Cellular delivery and enhanced anticancer activity of berberine complexed with a cationic derivative of γ–cyclodextrin

A cationic derivative of γ-cyclodextrin (GCD) modified with propylenediamine (PDA) was synthesized. It was shown that the derivative (GCD–PDA) is mucoadhesive and resistant to the digestion with?∝-amylase indicating that it may constitute an efficient oral delivery vehicle. GCD-PDA formed an inclusion complex with berberine (BBR), an alkaloid displaying a multitude of beneficial physiological effects. The complexed BBR penetrates a lipid membrane easier than the free one. Both uncomplexed BBR and that complexed with GCD-PDA was delivered to normal (NMuMG) and cancerous (4T1) murine mammary gland cells. In the normal cells both free and complexed BBR was homogeneously dispersed in the cytoplasm and was nontoxic up to 131?μM. In the cancerous cells uncomplexed BBR was also homogeneously dispersed but it was toxic to about 25% of cells at 131?μM, while the GCD-PDA/BBR complex was preferably localized in lysosomes and its toxicity doubled at this concentration compared to that of free BBR. Moreover, free BBR and GCD-PDA/BBR showed even more efficient inhibitory effect against murine melanoma (B16-F10) cells than against 4T1 cells.     

The AMP-dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma

Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1-altered (or mutant) compared to BAP1-unaltered (or wild-type [WT]) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM.     

lncRNA NEAT1 facilitates melanoma cell proliferation,migration, and invasion via regulating miR-495-3p and E2F3

Melanoma contributes a lot to skin cancer-related deaths. lncRNAs are implicated in various diseases, including melanoma. lncRNA NEAT1 is frequently dysregulated and can play important roles in multiple cancers. Nevertheless, little has been studied about the function of NEAT1 in melanoma progression. In our present research, we displayed NEAT1 was overexpressed in melanoma cells. A series of functional assays showed that overexpression of NEAT1 promoted the proliferation, migration, and invasion of melanoma cells. By contrast, NEAT1 knockdown obviously restrained melanoma cell progression. Mechanistically, it was revealed that NEAT1 could directly bind with miR-495-3p, which led to a negative effect on miR-495-3p levels. In addition, miR-495-3p was significantly decreased in melanoma cells. Furthermore, E2F3 was postulated as the target of miR-495-3p and overexpression of this miR could suppress the levels of E2F3. Meanwhile, it was exhibited that melanoma cell proliferation, migration, and invasion induced by E2F3 silence was abrogated by miR-495-3p. Moreover, an in vivo xenograft nude mice model was established using A375 cells and it was indicated that NEAT1 promoted melanoma progression in vivo via regulating the miR-495-3p/E2F3 axis. In conclusion, we suggest that NEAT1 exerts an oncogenic effect on melanoma development via inhibition of miR-495-3p and induction of E2F3. NEAT1 might serve as a crucial prognostic biomarker of melanoma.     

Promoter methylation as biomarkers for diagnosis of melanoma: A systematic review and meta-analysis

Melanoma is one of the most common skin cancer that is characterized by rapid growth, early metastasis, high malignant, and mortality. Accumulating evidence demonstrated that promoter methylation of tumor-suppressor genes is implicated in the pathogenesis of melanoma. In the current study, we performed a meta-analysis to identify promising methylation biomarkers in the diagnosis of melanoma. We carried out a systematic literature search using Pubmed, Embase, and ISI web knowledge database and found that gene promoter methylation of 50 genes was reported to be associated with the risk of melanoma. Meta-analysis revealed that hypermethylation of claudin 11 (CLDN11; odds ratio [OR], 16.82; 95% confidence interval [CI], 1.97–143.29; p = 0.010), O-6-methylguanine-DNA methyltransferase (MGMT; OR, 5.59; 95% CI, 2.51–12.47; p < 0.0001), cyclin-dependent kinase inhibitor 2A (p16; OR, 6.57; 95% CI, 2.19–19.75; p = 0.0008), retinoic acid receptor β (RAR-β2; OR, 24.31; 95% CI, 4.58–129.01; p = 0.0002), and Ras association domain family member (RASSF1A; OR, 9.35; 95% CI, 4.73–18.45; p < 0.00001) was significantly higher in melanoma patients compared with controls. CLDN11 (OR, 14.52; 95% CI, 1.84–114.55; p = 0.01), MGMT (OR, 8.08; 95% CI, 1.84–35.46; p = 0.006), p16 (OR, 9.44; 95% CI, 2.68–33.29; p = 0.0005), and RASSF1A (OR, 7.72; 95% CI, 1.05–56.50; p = 0.04) hypermethylation was significantly increased in primary melanoma compared with controls. Methylation frequency of CLDN11 (OR, 25.56; 95% CI, 2.32–281.66; p = 0.008), MGMT (OR, 4.64; 95% CI, 1.98–10.90; p = 0.0004), p16 (OR, 4.31; 95% CI, 1.33–13.96; p = 0.01), and RASSF1A (OR, 10.10; 95% CI, 2.87–35.54; p = 0.0003) was significantly higher in metastasis melanoma compared with controls. These findings indicated that CLDN11, MGMT, p16, RAR-β2, and RASSF1A hypermethylation is a risk factor and a potential biomarker for melanoma. CLDN11, MGMT, p16, and RASSF1A promoter methylation may take part in the development of melanoma and become useful biomarkers in the early diagnosis of the disease.     

Long noncoding RNA CPS1-IT1 suppresses melanoma cell metastasis through inhibiting Cyr61 via competitively binding to BRG1

Long noncoding RNA CPS1-IT1 is recently recognized as a tumor suppressor in several cancers. Here, we investigate the role of CPS1-IT1 in human melanoma. Presently, our study reveals the low expression of CPS1-IT1 in human melanoma tissues and cell lines, which is significantly associated with metastasis and tumor stage. Besides, the potential of CPS1-IT1 as a prognosis-predictor is strongly indicated. Functionally, CPS1-IT1 overexpression inhibits cell migration, invasion, epithelial–mesenchymal transition, and angiogenesis in melanoma cells. CYR61, an angiogenic factor that participates in tumor metastasis as well as a recognized oncogene in melanoma, is shown to be confined under CPS1-IT1 overexpression in melanoma cells. Furthermore, enforced expression of Cyr61 in CPS1-IT1-silenced melanoma cells dramatically normalized the protein level of Cyr61 and that of its downstream targets vascular endothelial growth factor and matrix metalloproteinase-9, as well as the repressive effect of CPS1-IT1 overexpression on melanoma cell metastasis. BRG1, a core component of SWI/SNF complex, is implied to interact with both CPS1-IT1 and Cyr61 in melanoma cells. Moreover, CPS1-IT1 negatively regulates Cyr61 expression by blocking the binding of BRG1 to Cyr61 promoter. Jointly, CPS1-IT1 controls melanoma metastasis through impairing Cyr61 expression via competitively binding with BRG1, uncovering a novel potential therapeutic and prognostic biomarker for patients with melanoma.     

Potential use of melatonin in skin cancer treatment: A review of current biological evidence

Skin cancer, particularly melanoma, is a leading cause of death worldwide. The therapeutic methods for this malignancy are not effective, and due to the side effects of these treatments, applying an appropriate alternative or complementary treatment is important. According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti-inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor-erythroid 2 p45-related factor 2 and others. Thus, adding melatonin to chemo- and radiotherapy may have synergistic therapeutic effects and increase the survival time in patients with skin cancer. Few clinical studies have evaluated the efficacy of melatonin in skin cancer. Based on the related mechanisms, this review discusses about how melatonin may improve outcomes in skin cancer patients.     

Long noncoding RNA OIP5-AS1 acts as a competing endogenous RNA to promote glutamine catabolism and malignant melanoma growth by sponging miR-217

The long noncoding RNA (lncRNA) OIP5-AS1 has been considered to promote the growth and metastasis of many human tumors. However, the role of OIP5-AS1 in melanoma has not been reported. In this study, we found that OIP5-AS1 levels were significantly elevated in melanoma tissue and that high OIP5-AS1 expression was an independent risk factor for the poor survival of patients with melanoma. miR-217 suppressed glutamine catabolism in melanoma cells by targeting glutaminase (GLS), the rate-limiting enzyme of glutamine catabolism. We also demonstrated that OIP5-AS1 acted as a sponge of miR-217 to upregulate GLS expression, thus promoting glutamine catabolism and melanoma growth. Overall, this result elucidates a new mechanism for OIP5-AS1 in metabolism in melanoma and provides a potential therapeutic target for patients with melanoma.     

Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment

1. Download high-res image (352KB)
2. Download full-size image