Fig. 6

Tumor-promoting role of CCN4 and its downregulation by tibial loading. Notably, load tibial loading, CN control, Dop dopamine, FP fluphenazine. a Cytokine array analysis using the serum proteins obtained from tumor-inoculated BALB/c mice showing the downregulation of CXCL13, endostatin, IL12, and CCN4 by tibial loading. b Reduction in CCN4 level by dopamine and FP in 4T1Br cells. c Downregulation of CCN4 by the silencing of Lrp5. d Increase in Snail, MMP9, and Runx2 by the administration of recombinant CCN4 proteins in 4T1Br cells. e Transcript level correlation between CCN4/Runx2 and CCN4/TGFβ in patients with breast cancer in the TCGA database. f Elevation of CCN4 transcripts in breast-cancer tissues and the increase in CCN4 gene copy number. g Reduced survival rates of patients (with breast, lung, or prostate cancer) with high levels of CCN4 transcripts. h Schematic illustration of the regulatory mechanism induced through the dopamine-Lrp5 axis. In this model, tibial loading and FP chiefly act on DRD1 and DRD2, respectively, and they downregulate Lrp5, CCN4, MMP9, Runx2, and Snail