Weizhao Li

Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24

Abstract Background Cervical cancer is often caused by persistent high-risk human papillomavirus (HPV) infection, causing precancerous lesions. Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEV) exhibit diverse effects on tumors. This study investigates hucMSC-sEV, the impact and mechanisms on HPV-positive cervical precancerous lesion cells to provide new treatment insights. Materials and Methods We previously obtained hucMSC and hucMSC-sEV. In vitro experiments evaluated hucMSC-sEV effects on the proliferation and migration of S12 cells (derived from cervical precancerous lesions). Bioinformatics identified key microRNA components, and their impact on S12 cell proliferation and migration was investigated. The target gene of the microRNA component was predicted and confirmed via bioinformatics and dual-luciferase reporter assays. Lentiviral systems overexpressed target gene in S12 cells to examine the effects on microRNA impacts. SH-42 inhibitor was used to investigate target gene treatment potential. Immunohistochemistry assessed target gene expression in cervical precancerous lesions tissue. Results hucMSC-sEV significantly inhibited S12 cell proliferation and migration. Bioinformatics identified miR-370-3p as an effective cargo, which also suppressed S12 cell proliferation and migration. miR-370-3p was confirmed targeting DHCR24 (24-Dehydrocholesterol Reductase). DHCR24 overexpression reversed miR-370-3p’s inhibitory effects, while SH-42 counteracted DHCR24 overexpression’s promoting effects. Clinical specimen analysis supported these findings, demonstrating a positive correlation between DHCR24 protein expression and cervical precancerous lesions’ progression. Conclusions hucMSC-sEV inhibits S12 cell proliferation and migration, mediated by miR-370-3p targeting DHCR24 to regulate cellular cholesterol content. DHCR24 inhibition reduces the cholesterol level and cell functions, suggesting its potential as a therapeutic target in cervical precancerous lesions.

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/β-catenin signaling activation

AbstractCervical cancer (CC) seriously affects women’s health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/β-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/β-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/β-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment.

Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway

Abstract Purpose Cervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods. Methods This study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells. Results The results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells. Conclusion MSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.