miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

Abstract

Summary MicroRNAs are involved in the control of tumour progression and in metastatic cascade dynamics. However, the role of microRNAs in distant organ reorganization at the premetastatic stage is less clear, although the process of premetastatic niche formation is a crucial event according to modern concepts of tumour dissemination. The role of the present study was to investigate the expression levels of miR‐155, miR‐21, miR‐205 and miR‐let7b, as well as that of their target genes, in target organs of melanoma metastasis at the premetastatic stage. The expression levels of both the pro‐oncogenic miR‐155 and the tumour suppressive miR‐205 were found to be altered in the premetastatic liver of melanoma B16‐bearing mice. Bioinformatics analysis identified the target genes of miR‐155 to be nuclear factor, erythroid 2 like 2 (NFE2L2), secretogranin II, miR‐205, semaphorin 5A and vascular endothelial growth factor A (VEGFA). Among those, the redox status regulatory factor NFE2L2 was downregulated, which corresponded to increased levels of miR‐155. Due to the ability of pro‐oxidative events to initiate angiogenesis, VEGFA levels were evaluated in the premetastatic liver by immunohistochemistry, which revealed increased VEGFA expression in the central parts of the organ and diminished expression in the periphery. Taken together, these findings may support the concept of functional organ reorganization due to melanoma progression.

The dual role of Nrf2 in melanoma: a systematic review

“…In the pre-metastatic liver of melanoma-bearing mice, a reduction in Nrf2 expression was discovered, leading to oxidative stress and acidosis. This state is consistent with the tumor microenvironment, enhances melanoma cell survival, and facilitates metastasis [36]. These findings imply that redox imbalance changes the environment in favor of metastasis and that the Nrf2 antioxidant response is critical in this process.…”

“… A reduction in NFE2L2 gene expression in the premetastatic organs may be associated with metastatic niche formation and stromal progression, results in premetastatic tissue reconstruction. [ 36 ] Chhabra et al, 2019 Neonatal human skin melanocyte UVA and/or UVB exposure increase ROS and downregulate Nrf2 expression in melanocytes. Nrf2-Keap1 pathway plays a key role in protecting skin cells against UVA and UVB induced oxidative damage.…”

Eupafolin inhibits breast cancer cell proliferation and induces apoptosis by inhibiting the PI3K/Akt/mTOR pathway

“…VEGF is abnormally expressed in liver cancer and plays an important role in liver cancer neovascularization and tumor growth ( 5 ). The treatment of cancer by targeting VEGF and its receptor, VEGFR, is a much-explored topic in drug research ( 16 ). After treatment with different concentrations of Eupafolin, the migration and invasion ability of breast cancer cells decreased significantly.…”

The Hepatic Pre-Metastatic Niche

“…Moreover, VEGFA (known promoter of angiogenesis) was found to be upregulated in the pre-metastatic liver tissue of melanoma-bearing mice [ 90 ]. This correlated with altered microRNA expression patterns in the liver, suggesting a line of communication from the primary tumors that promotes vascular reorganization.…”