a potential candidate for colorectal cancer therapy or a biomarker for diagnosis, prognosis, and therapeutic responses.