DTL promotes head and neck squamous cell carcinoma progression by mediating the degradation of ARGLU1 to regulate the Notch signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with a high incidence in squamous epithelium. The E3 ubiquitin ligase DTL is a component of the CRL4A complex and is widely involved in tumor progression. We aimed to analyze the role of DTL in HNSCC and to explore its mechanism of action. Through clinical analysis, we found that DTL is upregulated in HNSCC tissues and is associated with the tumor microenvironment and poor survival in patients. Through gain-of-function and loss-of-function assays, we showed that DTL promotes cell proliferation and migration in vitro and tumor growth in vivo. Mass spectrometry analysis and immunoprecipitation assays showed that DTL interacts with ARGLU1 to promote K11-linked ubiquitination-mediated degradation of ARGLU1, thereby promoting the activation of the CSL-dependent Notch signaling pathway. Furthermore, siARGLU1 blocks the inhibitory effects of DTL knockdown on HNSCC cells. In this study, we showed that DTL promotes HNSCC progression through K11-linked ubiquitination of ARGLU1 to activate the CSL-dependent Notch pathway. These findings identify a promising therapeutic target for HNSCC.

Nanocarrier-Mediated Delivery of MicroRNAs for Fibrotic Diseases.

MicroRNAs (miRNAs) are endogenous noncoding RNAs that mediate the fibrotic process by regulating multiple targets. MicroRNA-based therapy can restore or inhibit miRNA expression and is expected to become an effective approach to prevent and alleviate fibrotic diseases. However, the safe, targeted, and effective delivery of miRNAs is a major challenge in translating miRNA therapy from bench to bedside. In this review, we briefly describe the pathophysiological process of fibrosis and the mechanism by which miRNAs regulate the progression of fibrosis. Additionally, we summarize the miRNA nanodelivery tools for fibrotic diseases, including chemical modifications and polymer-based, lipid-based, and exosome-based delivery systems. Further clarification of the role of miRNAs in fibrosis and the development of a novel nanodelivery system may facilitate the prevention and alleviation of fibrotic diseases in the future.

The ubiquitin-proteasome system in melanin metabolism.

BACKGROUND: The ubiquitin-proteasome system (UPS) is a highly conserved way of regulating intracellular protein balance. UPS mediates proteolysis and disruption of variation or misfolding, while finely regulating proteins involved in differentiation and other biological processes. AIMS: The aim of this review is to systematically introduce UPS as a key regulator of melanin metabolism. METHODS: Systematic search and retrospective review were performed on the published data. RESULTS: Melanocyte-inducing transcription factor (MITF) is a substrate of the ubiquitin ligase VCHL1 and acts as a transcription factor to regulate the expression of key enzymes in melanin synthesis such as tyrosinase (TYR). The rate-limiting enzyme TYR is modified by the ubiquitin ligase Hrd1 during melanosynthesis. Melanin itself is also regulated by multiple ubiquitin ligases including Fbp1 and Vhl. By regulating the ubiquitination modification to target each link of melanin synthesis, it plays an important role in correcting the disorder of melanin metabolism. A number of chemical agents have been proven to inhibit the activity of ubiquitin ligase. CONCLUSIONS: Drugs targeting E3 ligase and deubiquitinating enzymes have great potential in the treatment of melanin metabolism disorders.

Current insight into the roles of microRNA in vitiligo.

Vitiligo is a common chronic depigmented skin disease characterized by melanocyte loss or dysfunction in the lesion. The pathogenesis of vitiligo has not been fully clarified. Most studies have suggested that the occurrence and progression of vitiligo are due to multiple factors and gene interactions in which noncoding RNAs contribute to an individual's susceptibility to vitiligo. Noncoding RNAs, including microRNAs (miRNAs), are a hot topic in posttranscriptional regulatory mechanism research. miRNAs are noncoding RNAs with a length of approximately 22 nucleotides and play a negative regulatory role by binding to the 3'-UTR or 5'-UTR of the target mRNA to inhibit translation or initiate mRNA degradation. Previous studies have screened the differential expression profiles of miRNAs in the skin lesions, melanocytes, peripheral blood mononuclear cells (PBMCs) and sera of patients and mouse models with vitiligo. Moreover, several studies have focused on miRNA-25, miRNA-155 and other miRNAs involved in melanin metabolism, oxidative stress, and melanocyte proliferation and apoptosis. These miRNAs and regulatory processes further illuminate the pathogenesis of vitiligo and provide hope for the application of small molecules in the treatment of vitiligo. In this review, we summarize miRNA expression profiles in different tissues of vitiligo patients and the mechanisms by which key miRNAs mediate vitiligo development.

Transgelin-2 contributes to proliferation and progression of hepatocellular carcinoma via regulating Annexin A2.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis is not clear. This study found that the expression of TAGLN2 mRNA and protein in HCC was higher than that in adjacent tissues. TCGA database analysis further confirmed this result, and found that the expression of TAGLN2 was positively correlated with the prognosis of HCC, suggesting that TAGLN2 may be a tumor promoter gene. Then the TAGLN2-Annexin A2 (ANXA2) interaction and NF-κB signaling pathway were further clarified during the invasion and metastasis of HCC. This mechanism provides a theoretical basis for further finding molecular targets and drug targets related to HCC metastasis.

The integrative regulatory network of circRNA and microRNA in keloid scarring.

Circular RNA (circRNA), a novel type of non-coding RNA that consists of a circular loop, has been demonstrated to act as a "sponge" for microRNAs (miRNAs). However, the role of circRNAs in keloid remains unknown. In this study, we investigated circRNA expression profiles in keloid to identify potential diagnostic and therapeutic circRNAs. We performed a circRNA microarray assay to determine circRNA expression in keloid and paired normal skin tissues. Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression levels of candidate circRNAs. The most significantly over-expressed circRNA was used to predict putative miRNA targets and the binding sites of miRNAs with this circRNA. Finally, we constructed a circRNA-miRNA interaction network and carried out gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We found 52 significantly upregulated and 24 downregulated circRNAs in keloid compared with normal skin tissue. We confirmed that hsa_circ_0057452, hsa_circ_0007482, hsa_circ_0020792, hsa_circ_0057342, and hsa_circ_0043688 were significantly upregulated in keloid tissues. Analysis of the circRNA-miRNA interaction network revealed that circRNAs could interact with miRNAs, including miRNA-29a, miRNA-23a-5p and miRNA-1976. GO and KEGG analyses indicated that these target genes were involved in biological functions and signaling pathways that may play vital roles in the pathogenesis of keloid. This study revealed that circRNAs are potentially implicated in the development of keloid and could serve as novel diagnostic and therapeutic targets.