Min Wang

The pivotal role of ZNF384: driving the malignant behavior of serous ovarian cancer cells via the LIN28B/UBD axis

Zinc finger protein 384 (ZNF384) is a highly conserved transcribed gene associated with the development of multiple tumors, however, its role and mechanism in serous ovarian cancer (SOC) are unknown. We first confirmed that ZNF384 was abnormally highly expressed in SOC tissues by bioinformatics analysis and immunohistochemistry. We further used lentivirus packaging and transfection techniques to construct ZNF384 overexpression or knockdown cell lines, and through a series of cell function experiments, gradually verified that ZNF384 promoted a series of malignant behaviors of SOC cell proliferation, migration, and invasion. By establishing a xenotransplantation model in nude mice, it was confirmed that ZNF384 promoted the progress of SOC in vivo. Mechanistically, Overexpression of ZNF384 enhanced the transcriptional activity of Lin-28 homolog B (LIN28B), which promoted the malignant behavior of SOC cells. In addition, LIN28B could regulate the expression of the downstream factor ubiquitin D (UBD) in SOC cells, further promoting the development of SOC. This study shows that ZNF384 aggravates the malignant behavior of SOC cells through the LIN28B/UBD axis, which may be used as a diagnostic biomarker for patients with SOC.

CircCCL22 Regulates CDC25A via Sponging miR-543 and Promotes Proliferation and Metastasis in Endometrial Cancer

Endometrial cancer (EC) is the most common gynecological tumor. Circular RNAs are a novel type of non-coding RNA that have important regulatory functions, particularly in the pathogenic progression of cancer. In this study, we investigated the function of circCCL22, and elucidated its molecular mechanism in EC progresssion. The expression of circCCL22, miR-543 and CDC25A in EC tissues and cells were determined by qRT-PCR and western blot. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing and transwell assays were executed to assess the cell viability, proliferation, migration and invasion. Dual-luciferase report assay was utilized to investigate the interaction of miR-543 with circCCL22 and CDC25A. The role of circCCL22 in EC in vivo was investigated by xenograft assay. CircCCL22 was notably upregulated in EC tissues and cells. Functionally, circCCL22 knockdown suppressed EC cell proliferation, migration and invasion in vitro, and inhibited tumor growth in vivo. Mechanistically, circCCL22 acted as "miR-543 sponges" to regulate its targeted gene CDC25A expression in EC cells. The inhibiting effect induced by circCCL22 knockdown on EC cell proliferation, migration and invasion was greatly reversed by miR-543 inhibition or CDC25A overexpression. Our results revealed that circCCL22 regulated EC progression through targeting miR-543/CDC25A axis, and it could be a novel therapeutic target of EC.

Advances in natural products modulating autophagy influenced by cellular stress conditions and their anticancer roles in the treatment of ovarian cancer

Abstract Autophagy is a conservative catabolic process that typically serves a cell‐protective function. Under stress conditions, when the cellular environment becomes unstable, autophagy is activated as an adaptive response for self‐protection. Autophagy delivers damaged cellular components to lysosomes for degradation and recycling, thereby providing essential nutrients for cell survival. However, this function of promoting cell survival under stress conditions often leads to malignant progression and chemotherapy resistance in cancer. Consequently, autophagy is considered a potential target for cancer therapy. Herein, we aim to review how natural products act as key modulators of autophagy by regulating cellular stress conditions. We revisit various stressors, including starvation, hypoxia, endoplasmic reticulum stress, and oxidative stress, and their regulatory relationship with autophagy, focusing on recent advances in ovarian cancer research. Additionally, we explore how polyphenolic compounds, flavonoids, alkaloids, terpenoids, and other natural products modulate autophagy mediated by stress responses, affecting the malignant biological behavior of cancer. Furthermore, we discuss their roles in ovarian cancer therapy. This review emphasizes the importance of natural products as valuable resources in cancer therapeutics, highlighting the need for further exploration of their potential in regulating autophagy. Moreover, it provides novel insights and potential therapeutic strategies in ovarian cancer by utilizing natural products to modulate autophagy.

β-Catenin: oncogenic role and therapeutic target in cervical cancer

AbstractCervical cancer is a common and fatal malignancy of the female reproductive system. Human papillomavirus (HPV) is the primary causal agent for cervical cancer, but HPV infection alone is insufficient to cause the disease. Actually, most HPV infections are sub-clinical and cleared spontaneously by the host immune system; very few persist and eventually develop into cervical cancer. Therefore, other host or environmental alterations could also contribute to the malignant phenotype. One of the candidate co-factors is the β-catenin protein, a pivotal component of the Wnt/β-catenin signaling pathway. β-Catenin mainly implicates two major cellular activities: cell–cell adhesion and signal transduction. Recent studies have indicated that an imbalance in the structural and signaling properties of β-catenin leads to various cancers, such as cervical cancer. In this review, we will systematically summarize the role of β-catenin in cervical cancer and provide new insights into therapeutic strategies.

A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

AbstractDiscovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.

Diagnostic value of high‐risk human papillomavirus viral load on cervical lesion assessment and ASCUS triage

AbstractThis study aims to evaluate HR‐HPV viral load in the cervical lesion assessment and its diagnostic value on the triage of ASCUS. The three‐step protocol for cervical cancer screening was carried out in 5171 patients from June 2017 to August 2019, and 1620 histopathological results were obtained. The positive rate of HR‐HPV and TCT increased with the aggravation of pathological grades of cervical lesions. The sensitivity and specificity of HR‐HPV (DH3) to detect CIN II+ were 91.91% and 84.46%, respectively. In comparison, the corresponding results of the cytology test were 80.51% and 83.12%. HPV16/18 viral load was positively correlated with the grade of cervical lesions (p < 0.001, r = 0.321). The diagnostic efficiency of AUC by applying HPV16/18 viral load was 0.682 for the diagnosis of CIN II+. The optimal HPV16/18 viral load for predicting CIN II+ was 6.80 RLU/CO (relative light units/cut‐off), with corresponding sensitivity of 48.6%, specificity of 79.7%, and Youden index of 0.283. In the ASCUS population, viral loads were statistically different in HPV16/18 and the other 12 HR‐HPV when compared cervicitis group with CIN I group and CIN II+ group (all p < 0.05). Statistical differences were detected concerning HPV16/18 viral load, contact bleeding status, and smoking status when compared cervicitis group with CIN I group and CIN II+ group (p < 0.05), with a corresponding odds ratio of 1.004, 1.533, and 5.513, respectively. Our findings suggest that HR‐HPV viral load can be regarded as a useful tool to predict the grade of cervical lesions for ASCUS triage.ClinicalTrials.gov ID: NCT03178136.

RGS1 and related genes as potential targets for immunotherapy in cervical cancer: computational biology and experimental validation

Abstract Background Effective treatment is needed for advanced, inoperable, or chemotherapy-resistant cervical cancer patients. Immunotherapy has become a new treatment modality for cervical cancer patients, and there is an urgent need to identify additional targets for cervical cancer immunotherapy. Methods In this study the core gene, RGS1, which affects immune status and the FIGO stage of cervical cancer patients was identified by WGCNA analysis and differential analysis using TCGA database. 10 related genes interacting with RGS1 were identified using PPI network, and the functional and immune correlations were analyzed. Based on the expression of RGS1 and related genes, the consensus clustering method was used to divide CESC patients into two groups (group 1, high expression of RGS1; group 2, low expression of RGS1). Then, the functional enrichment analysis was used to search for the functional differences in differentially expressed genes (DEGs) between group 1 and group 2. Immune infiltration analysis was performed using ESTIMATE, CIBERSORT, and ssGSEA, and the differences in expression of immune checkpoint inhibitors (ICIs) targets were assessed between the two groups. We investigated the effect of RGS1 on the clinical relevance of CESC patients, and experimentally verified the differences in RGS1 expression between cervical cancer patient tissues and normal cervical tissues, the role of RGS1 in cell function, and the effect on tumor growth in tumor-bearing mice. Results We found that RGS1 was associated with CD4, GNAI3, RGS2, GNAO1, GNAI2, RGS20, GNAZ, GNAI1, HLA-DRA and HLA-DRB1, especially CD4 and RGS2. Functional enrichment of DEGs was associated with T cell activation. Compared with group 2, group 1 had stronger immune infiltration and higher ICI target expression. RGS1 had higher expression in cervical cancer tissues than normal tissues, especially in HPV-E6 positive cancer tissues. In cervical cancer cell lines, knockdown of RGS1 can inhibited cell proliferation, migration, invasion, and tumor growth in nude mice and promoted apoptosis. Conclusions RGS1, as an oncogenic gene of cervical cancer, affects the immune microenvironment of patients with cervical cancer and may be a target of immunotherapy.

Nocardia rubra cell‐wall skeleton influences the development of cervical carcinoma by promoting the antitumor effect of macrophages and dendritic cells

AbstractBackgroundAs an immune enhancer, Nocardia rubra cell‐wall skeleton (Nr‐CWS) has been used to treat persistent human papillomavirus infection and cervical precancerous lesions. However, it is still unclear whether it can be used to treat cervical carcinoma.MethodsIn our study, the aim was to determine whether Nr‐CWS affects the apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages in vivo and in vitro.ResultsThe experimental results showed that Nr‐CWS can promote the activity of dendritic cells and macrophages and reduce their apoptosis. It also increased the cytokines IL‐6, IL‐12, TNF‐ɑ, and IL‐1β secreted by dendritic cells and macrophages and reduced their PD‐L1 expression. In vitro, Nr‐CWS inhibited the proliferation, colony forming ability of HeLa and SiHa cervical carcinoma cell lines cultured with macrophages, and more cells were blocked in G2/M phase. Nr‐CWS promoted TNF‐ɑ/TNFR1/caspase‐8‐mediated apoptosis by increasing macrophages secretion of TNF‐ɑ and inhibited cell migration and invasion regulated by the WNT/β‐catenin‐EMT pathway. Nr‐CWS also reduced the expression of the cervical carcinoma genes E6 and E7 thereby increasing expression of p53 gene and decreasing expression of PD‐L1 gene. In vivo, Nr‐CWS inhibited tumor growth and decreased the expression of E6, E7, PD‐L1, P16, Ki67, and PCNA in tumors.ConclusionsTherefore, our results suggest that Nr‐CWS can promote apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages.

Transforming a highly toxic agent DM1 into injectable safe nanomedicines via prodrug self-assembly for the treatment of taxane-resistant cancer

Through a PUFA strategy, highly toxic DM1 was transformed into a safe self-assemble nanoprodrug, which had low systemic toxicity and could be used to treat taxane-resistant cervical cancer.

Ubiquitin Ligase TRIM22 Inhibits Ovarian Cancer Malignancy via TCF4 Degradation

Abstract Ovarian cancer is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in ovarian cancer. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in ovarian cancer. TRIM22 protein and mRNA levels were analyzed in samples from clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, coimmunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in ovarian cancer tissues. Furthermore, upregulation of TRIM22 significantly inhibited ovarian cancer cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in ovarian cancer cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in ovarian cancer is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of ovarian cancer.

PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies

Abstract Expression of protein arginine methyltransferase 5 (PRMT5) is highly positively correlated to DNA damage repair (DDR) and DNA replication pathway genes in many types of cancer cells, including ovarian and breast cancer. In the current study, we investigated whether pharmacologic inhibition of PRMT5 downregulates DDR/DNA replication pathway genes and sensitizes cancer cells to chemotherapy and PARP inhibition. Potent and selective PRMT5 inhibitors significantly downregulate expression of multiple DDR and DNA replication genes in cancer cells. Mechanistically, PRMT5 inhibition reduces the presence of PRMT5 and H4R3me2s on promoter regions of DDR genes such as BRCA1/2, RAD51, and ATM. PRMT5 inhibition also promotes global alternative splicing changes. Our data suggest that PRMT5 inhibition regulates expression of FANCA, PNKP, and ATM by promoting exon skipping and intron retention. Combining C220 or PRT543 with olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Moreover, combination of PRT543 with olaparib effectively inhibits the growth of patient-derived breast and ovarian cancer xenografts. Furthermore, PRT543 treatment significantly inhibits growth of olaparib-resistant tumors in vivo. These studies reveal a novel mechanism of PRMT5 inhibition and suggest beneficial combinatorial effects with other therapies, particularly in patients with tumors that are resistant to therapies dependent on DNA damage as their mechanism of action. Significance: Patients with advanced cancers frequently develop resistance to chemotherapy or PARP inhibitors mainly due to circumvention and/or restoration of the inactivated DDR pathway genes. We demonstrate that inhibition of PRMT5 significantly downregulates a broad range of the DDR and DNA replication pathway genes. PRMT5 inhibitors combined with chemotherapy or PARP inhibitors demonstrate synergistic suppression of cancer cell proliferation and growth in breast and ovarian tumor models, including PARP inhibitor–resistant tumors.

HR-HPV Multi-site Opportunistic Screening in Liaoning, China

It is universally accepted that the persistent infection of high-risk human papillomavirus(HR-HPV) is the cause of cervical intraepithelial neoplasias and cancer. Some researches indicate that the virus load may relate the extent of the disease. The objective of the study is to detect the virus load of 14 types HR-HPV among the participants, using a new HPV DNA hybrid capture technology,sequentially find the diagnostic significance of virus load of HPV.