4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways

Abstract

In order to identify the anti-invasive and anti-metastatic effect of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on the human bladder cancer EJ cell line, and to study its impact on the expression of wingless-type mouse mammary tumor virus integration site family, member 5a (Wnt5a), the phosphorylation of c-Jun N-terminal kinase (JNK), the expression levels of matrix metalloproteinase-2 (MMP-2), and the migration and invasion of EJ cells, migration and Matrigel invasion assays, as well as western blot analyses, were used in the present study. The results of the migration and Matrigel invasion assays indicated that the inhibitor of JNK SP600125 could inhibit the effect of 4-HPR on EJ cells. The expression of Wnt5a and MMP-2, and the phosphorylation of JNK, were analyzed by western blotting. The data revealed that 4-HPR inhibited the migration and invasion of bladder cancer cells through stimulating Wnt5a activation, causing the downregulation of MMP-2 expression and enhancing the phosphorylation of JNK in these cells. However, JNK signaling did not appear to have a direct effect on the expression of MMP-2. The present study demonstrated that 4-HPR may be a potent anti-invasive and anti-metastatic agent that functions via the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways.

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

“…There are no other sources of information on the MMP2 regulation by WNT5A in arthritis, but in cancer cells the two types of results can be found. Several cells show induction of MMP2 by WNT5A (55,56), but others show inhibition (57). The cancer studies are also of interest because they show that WNT5A stimulates MMP2 expression through ROR2 (55,56), a receptor that was expressed at low levels in the RA FLS and that was not involved in the WNT5A modulation of migration suggesting a possible mechanism of the differential MMP2 regulation.…”

Upregulated Vav2 in gastric cancer tissues promotes tumor invasion and metastasis

“…MMP-2 and MMP-9 play a significant role in promoting the invasion and migration of gastric cancer cells, whereas TIMP-1 inhibits this process by regulating MMP-9. 27–32 This study showed that inhibition of Vav2 in BGC823 cells leads to markedly reduced expression of MMP-2 and MMP-9 and significantly increased expression of TIMP-1, suggesting that Vav2 gene in gastric cancer cells may be involved in invasion and metastasis of gastric cancer cells by regulating MMP-2, MMP-9, and TIMP-1. However, the molecular mechanism needs further study.…”

“…MMP-2 and MMP-9 play a significant role in promoting the invasion and migration of gastric cancer cells, whereas TIMP-1 inhibits this process by regulating MMP-9. [27][28][29][30][31][32] This study showed that inhibition of Vav2 in Table 2. Expression of Rac1, MMP-2, MMP-9, and TIMP-1 proteins in gastric cancer and normal gastric mucosa (n = 115).…”

SOX4 regulates invasion of bladder cancer cells via repression of WNT5a

“…Moreover, WNT5a is one of the most statistically significant upregulated genes as a result of SOX4 knockdown and significantly downregulated upon the re-expression of SOX4. WNT5a expression has been shown to decrease the migratory or invasive characteristics in FTC-133 thyroid cell lines and EJ bladder cancer cell lines (53,54), a derivative of T24 cells. In this study, we confirmed the high expression of WNT5a in T24-SOX4-KD cell lines compared to the T24-Scr and T24-SOX4-Rescue cell lines by RT-qPCR (Fig.…”