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Research Paper|Volume 14, Issue 17|pp 7093—7108

Tyrosine kinase receptor RON activates MAPK/RSK/CREB signal pathway to enhance CXCR4 expression and promote cell migration and invasion in bladder cancer

Junfeng Chen1,2, Kejie Wang1,2, Shazhou Ye1,2, Xiangyu Meng1,2, Xiaolong Jia2, Youju Huang3, Qi Ma1,2,4
  • 1Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
  • 2Ningbo Clinical Research Center for Urological Disease, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
  • 3College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Zhejiang, China
  • 4Comprehensive Urogenital Cancer Center, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo 315010, Zhejiang, China
Received: May 17, 2022Accepted: August 23, 2022Published: September 13, 2022
https://doi.org/10.18632/aging.204279

Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Bladder cancer (BC) is one of the most lethal malignancies worldwide. The poor survival may be due to a high proportion of tumor metastasis. RON and CXCR4 are the key regulators of cell motility in BC, while the relationship between RON and CXCR4 remains elusive. In the present study, immunohistochemistry analysis of BC and adjacent normal tissues found that higher RON expression was positively correlated with CXCR4 expression. Inhibiting and replenishing RON level were used to regulate CXCR4 expression, observing the effects on migration and invasion of BC cells. Overexpression of RON reversed the inhibited cell migration and invasion following siCXCR4 treatment. Conversely, overexpression of CXCR4 restored the inhibition of cell migration and invasion caused by shRON. The activation of RON-MAPK/RSK/CREB pathway was demonstrated in BC cells under MSP treatment. Dual luciferase and CHIP assay showed that p-CREB targeted CXCR4 by binding to its CRE sequence. RON knockdown suppressed BC tumor growth in xenograft mouse tumors, accompanied by reduced expression of CXCR4. In conclusion, our data adds evidence that RON, a membrane tyrosine kinase receptor, promotes BC migration and invasion not only by itself, but also by activating MAPK/RSK/CREB signaling pathway to enhance CXCR4 expression.