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PLXND1/SEMA3E Promotes Epithelial–Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer

  • Translational Research
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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.

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Acknowledgment

We thank Ms. Miki Sakaue for her technical support in this study. This work was supported by a Grant-in-Aid for Young Scientists (19K18117). The funding source played no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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Author notes

  1. Kiyotaka Hagihara and Naotsugu Haraguchi have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Kiyotaka Hagihara MD, 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, Yuichiro Doki MD, PhD & Hidetoshi Eguchi MD, PhD

  2. Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka-shi, Osaka, Japan

    Naotsugu Haraguchi MD, PhD, Junichi Nishimura MD, PhD & Asuka Yasueda MD, PhD

  3. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masaki Mori MD, PhD

Authors
  1. Kiyotaka Hagihara MD
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  2. Naotsugu Haraguchi MD, PhD
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Correspondence to Naotsugu Haraguchi MD, PhD.

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Hagihara, K., Haraguchi, N., Nishimura, J. et al. PLXND1/SEMA3E Promotes Epithelial–Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer. Ann Surg Oncol 29, 7435–7445 (2022). https://doi.org/10.1245/s10434-022-11945-y

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