Weipei Zhu

Curcumin induces mitochondrial dysfunction-associated oxidative DNA damage in ovarian cancer cells

Resistance to chemotherapeutic agents is a critical challenge for the clinical management of ovarian cancer. While curcumin has been reported to possess anti-cancer properties, how it exerts its anti-neoplastic effect on ovarian cancer cells remains to be explored. We here characterized the fate of human ovarian cancer cell lines HO8910 and OVCAR3 treated with curcumin. Cell proliferation, cell death, mitochondrial function, oxidative damage and tumor formation in nude mice were examined. Significant inhibition of proliferation and induction of apoptosis were observed in ovarian cells treated with curcumin. The cancer cells exhibit cell cycle arrest at G2/M phase, mitochondrial accumulation, mitochondrial oxidative stress and high level of DNA damage after curcumin treatment. This effect of curcumin is independent of the BRCA mutation status. Curcumin-induced proliferation inhibition and apoptosis were effectively attenuated by the application of antioxidant N-acetylcysteine (NAC), suggesting that curcumin exerts its anti-cancer effect by inflicting oxidative stress. Curcumin applied at 200 mg/kg intraperitoneal infusion daily also inhibited the growth, oxidative damage, and mitochondrial accumulation of tumor xenografts in vivo. Together, the results indicate that curcumin can exert its anti-tumor effect via inducing mitochondrial dysfunction-associated oxidative DNA damage and can be potentially used in combination with other DNA repair-interfering therapeutics, such as PARP inhibitor, in the treatment of ovarian cancer.

SPOCK2 promotes the invasion and migration of ovarian cancer cells through FAK signaling pathway

Ovarian cancer is one of the most prevalent malignancies worldwide, with the highest mortality rate among gynecological cancers. This study aims to investigate the molecular mechanisms of SPOCK2 in ovarian cancer progression and metastasis and evaluate its potential as a therapeutic target. The expression levels of SPOCK2 in ovarian cancer tissues and normal tissues were analyzed using data from The Cancer Genome Atlas (TCGA) and immunohistochemistry experiments. Functional assays, including epithelial-mesenchymal transition (EMT), invasion, and migration assays, were performed in high-grade serous ovarian cancer (HGSOC) cells to explore the role of SPOCK2. The interaction between SPOCK2 and ITGA3 and the subsequent activation of focal adhesion kinase (FAK) signaling were investigated. In vivo experiments were conducted to validate the effects of SPOCK2 knockdown on tumor metastasis and invasiveness. SPOCK2 expression was significantly upregulated in ovarian cancer tissues compared to normal tissues and was associated with poor prognosis. Functional assays demonstrated that SPOCK2 promotes EMT, invasion, and migration in HGSOC cells by interacting with ITGA3 and activating FAK signaling. In vivo experiments confirmed that SPOCK2 knockdown significantly suppressed tumor metastasis and invasiveness. This study highlights the critical role of the SPOCK2/ITGA3 axis in driving ovarian cancer progression and provides evidence for SPOCK2 as a potential molecular marker and therapeutic target. These findings offer new insights into the early diagnosis and treatment of ovarian cancer, with significant clinical implications for improving patient outcomes.

RETRACTED: Development of gene panel for predicting recurrence in early‐stage cervical cancer patients

Abstract Cervical cancer (CC) is a common malignancy affecting women worldwide. Our objective was to develop a consensus‐based gene panel using multi‐omics data that could effectively predict recurrence in early‐stage cervical cancer patients. We utilized the “Multi‐Omics Consensus Integration Analysis (MOVICS)” package for consensus clustering design to integrate multiple omics datasets and improve the molecular classification landscape of early‐stage CC. We identified the “resting and naive” tumor microenvironment (TME) as cancer subtype (CS) 2. Leveraging the feature genes from the CS classifier, we employed machine learning algorithms to identify a gene panel, including ALDH1A1, CLDN10, MUC13, and C10orf99, which could generate a consensus machine learning‐driven score (CMLS) for each patient. Stratifying patients into high and low CMLS groups resulted in Kaplan–Meier curves demonstrating a significant difference in recurrence rates between the two groups. This difference remained significant even after adjusting for clinical features in multivariate Cox regression analysis, with the risk ratio of CMLS surpassing that of clinical characteristics. Furthermore, the TME exhibited notable differences between the different CMLS groups, suggesting that patients with low CMLS may exhibit a better response to immunotherapy. This study highlights the potential of the CMLS approach in predicting recurrence in early‐stage cervical cancer patients and provides a screening model for selecting patients suitable for immunotherapy.

Hsa_circ_0001535 inhibits the proliferation and migration of ovarian cancer by sponging miR-593-3p, upregulating PTEN expression

Hsa_circ_0001535 is involved in biological processes in various tumors. However, the biological effects and related mechanism of hsa_circ_0001535 in ovarian cancer (OC) is unclear. This work is aimed to probe the biological function and underlying mechanism of hsa_circ_0001535 in OC, especially sponged with mi-RNA, require further elucidation. Hsa_circ_0001535 expression in OC tissues and cell lines were examined by qRT-PCR. Hsa_circ_0001535 overexpression model was constructed by lentivirus-mediated transfection in two OC cell lines, and the biological functions of hsa_circ_0001535 were evaluated by CCK-8, transwell assay and Western blot. Dual luciferase reporter gene assay was respectively used to explore the relationship between hsa_circ_0001535 and miR-593-3p, as well as miR-593-3p and PTEN. The expression of miR-593-3p and PTEN were detected by qRT-PCR in two OC cell lines and OC tissues. Hsa_circ_0001535 was down-regulated in OC tissues and cell lines. Hsa_circ_0001535 overexpression inhibited proliferation, migration and EMT marker expression in OC cells. Of interest, hsa_circ_0001535 targeted miR-593-3p and reduced its RNA level in OC cells. PTEN was a target gene of miR-593-3p, which was up-regulated by inhibiting miR-593-3p in OC cells. Furthermore, miR-593-3p mimic treatment reversed the up-regulation of PTEN by hsa_circ_0001535 overexpression in OC cells. The above results showed that hsa_circ_0001535 acted as a molecular sponge for miR-593-3p to repress miR-593-3p expression, and promoted the expression of PTEN, thus inhibited proliferation and migration of OC cells. Our research provides a potential therapeutic target for ovarian cancer patients.

MicroRNA-301a Promotes Cell Proliferation and Resistance to Apoptosis through PTEN/PI3K/Akt Signaling Pathway in Human Ovarian Cancer

<b><i>Background:</i></b> MicroRNAs are endogenous small noncoding RNAs, which play a critical role in regulating various biological and pathologic processes. Furthermore, miR-301a has been detected to be overly expressed in tumorigenic progression of ovarian cancer. However, the effects of miR-301a on ovarian cancer are still unclear. <b><i>Objective:</i></b> The objective of this study is to investigate the molecular mechanisms of miR-301a in epithelial ovarian cancer cells. <b><i>Methods:</i></b> The miR-301a expression in ovarian cancer cells was detected. Then, cell proliferation, cell cycle, and apoptosis of the miR-301a-mimic-transfected ovarian cancer cells were determined, as well as the effects of the miR-301a mimic on the PTEN/phosphoinositide 3-kinase (PI3K) signaling pathway were explored. <b><i>Results:</i></b> We found that the miR-301a expression levels were markedly upregulated in ovarian cancer tissues and cells, and upregulation of miR-301a-promoted cell viability and proliferation. Our results also showed that the miR-301a-mimic accelerated cell cycle progression of ovarian cancer cells by targeting the CDK4/Cyclin-D1 pathway but not the CDK2/Cyclin-E pathway. Moreover, transfection of the miR-301a mimic into ovarian cancer cells could decrease the PTEN expression while increasing the PI3K and Akt phosphorylation, as compared with the miR-301a inhibitor group and the negative control group. <b><i>Conclusion:</i></b> Therefore, miR-301a should be an oncogene in ovarian cancer, and overexpression of miR-301a promoted proliferation of ovarian cancer cells by modulating the PTEN/PI3K/Akt signaling pathway.

TET3-mediated DNA demethylation modification activates SHP2 expression to promote endometrial cancer progression through the EGFR/ERK pathway

Src homology phosphotyrosin phosphatase 2 (SHP2) has been implicated in the progression of several cancer types. However, its function in endometrial cancer (EC) remains unclear. Here, we report that the ten-eleven translocation 3 (TET3)-mediated DNA demethylation modification is responsible for the oncogenic role of SHP2 in EC and explore the detailed mechanism. The transcriptomic differences between EC tissues and control tissues were analyzed using bioinformatics tools, followed by protein-protein interaction network establishment. EC cells were treated with shRNA targeting SHP2 alone or in combination with isoprocurcumenol, an epidermal growth factor receptor (EGFR) signaling activator. The cell biological behavior was examined using cell counting kit-8, colony formation, flow cytometry, scratch assay, and transwell assays, and the median inhibition concentration values to medroxyprogesterone acetate/gefitinib were calculated. The binding of TET3 to the SHP2 promoter was verified. EC cells with TET3 knockdown and combined with SHP2 overexpression were selected to construct tumor xenografts in mice. TET3 and SHP2 were overexpressed in EC cells. TET3 bound to the SHP2 promoter, thereby increasing the DNA hydroxymethylation modification and activating SHP2 to induce the EGFR/extracellular signal-regulated kinase (ERK) pathway. Knockdown of TET3 or SHP2 inhibited EC cell malignant aggressiveness and impaired the EGFR/ERK pathway. Silencing of TET3 inhibited the tumorigenic capacity of EC cells, and ectopic expression of SHP2 or isoprocurcumenol reversed the inhibitory effect of TET3 knockdown on the biological activity of EC cells. TET3 promoted the DNA demethylation modification in the SHP2 promoter and activated SHP2, thus activating the EGFR/ERK pathway and leading to EC progression.