Endoplasmic reticulum–resident protein Sec62 drives colorectal cancer metastasis via MAPK/ATF2/UCA1 axis. Issue 12 (5th October 2022) - Jin, Yirong
Abstract: Objective: Metastasis is responsible for the poor prognosis of patients with colorectal cancer (CRC), and the role of aberrant expression of endoplasmic reticulum (ER) receptors in tumour metastasis has not been fully elucidated. The aim of the study is to ensure the role of ER‐resident protein Sec62 in CRC metastasis and illuminate associated molecular mechanisms. Materials and Methods: Bioinformatics analysis, qRT‐PCR, western blot and immunohistochemistry assays were performed to evaluate the expression level and clinical significance of Sec62 in CRC. The specific role of Sec62 in CRC was identified by a series of functional experiments. We conducted RNA sequencing and rescue experiments to analyse the differentially expressed genes and identified UCA1 as a novel pro‐metastasis target of Sec62 in CRC. Besides, the efficacy of MAPK/JNK inhibitor or agonist on Sec62‐mediated CRC metastasis was evaluated by trans‐well and wound healing assays. Finally, luciferase reporter and ChIP assay were employed to further explore the potential mechanisms. Results: The abnormally elevated expression of Sec62 predicted poor prognosis of CRC patients and facilitated malignant metastasis of CRC cells. Mechanistically, Sec62 enhanced UCA1 expression through activating MAPK/JNK signalling pathway. And the p‐JNK activating ATF2 could transcriptionally regulate UCA1 expression. Furthermore, blocking or activating MAPK/JNK signalling with JNK inhibitor or agonist potently suppressed or enhanced Sec62 mediated CRC metastatic process. Conclusions: Our study reports for the first time that the Sec62/MAPK/ATF2 /UCA1 axis exists in CRC metastatic process, which could be a potential treatment target of metastatic CRC. Abstract : Metastasis accounts for poor prognosis of patients with CRC. The effects of aberrant expression of endoplasmic reticulum (ER) receptors in cancer have not been fully elucidated, especially in CRC. Here, we unveiled that ectopic expression of Sec62 could predict poor prognosis of CRC patients and facilitate malignant metastasis of CRC cells. Mechanistically, Sec62 enhanced UCA1 expression through activating MAPK/ JNK signalling, subsequently potentiated CRC migration and invasion. The p‐JNK activating ATF2 could directly bind to UCA1 promoter and transcriptionally activate UCA1. Clinically, blocking or activating MAPK signalling by inhibitors or agonists potently suppressed or enhanced Sec62‐mediated CRC metastasis. Our study reports the Sec62/MAPK/ATF2 /UCA1 axis may serve as a potential target in metastatic CRC treatment.