Erschienen in:
02.08.2022 | Translational Research
PLXND1/SEMA3E Promotes Epithelial–Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer
verfasst von:
Kiyotaka Hagihara, MD, Naotsugu Haraguchi, MD, PhD, Junichi Nishimura, MD, PhD, Asuka Yasueda, MD, PhD, Shiki Fujino, MD, PhD, Takayuki Ogino, MD, PhD, Hidekazu Takahashi, MD, PhD, Norikatsu Miyoshi, MD, PhD, Mamoru Uemura, MD, PhD, Chu Matsuda, MD, PhD, Tsunekazu Mizushima, MD, PhD, Hirofumi Yamamoto, MD, PhD, Masaki Mori, MD, PhD, Yuichiro Doki, MD, PhD, Hidetoshi Eguchi, MD, PhD
Erschienen in:
Annals of Surgical Oncology
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Ausgabe 12/2022
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Abstract
Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced by the transforming growth factor beta (TGF-β)-mediated canonical Smad pathway. This study focused on plexin D1 (PLXND1), a chemoreceptor for the ligand SEMA3E to mechanosensory, showing that PLXND1 induces EMT via activation of the PI3K/AKT pathway in CRC cells. The findings showed that PLXND1-knockdown decreases cell migration and invasion significantly, and that the binding of p61-SEMA3E to the PLXND1 enhances the invasiveness and migration through EMT. Furin inhibitor suppresses EMT, decreasing cell migration and invasion. Furin cleaves full-length SEMA3E and converts it to p61-SEMA3E, suggesting that furin inhibitors block PLXND1 and p61-SEMA3E binding. Furin is a potential therapeutic target for the purpose of suppressing EMT by inhibiting the binding of p61-SEMA3E to PLXND1. In vivo experiments have shown that PLXND1-knockdown suppresses EMT. Mesenchymal cells labeled with ZEB1 showed heterogeneity depending on PLXND1 expression status. The high-expression group of PLXND1 in 182 CRC samples was significantly associated with poor overall survival compared with the low-expression group (P = 0.0352, median follow-up period of 60.7 months) using quantitative real-time polymerase chain reaction analysis. Further research is needed to determine whether cell fractions with a different expression of PLXND1 have different functions.