Neuropilin-1 is up-regulated by cancer-associated fibroblast-secreted IL-8 and associated with cell proliferation of gallbladder cancer

  • J Cell Mol Med. 2020 Nov;24(21):12608-12618. doi: 10.1111/jcmm.15825.
Chen Chen  1 ,  Rui Zhang  1 ,  Li Ma  2 ,  Qi Li  1 ,  Ya-Ling Zhao  3 ,  Guan-Jun Zhang  4 ,  Dong Zhang  1 ,  Wen-Zhi Li  1 ,  Sheng Cao  5 ,  Lin Wang  1 ,  Zhi-Min Geng  1
Affiliations
  • 1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
  • 2. Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
  • 3. Department of of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi Province, China.
  • 4. Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
  • 5. Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
PMID: 32951327 DOI: 10.1111/jcmm.15825
Abstract

We previously demonstrated that cancer-associated fibroblasts (CAFs) promoted the proliferation of gallbladder Cancer (GBC) cells, but the mechanism is not clear. Neuropilin-1 (NRP-1) plays an important role in various malignancies as Transmembrane Glycoprotein. Our goal was to reveal the relationship between CAFs and NRP-1 and their potential functions in GBC. In this study, we found NRP-1 was overexpressed in GBC tissue, associated with poor survival and was up-regulated by CAFs. The cytokine array cluster analysis revealed IL-8 secreted by CAFs facilitated the up-regulation of NRP-1 in tumour cells. NRP-1 knockdown suppressed tumour growth in vivo. Gene expression microarray analysis showed 581 differentially regulated genes under NRP-1 knockdown conditions. Ingenuity pathway analysis demonstrated that NRP-1 knockdown may inhibit tumour progression by affecting cell proliferation. We then confirmed that NRP-1 knockdown in NOZ and GBC-SD cells significantly inhibited cell proliferation. Additionally, the IL-8 mediated MDM2 and CCNA2 expression were affected by NRP-1 knockdown. Our findings suggested that NRP-1 was up-regulated by CAF-secreted IL-8, which subsequently promoted GBC cell proliferation, and these molecules may serve as useful prognostic biomarkers and therapeutic targets for GBC.

Keywords
cancer-associated fibroblasts; cell proliferation; gallbladder cancer; neuropilin-1; prognostic factor.
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