Natural small molecule compounds targeting Wnt signaling pathway inhibit HPV infection.

BACKGROUND: High-risk human papillomavirus (HPV) infection is a major risk factor of HPV-related tumors, especially cervical cancer. To date, there is no specific drug for the treatment of HPV infection. PURPOSE: To explore the role of canonical Wnt signaling pathway in HPV16 infection and to screen inhibitors against HPV16 infection from natural small molecule compounds targeting the canonicalWnt pathway. METHODS: Wnt pathway inhibitor IWP-2 and FH535 were used to inhibit Wnt/ß-catenin signaling pathway. HPV16-GFP pseudovirus infectivity were analyzed by fluorescence microscopy and fluorescence activated cell sorting. A small molecule screening of a total of CFDA-approved 29 natural compounds targeting the Wnt pathway was performed. RESULTS: Wnt signaling pathway inhibitor suppressed HPV16-GFP pseudovirus infection in HaCat cells. Natural small molecule compounds screening identified 6-Gingerol, gossypol, tanshinone II2A, and EGCG as inhibitors of HPV16-GFP pseudovirus infection. CONCLUSION: Wnt signaling pathway is involved in the process of HPV infection of host cells. 6-Gingerol, gossypol, tanshinone II2A, and EGCG inhibited HPV16-GFP pseudovirus infection and suppressed Wnt/ß-catenin pathway in HaCat cells.

PD-1/PD-L1 Inhibitors Monotherapy for the Treatment of Endometrial Cancer: Meta-Analysis and Systematic Review.

PURPOSE: The efficacy of programmed cell death protein 1(PD-1)/Programmed cell death 1 ligand 1 (PD-L1) inhibitors for endometrial cancer remain controversial, and guidelines are inconsistent on which are preferred therapies for advanced disease, or who develop metastases and recurrence. Therefore, we aimed to estimate the efficacy and safety of PD-1/PD-L1 inhibitors in endometrial cancer on a more complete database by adding multiple randomized trials. METHODS: A systematic and comprehensive search was carried out in PD-1/PD-L1 inhibitors monotherapy. RESULTS: The ORR of PD-1/PDL-1 inhibitors was 29%, and subgroup analysis showed that the pooled ORR of the proficient mismatch repair (pMMR) group was 4% and which was 45% of the deficient mismatch repair (dMMR) group. The DCR of PD-1/PD-L1 inhibitors was 48%, through subgroup analysis, we found that the DCR of the pMMR group was 21% and which was 58% of the dMMR group. The proportion of patients occurring overall adverse events was 65% and grade three or higher adverse events was 14%. The proficient mismatch repair (pMMR) group and the deficient mismatch repair (dMMR) group showed different results. CONCLUSION: PD-1/PD-L1 inhibitors had shown little success in the pMMR population and better efficacy in the dMMR population.

Identification of cervical cancer stem cells using single-cell transcriptomes of normal cervix, cervical premalignant lesions, and cervical cancer.

BACKGROUND: Cervical cancer is the fourth leading cause of mortality among gynecological malignancies. However, the identification of cervical cancer stem cells remains unclear. METHODS: We performed single-cell mRNA sequencing on ∼122,400 cells from 20 cervical biopsies, including 5 healthy controls, 4 high-grade intraepithelial neoplasias, 5 microinvasive carcinomas of the cervix, and 6 invasive cervical squamous carcinomas. Bioinformatic results were validated by multiplex immunohistochemistry (mIHC) in cervical cancer tissue microarrays (TMA) (n = 85). FINDINGS: We identified cervical cancer stem cells and highlighted the functional changes in cervical stem cells during malignant transformation. The original non-malignant stem cell properties (characterized by high proliferation) gradually diminished, whereas the tumor stem cell properties (characterized by epithelial-mesenchymal transformation and invasion) were enhanced. The mIHC results of our TMA cohort confirmed the existence of stem-like cells and indicated that cluster correlated with neoplastic recurrence. Subsequently, we investigated malignant and immune cell heterogeneity in the cervical multicellular ecosystem across different disease stages. We observed global upregulation of interferon responses in the cervical microenvironment during lesion progression. INTERPRETATION: Our results provide more insights into cervical premalignant and malignant lesion microenvironments. FUNDING: This research was supported by the Guangdong Provincial Natural Science Foundation of China (2023A1515010382), Grant 2021YFC2700603 from the National Key Research & Development Program of China and the Hubei Provincial Natural Science Foundation of China (2022CFB174 and 2022CFB893).

LncRNA TRPM2-AS promotes ovarian cancer progression and cisplatin resistance by sponging miR-138-5p to release SDC3 mRNA.

The role of TRPM2-AS lncRNA in OvC has not been explored. This study aimed to investigate whether and how TRPM2-AS contributes to the progression of OvC. First, qRT-PCR was employed to measure the expression of TRPM2-AS, miR-138-5p and SDC3 in OvC samples. A xenograft formation assay was subsequently performed to detect the tumor growth in vivo. The cell viability, colony formation, cell migration, cell invasion and cell apoptosis were later evaluated using a series of experiments. The western blot assay was utilized to detect the SDC3 protein expression and cell-apoptosis markers. Luciferase reporter gene assay, RIP, and RNA pull-down assays were performed to identify the association between TRPM2-AS, miR-138-5p and SDC3. Findings indicated that the expression of TRPM2-AS and SDC3 was significantly upregulated in OvC tissues and cells, while miR-138-5p expression was significantly downregulated in OvC samples. Unlike miR-138-5p, TRPM2-AS and SDC3 were found to promote OvC development. It was also found that TRPM2-AS could sponge miR-138-5p to release SDC3, thus promoting OvC progression. Apart from that, we discovered that both sh-TRPM2-AS and cisplatin could enhance the apoptosis of OvC cells. Overall, our findings suggested that the TRPM2-AS/miR-138-5p/SDC3 axis was closely associated with OvC tumorigenesis and cisplatin resistance.