Induction of exportin-5 expression during melanoma development supports the cellular behavior of human malignant melanoma cells

Ott, Corinna; Linck, Lisa; Kremmer, Elisabeth; Meister, Gunter; Bosserhoff, Anja‐Katrin

doi:10.18632/oncotarget.11410

Cited by 21 publications

(22 citation statements)

References 59 publications

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“…Recent studies have shown that Exportin-5 plays an important role in tumorigenesis. A study by Ott et al [ 14 ] found that a high abundance of exportin-5 in the melanoma leads to enhanced survival, proliferation and metastasis and thereby supports the aggressiveness of the cancer [ 14 ]. Studies have reported that endogenous IL-18 can affect hepatic metastasis by upregulating melanoma cell adhesion to HSE cells and tumor growth, implicating a possible antimetastatic benefit of neutralizing IL-18.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

Song

Chen

et al. 2018

Cancer Res Treat

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PurposeThe purpose of this study was to investigate the effect of human antigen R (HuR) downregulation and the potential target genes of HuR on the progression of esophageal squamous cell carcinoma (ESCC).Materials and MethodsIn this study, a proteomics assay was used to detect the expression of proteins after HuR downregulation, and a luciferase assay was used to detect the potential presence of a HuR binding site on the 3’-untranslated region (3'-UTR) of interleukin 18 (IL-18). In addition, colony formation assay, MTT, EdU incorporation assay, Western blot, flow cytometry, immunohistochemistry, transwell invasion assay, and wound healing assay were used.ResultsIn the present study, we found that the expression of both HuR protein and mRNA levels were higher in tumor tissues than in the adjacent tissues. HuR downregulation significantly suppressed cell proliferation. In addition, the metastasis of esophageal cancer cells was inhibited, while the expression of E-cadherin was increased and the expression of matrix metalloproteinase (MMP) 2, MMP9, and vimentin was decreased after HuR knockdown. Moreover, silencing of HuR disturbed the cell cycle of ESCC cells mainly by inducing G1 arrest. Furthermore, proteomics analysis showed that downregulation of HuR in TE-1 cells resulted in 100 upregulated and 122 downregulated proteins, including IL-18 as a significantly upregulated protein. The expression of IL-18 was inversely regulated by HuR. IL-18 expression was decreased in ESCC tissues, and exogenous IL-18 significantly inhibited the proliferation and metastasis of ESCC cells. The 3'-UTR of IL-18 harbored a HuR binding site, as shown by an in vitro luciferase assay.ConclusionHuR plays an important role in the progression of esophageal carcinoma by targeting IL-18, which may be a potential therapeutic target for the treatment of ESCC.

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Section: Resultsmentioning

confidence: 99%

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

Song

Chen

et al. 2018

Cancer Res Treat

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“…MicroRNAs (miRs) are posttranscriptional regulators of gene expression and crucial mediators of tumorigenicity in melanoma (Bosserhoff, ; Dietrich & Bosserhoff, ; Kappelmann, Kuphal, Meister, Vardimon, & Bosserhoff, ; Mione & Bosserhoff, ; Ott, Linck, Kremmer, Meister, & Bosserhoff, ). For example, miR‐125b was shown by our group to control melanoma progression by direct regulation of c‐Jun (Kappelmann et al., ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐622 is a novel mediator of tumorigenicity in melanoma by targeting Kirsten rat sarcoma

Dietrich

Kuphal

Spruß

et al. 2018

Pigment Cell Melanoma Res

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The network of molecular players is similar when comparing neural crest-derived, actively migrating melanoblasts to melanoma cells. However, melanoblasts are sensitive to differentiation-initiating signals at their target site (epidermis), while melanoma cells maintain migratory and undifferentiated features. We aimed at identifying downregulated genes in melanoma that are particularly upregulated in melanoblasts. Loss of such genes could contribute to stabilization of a dedifferentiated, malignant phenotype in melanoma. We determined that microRNA-622 (miR-622) expression was strongly downregulated in melanoma cells and tissues compared to melanocytes and melanoblast-related cells. miR-622 expression correlated with survival of patients with melanoma. miR-622 re-expression inhibited clonogenicity, proliferation, and migration in melanoma. Inhibition of miR-622 in melanocytes induced enhanced migration. Kirsten rat sarcoma (KRAS) was identified as a major functional target of miR-622 in melanoma. We conclude that miR-622 is a novel tumor suppressor in melanoma and identify the miR-622-KRAS axis as potential therapeutic target.

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“…Small molecule targeting of epigenetic enzymes, for example, histone deacetylases (HDACs) or specific transcription factors (TF) can reactivate the expression of tumor-suppressive miRNAs [196,258,266,270]. Drosha expression could be induced or XPO5 expression could be inhibited by siRNA leading to induction or repression of tumorigenic miRNAs [271,272]. To inhibit binding of the negative regulator LIN28 to the tumor-suppressive miRNA let-7, short, loop-targeting "looptomiRs" can be used [273].…”

Section: Genetic Alterations Transcriptional Regulation and Mirna-edmentioning

confidence: 99%

“…We identified XPO5 as significantly overexpressed in melanoma compared to normal human epidermal melanocytes (NHEM), contributing to enhanced survival, proliferation and metastasis of melanoma cells [272]. The enhanced XPO5 expression is partly due to constitutively active MEK/ERK signaling in melanoma and partly due to increased mRNA stability because of a single nucleotide polymorphism (SNP; rs11077) in the miR-617 binding site [272]. In HCC, the A/A genotype of the same SNP is associated with worse survival of HCC patients [296].…”

Section: Protein Regulators Of Microrna Expression and Functionmentioning

confidence: 99%

“…In HCC, the A/A genotype of the same SNP is associated with worse survival of HCC patients [296]. As siRNA mediated knockdown of XPO5 leads to reduced levels of plenty of the cellular miRNAs in melanoma [272], it is reasonable to assume that elevated XPO5 protein levels as seen in melanoma are responsible for the general elevation of miRNA levels which is a quite exclusive feature in melanoma (see section "the role of miRNAs in melanoma and hepatocellular carcinoma").…”

Section: Protein Regulators Of Microrna Expression and Functionmentioning

confidence: 99%

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Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Linck-Paulus

Hellerbrand

Bosserhoff

et al. 2020

Cells

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In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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Induction of exportin-5 expression during melanoma development supports the cellular behavior of human malignant melanoma cells

Cited by 21 publications

References 59 publications

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

MicroRNA‐622 is a novel mediator of tumorigenicity in melanoma by targeting Kirsten rat sarcoma

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

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