Loss Of PTPN4 Activates STAT3 To Promote The Tumor Tumorigenesis In Rectal Cancer

Colorectal cancer(CRC)is one of the most common types of malignant tumor.Although many environmental and genetic factors have been proved to show high association with the occurrence and development of CRC,somatic mutations are still considered to be the main cause of CRC.PTPN4/PTP-MEG1 is a widely expressed non-receptor protein tyrosine phosphatase.PTPN4 has been well studied to participate in many biological processes in the past three decades.However,whether PTPN4 takes participation in the CRC tumorigenesis is still unknown and the detailed mechanism remains to be elucidated.In this study,we identified a nonsense mutation of PTPN4 with a mutation ratio of 90.90%from one case of rectal cancer,leading to loss-of-function in PTPN4 gene.Several somatic mutations,including nonsense mutations,were found in colorectal cancer samples from TCGA database.Interestingly,we found that low expression of PTPN4 in rectal cancer was highly associated with poor prognosis.Overexpression of PTPN4 suppressed the cell growth,whereas,the loss of PTPN4 accelerated cell growth and boosted clonogenicity of colorectal cancer cells.Furthermore,we revealed that the deletion of PTPN4 promoted the tumor formation of NCM460 cells in vivo.In terms of the molecular mechanism,we demonstrated that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction and inhibits transportation of STAT3 into nucleus.Ultimately PTPN4 can suppress the transcriptional activity of STAT3.In summary,our study revealed a novel mechanism that the tumorigenesis of colorectal cancer might be caused by the loss of PTPN4 through activating the STAT3,which will broaden the therapy strategy for anti-colorectal cancer in the future.