Search

Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

RING finger and WD repeat domain (RFWD) proteins belong to E3 ubiquitin ligase and play an important role in the regulation of cell proliferation, apoptosis and DNA damage repair. Evidence indicates that RFWD proteins are involved in tumor development by targeting their substrates' ubiquitination and degradation. RFWD proteins have different inhibitory and carcinogenic effects in different types of human malignant tumors, which may be attributed to the functions of their substrate proteins. In this paper, the structure and function of RFWD protein family members (RFWD1, RFWD2, RFWD3) were analyzed, the known substrates of RFWD protein family members were summarized, and their different functions in different tumors were described. In addition, the possibility and the potential targeting strategies of RFWD family members for cancer therapy were discussed.

Background and purpose: Destroying the balance of copper ions in the body may promote the occurrence and development of cancer. This study aimed to investigate the effects of copper ion on cell proliferation and elucidate the clinical significance of copper chaperone genes in lung cancer. Methods: The effects of copper ion on cell proliferation were determined by trypan blue exclusion experiment. Western blot assays were performed to test the effects of copper on the expressions of extracellular regulated protein kinase (ERK) and phosphorylated ERK (p-ERK). Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) was used to induce lung cancer in mice, and the copper content in lung cancer tissues and normal lung tissues was detected by inductively coupled plasma mass spectrometry (ICP-MS). Databases including The Cancer Genome Atlas (TCGA), Oncomine and the Kaplan-Meier Plotter website containing the microarray data of patients with non-small cell lung cancer (NSCLC) were used to analyze the correlation between the mRNA expression levels of copper chaperone for superoxide dismutase (CCS), cytochrome C oxidase copper chaperone (COX17) and antioxidant 1 copper chaperone (ATOX1) and the prognosis of lung cancer patients. Results: In vitro experimental results showed that copper ions at a concentration of 5 μmol/L was able to significantly promote the proliferation of lung cancer cells and normal lung epithelia cells, and induced the activation of intracellular ERK signaling pathways. In the NNK-induced lung cancer mouse model, the concentration of copper ion was significantly higher in cancer tissues than in normal lung tissues. In TCGA and Oncomine databases, the expression levels of CCS, COX17 and ATOX1 were significantly higher in cancer tissues than in counterpart normal controls. The expression levels were inversely associated with prognosis of the patients. Conclusion: Under specific concentration range, copper ions can promote cell proliferation. The copper chaperone genes could potentially be used as biomarkers to predict the prognosis of lung cancer patients.