The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma

Malekan, Mohammad; Ebrahimzadeh, Mohammad Ali; Sheida, Fateme

doi:10.1016/j.biopha.2021.111873

Cited by 74 publications

(57 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our immunoblot data report that ONC administration almost suppresses the expression of HIF1α transcription factor present in A375 control cells, even if they were cultured at normal oxygen pressure. Recent studies revealed that HIF1α can be induced by different signaling pathways, such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, and NF-κB pathways controlling melanoma tumor growth, metabolism, motility, and apoptosis evasion [70]. Previously, we showed that ONC decreases expression and activity of both NF-κB [17,25] and STAT3 [12] in A375 melanoma cells.…”

Section: Discussionmentioning

confidence: 82%

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins

Tomi

Campagnari

et al. 2022

IJMS

View full text Add to dashboard Cite

Onconase (ONC) is an amphibian secretory ribonuclease displaying cytostatic and cytotoxic activities against many mammalian tumors, including melanoma. ONC principally damages tRNA species, but also other non-coding RNAs, although its precise targets are not known. We investigated the ONC ability to modulate the expression of 16 onco-suppressor microRNAs (miRNAs) in the A375 BRAF-mutated melanoma cell line. RT-PCR and immunoblots were used to measure the expression levels of miRNAs and their regulated proteins, respectively. In silico study was carried out to verify the relations between miRNAs and their mRNA targets. A375 cell transfection with miR-20a-3p and miR-34a-5p mimics or inhibitors was performed. The onco-suppressors miR-20a-3p, miR-29a-3p and miR-34a-5p were highly expressed in 48-h ONC-treated A375 cells. The cytostatic effect of ONC in A375 cells was mechanistically explained by the sharp inhibition of cyclins D1 and A2 expression level, as well as by downregulation of retinoblastoma protein and cyclin-dependent-kinase-2 activities. Remarkably, the expression of kinases ERK1/2 and Akt, as well as of the hypoxia inducible factor-1α, was inhibited by ONC. All these proteins control pro-survival pathways. Finally, many crucial proteins involved in migration, invasion and metastatic potential were downregulated by ONC. Results obtained from transfection of miR-20a-3p and miR-34a-5p inhibitors in the presence of ONC show that these miRNAs may participate in the antitumor effects of ONC in the A375 cell line. In conclusion, we identified many intracellular downregulated proteins involved in melanoma cell proliferation, metabolism and progression. All mRNAs coding these proteins may be targets of miR-20a-3p, miR-29a-3p and/or miR-34a-5p, which are in turn upregulated by ONC. Data suggest that several known ONC anti-proliferative and anti-metastatic activities in A375 melanoma cells might depend on the upregulation of onco-suppressor miRNAs. Notably, miRNAs stability depends on the upstream regulation by long-non-coding-RNAs or circular-RNAs that can, in turn, be damaged by ONC ribonucleolytic activity.

show abstract

Section: Discussionmentioning

confidence: 82%

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins

Tomi

Campagnari

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…To determine the potential of the novel therapeutic approach to target the invasive properties of melanoma cells, we investigated the intratumor production of HIF-1, a major promoter of invasiveness and metastasis in melanoma ( Malekan et al, 2021 ). Our data suggested that there was no difference between HIF-1 α protein levels in experimental conditions after various treatments compared to the control, untreated group ( Supplementary Figure S4 ).…”

Section: Resultsmentioning

confidence: 99%

“…As HIF-1 is known to play a direct role in VEGF-mediated angiogenesis ( Malekan et al, 2021 ) and several of our studies have reported strong inhibitory action of SIM on this important transcriptional regulator in tumor cells ( Licarete et al, 2017 ; Rauca et al, 2018 ; Rauca et al, 2021 ), we investigated by WB whether our novel sequential therapy induced a similar effect. However, none of the tested treatments induced significant modifications in the expression levels of HIF-1 α compared to the control untreated group ( Supplementary Figure S4 ).…”

Section: Discussionmentioning

confidence: 99%

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

et al. 2022

View full text Add to dashboard Cite

Primary melanoma aggressiveness is determined by rapid selection and growth of cellular clones resistant to conventional treatments, resulting in metastasis and recurrence. In addition, a reprogrammed tumor-immune microenvironment supports melanoma progression and response to therapy. There is an urgent need to develop selective and specific drug delivery strategies for modulating the interaction between cancer cells and immune cells within the tumor microenvironment. This study proposes a novel combination therapy consisting of sequential administration of simvastatin incorporated in IL-13-functionalized long-circulating liposomes (IL-13-LCL-SIM) and doxorubicin encapsulated into PEG-coated extracellular vesicles (PEG-EV-DOX) to selectively target both tumor-associated macrophages and melanoma cells. To this end, IL-13 was conjugated to LCL-SIM which was obtained via the lipid film hydration method. EVs enriched from melanoma cells were passively loaded with doxorubicin. The cellular uptake of rhodamine-tagged nano-particles and the antiproliferative potential of the treatments by using the ELISA BrdU-colorimetric immunoassay were investigated in vitro. Subsequently, the therapeutic agents were administered i.v in B16.F10 melanoma-bearing mice, and tumor size was monitored during treatment. The molecular mechanisms of antitumor activity were investigated using angiogenic and inflammatory protein arrays and western blot analysis of invasion (HIF-1) and apoptosis markers (Bcl-xL and Bax). Quantification of oxidative stress marker malondialdehyde (MDA) was determined by HPLC. Immunohistochemical staining of angiogenic markers CD31 and VEGF and of pan-macrophage marker F4/80 was performed to validate our findings. The in vitro data showed that IL-13-functionalized LCL were preferentially taken up by tumor-associated macrophages and indicated that sequential administration of IL-13-LCL-SIM and PEG-EV-DOX had the strongest antiproliferative effect on tumor cells co-cultured with tumor-associated macrophages (TAMs). Accordingly, strong inhibition of tumor growth in the group treated with the sequential combination therapy was reported in vivo. Our data suggested that the antitumor action of the combined treatment was exerted through strong inhibition of several pro-angiogenic factors (VEGF, bFGF, and CD31) and oxidative stress-induced upregulation of pro-apoptotic protein Bax. This novel drug delivery strategy based on combined active targeting of both cancer cells and immune cells was able to induce a potent antitumor effect by disruption of the reciprocal interactions between TAMs and melanoma cells.

show abstract

“…In melanoma, IL22RA1 mutation upregulated the expression of genes involved in the hypoxia-inducible factor-1alpha (HIF-1a) signaling pathway, whereas the metabolic pathways including biosynthesis of unsaturated fatty acids and butanoate metabolism were downregulated. Hypoxia, as a major feature of solid tumors, activates HIF-1a that enhances tumor growth and leads to melanoma progression by regulating the expression of genes involved in angiogenesis, metabolism, cell proliferation, and metastasis (36).…”

Section: Discussionmentioning

confidence: 99%

IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis

Zhang

Yang

2022

Front. Immunol.

View full text Add to dashboard Cite

Cytokines and cytokine receptors are important mediators in immunity and cancer development. Interleukin 22 (IL22) is one of the most important cytokines which has protumor effect. Given that common and specific roles of cytokines/receptors in multiple cancers, we conducted a pan-cancer study to investigate the role of IL22RA1 in cancer using The Cancer Genome Atlas (TCGA) database. Notably, we found IL22RA1 transcript was upregulated in 11 cancer types compared with their corresponding control. The mRNA expression level of IL22RA1 was highest in the pancreas among tumor tissues. The higher expression of IL22RA1 was associated with worse overall survival rate in patients. A total of 30 IL22RA1-correlated genes (e.g. IL17D, IL22RA2, IL20RB, IL10RA, IL10RB, TSLP and TYK2) are involved in the JAK/STAT pathway which promotes tumor progression. The upregulation of IL22RA1 in tumors was correlated with immune cell infiltration level. Higher expression of IL22RA2, IL20RB, IL10RA, IL10RB, TSLP, TYK2, STAT1 and STAT3 was associated with decreased overall survival rate in patients. IL22RA1 mutation was observed more in uterine cancer and melanoma compared with the other cancer types. Deactivation of IL22RA1 induced a lot of changes in gene expression. IL22RA1 mutants had upregulated DNA damage/repair genes in uterine cancer, whereas downregulated genes in the FoxO signaling pathway. In melanoma, mutation of IL22RA1 can upregulate the HIF signaling pathway but downregulate metabolic pathways. Our study suggests that IL22RA1/JAK/STAT signaling can be an important target for cancer treatment.

show abstract

The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma

Cited by 74 publications

References 114 publications

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis

Contact Info

Product

Resources

About