Fang Peng

UHRF1-mediated HIF-1α stabilization promotes ovarian cancer through metabolic reprogramming and angiogenesis

Abstract Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is an important epigenetic regulatory factor that is highly expressed in various cancers and participates in tumorigenesis and progression. However, the role and molecular mechanisms of UHRF1 in ovarian cancer (OC) remain unclear. Through survival analysis, cellular functional experiments, and animal studies, we identified UHRF1 as a key gene influencing OC progression and prognosis. Hypoxia-inducible factor-1 (HIF-1α), a well-known pro-cancer molecule, undergoes classic degradation via the ubiquitin–proteasome pathway. We discovered that UHRF1 interacts with HIF-1α, affecting its hydroxylation level, thereby inhibiting HIF-1α polyubiquitination and degradation. Functional experiments revealed that knocking down HIF-1α in stable UHRF1-overexpressing cell lines significantly reversed the malignant phenotype of OC cells. Furthermore, UHRF1 can also regulate the expression of key downstream molecules such as GLUT1, HK2, LDHA, and VEGFA by modulating HIF-1α, thus influencing tumor cell metabolism and angiogenesis. In summary, our findings suggest that UHRF1 plays a crucial role in the development of OC by regulating the expression of HIF-1α.

New insights into tumor microenvironment and HPV integrations in cervical cancer pathogenesis revealed by single-cell transcriptome data

Abstract HPV infection is common among women and can result in serious illnesses. This research utilizes single-cell RNA-sequencing (scRNA-seq) to study the connection between cellular heterogeneity and HPV integrations in cervical histopathology. scRNA-seq was used to examine heterogeneity among normal patients and those in three disease stages: high-grade squamous intraepithelial lesions (HSIL), microinvasive carcinoma (MIC), and cervical squamous epithelium carcinoma cancer (CSCC) tissues. A method was developed to identify HPV integration events from scRNA-seq data. Our results indicated an increase in squamous epithelial cells and a decrease in columnar epithelial cells as the disease progressed from normal to CSCC. We discovered HPV genes that were differentially expressed across normal patients and those in the three disease stages. Notably, HPV integration events were more common in squamous epithelial cells at the single-cell level. The ratio of HPV-integrated cells increased as the disease progressed from normal tissue to CSCC, eventually stabilizing. Several genes, such as EGR1, S100A11, S100A8, KRT5, RPL34, ATP1B1, RPS4X and EEF2, were frequently integrated by HPV across patients. In contrast, genes like PAN3, BABAM2, SPEN, TCIM-SIRLNT, TEX41-PABPC1P2 and KCNV1-LINC01608 showed frequent integration events across cells. KRT5, ATP1B1, RPS4X, PAN3 and SPEN were novel recurrent HPV-integrated genes we observed at the patient or cell level in this study. Additionally, we found that HPV genes from various HPV types exhibited integration preferences in various samples and disease stages. This provides a valuable insight into the mechanism of HPV-induced cervical cancer from a single-cell standpoint, highlighting its clinical relevance.