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    • Fibronectin protein level was not affected by DIF although

    2022-07-30

    Fibronectin protein level was not affected by DIF-1, although fibronectin has also been considered a canonical Wnt signaling pathway target gene product [39]. Thus, the canonical Wnt signaling pathway may not be critical for the regulation of the expression of fibronectin in malignant melanoma cells. Further studies are necessary to clarify the precise mechanism that mediates differential expression of MMP-2 and fibronectin in malignant melanoma cells. In addition, as it has been reported that fibronectin suppressed cell invasion and metastasis in malignant melanomas, including B16BL6 mln4924 synthesis [43], it may not be a positive regulator of cell migration and invasion in malignant melanoma cells. The previous report demonstrated that inhibition of MMP-2 expression by siRNA altered the expression of VEGFR2 in lung cancer cells [44]. However, in the present study, we found that MMP-2 knockdown by siRNA did not affect the expression level of VEGFR2 in HUVECs. This result suggests that MMP-2 might not be involved with the regulation of VEGFR2 expression in HUVECs. Further studies are required to clarify the role of MMP-2 in VEGFR2 expression in vivo. In the in vivo experiment, DIF-1 exhibited an anti-tumor effect in the mouse model of lung tumor formation. In the steps of the metastasis formation in lung, cancer cells in circulating blood adhere to capillary endothelial cells and infiltrate to lung parenchyma to proliferate in it [45]. Therefore, the tumor formation in lung is mediated by not only adhesion but also invasion and proliferation. As shown in A, oral administration of DIF-1 decreased the number of tumor and also the size of tumors, suggesting that DIF-1 affected not only adhesion but also invasion and proliferation. Moreover, we showed that DIF-1-treatment decreased the expression levels of cyclin D1, c-Myc, β-catenin, TCF7L2, MMP-2 and PECAM-1 in the lungs (Fig. 9, Fig. 10). Injection of melanoma cells appeared to upregulate the expression levels of cyclin D1, MMP-2 and PECAM-1 in the whole lung, though it was not statistically significant. Because DIF-1 reduced these expression levels to the control levels, anti-cancer effect of DIF-1 seemed to be mediated by these inhibitions. However, we have to mention that as these lung samples contained healthy tissue as well as melanoma cells, DIF-1 may have affected the expression of these proteins in both B16BL6 melanoma cells and healthy tissue. Indeed, c-Myc, β-catenin and TCF7L2 expression levels were significantly lower in DIF-1-treated samples compared with those in control samples, suggesting that DIF-1 possibly suppressed the expression of these proteins in healthy tissue. However, even though, DIF-1-treatment did not cause any apparent adverse reactions as we showed in previous reports [25], [28], [29]. The results of the in vivo experiments of the present study showed that DIF-1 inhibited tumor growth, cell invasion and angiogenesis, all of which are required for metastasis of malignant melanoma. Five-year survival rates are relatively favorable for stage I and stage II melanoma patients (98.3 and 64.2%, respectively), whereas prognosis for patients with distal metastasis is extremely poor (16.1%) [46]. Therefore, inhibition of metastases by DIF-1 could extend survival period of patients. In conclusion, we revealed that DIF-1 exhibited GSK-3-dependent anti-proliferative effect and GSK-3-independent anti-migratory and anti-invasive effects in malignant melanoma cells. However, despite our efforts and those of other research groups, the target molecule(s) through which DIFs exert their biological effects (suppression of cell proliferation, migration, invasion, and angiogenesis) on mammalian cells has not yet been identified [20], [21], [24], [25], [26], [27], [28], [47], [48]. Therefore, further studies are necessary to elucidate the direct target molecule(s) to reveal the precise mechanisms of DIF-1 action. Such data could facilitate the development of novel anti-cancer agents, which can strongly suppress tumor growth, invasion, and angiogenesis.