Rong Ma

SLC7A5-ERBB2 axis drives olaparib resistance via de novo lipid synthesis in ovarian cancer

In the treatment of ovarian cancer, PARP inhibitors such as olaparib have shown promise, yet resistance in advanced cases remains a significant challenge. Our study identified SLC7A5 as a key gene associated with olaparib resistance through differential gene expression and prognostic analysis. High SLC7A5 expression was found to correlate with poor prognosis. In vivo and in vitro experiments revealed that SLC7A5 enhances olaparib resistance by stabilizing ACLY and promoting de novo lipid synthesis via the ERBB2 axis, independent of leucine. Mechanistically, SLC7A5 upregulates ERBB2 transcription through ELK1, and ERBB2 competes with CUL3 to prevent ACLY degradation. These findings suggest that targeting SLC7A5 may reverse olaparib resistance, offering new strategies for combination therapies and improving clinical outcomes in ovarian cancer treatment.

ZNF146 regulates cell cycle progression via TFDP1 and DEPDC1B in ovarian cancer cells

In brief Aberration in cell cycle progression is one of the essential mechanisms underlying tumorigenesis, making regulators of cell cycle reasonable anti-cancer therapeutic targets. Here, we dissected the regulatory mechanism involving the novel axis ZNF146/TFDP1/DEPDC1B in the cell cycle in ovarian cancer. Abstract Ovarian cancer (OC) is the third most common kind of gynecological tumor, in addition to being the most lethal. Transcription factor Dp-1 (TFDP1) functions as a binding partner for E2F transcription factors, and its target genes include those involved in DNA synthesis, cell cycle, and apoptosis. However, the regulatory role of TFDP1 in OC remains incompletely understood. This study aimed to investigate the role and mechanism of TFDP1 in OC. TFDP1 was highly expressed in the ovarian epithelial tissues of OC patients, and the expression of TFDP1 in OC cells was higher than that in normal ovarian epithelial cells. Silencing of TFDP1 inhibited the biological activity of OC cells and hindered cell cycle entry. Zinc finger protein 146 (ZNF146) knockdown induced cell cycle arrest at the G0/G1 phase and tumor growth by blocking TFDP1 transcription, which was overturned by ectopic expression of TFDP1. TFDP1 stimulated DEP domain-containing protein 1B (DEPDC1B) expression through transcriptional activation. DEPDC1B increased the proportion of OC cells in the G2/M phase and potentiated tumor malignant progression in nude mice inhibited by sh-ZNF146. Taken together, these findings demonstrate that ZNF146 participates in TFDP1/DEPDC1B activation and plays a vital role in the cell cycle in OC.

Unveiling the ZNF384-INTS13-hnRNPC axis as a therapeutic vulnerability in cervical cancer

Abstract Cervical cancer remains a major global health burden, necessitating the identification of novel therapeutic targets to overcome the limitations of current treatments. Here, we comprehensively investigated the role of integrator complex subunit 13 (INTS13) in cervical cancer progression. Our analysis of publicly available The Cancer Genome Atlas (TCGA) datasets revealed that INTS13 is significantly overexpressed in cervical cancer tissues across various histological subtypes, correlating with advanced tumor T-stage and predicting poorer overall survival. Single-cell RNA sequencing further localized INTS13 expression predominantly to malignant epithelial cells within the tumor microenvironment, where its expression correlated with genes involved in critical cellular processes. Furthermore, elevated expression has been observed in cervical cancer tissues from surgically-treated patients and in various primary human cervical cancer cells. In vitro functional studies demonstrated that genetic silencing or CRISPR/Cas9-mediated knockout of INTS13 significantly inhibited the proliferation, migration, and invasion of primary cervical cancer cells, while selectively inducing apoptosis. Conversely, ectopic INTS13 overexpression markedly enhanced these malignant phenotypes. Mechanistically, we identified heterogeneous nuclear ribonucleoprotein C (hnRNPC) as a critical downstream effector, with INTS13 regulating hnRNPC expression, and the restoration of hnRNPC effectively reversing the anti-cervical cancer effects observed upon INTS13 silencing. Furthermore, the transcription factor ZNF384 (zinc finger protein 384) was identified as an upstream regulator that directly binds to and positively governs INTS13 expression. Finally, in vivo animal models confirmed that targeted silencing of INTS13 significantly impeded cervical cancer xenograft growth in nude mice, reduced cellular proliferation, and augmented apoptosis, consistently accompanied by a reduction in hnRNPC expression. These findings collectively establish INTS13 as a crucial precancerous gene in cervical cancer, promoting malignant phenotypes primarily through the ZNF384-INTS13-hnRNPC signaling axis.

PRDM1-driven SLC30A9 overexpression contributes to the malignant phenotype of cervical cancer cells via promoting mitochondrial hyperfunction

Abstract Mitochondrial hyperfunction is important for cervical cancer progression. Solute carrier family 30 member 9 (SLC30A9) is a member of the solute carrier family 30, specifically a zinc transporter that plays a critical role in mitochondrial zinc homeostasis and maintaining mitochondrial function. We investigated the expression, function, and underlying mechanisms of SLC30A9 in the context of cervical cancer. Single-cell RNA sequencing analysis revealed a marked overexpression of SLC30A9 within the malignant epithelial cell population of cervical squamous cell carcinoma. This elevated SLC30A9 expression was further corroborated in clinical specimens from local patients and across various established and primary cervical cancer cells. SLC30A9 shRNA or knockout (via CRISPR/Cas9 method) significantly impeded the viability, proliferation, cell cycle progression and migration, and triggered apoptosis in cervical cancer cells. SLC30A9 depletion disrupted mitochondrial function, inhibiting mitochondrial respiration, mitochondrial membrane potential, mitochondrial complex I activity, and ATP production, also caused mitochondrial Zn 2+ accumulation, reactive oxygen species (ROS) production and oxidative injury. Conversely, overexpression of SLC30A9 in cervical cancer cells demonstrated enhanced mitochondrial complex I activity, increased ATP production, and augmented cellular proliferation and migration. Bioinformatic analysis, coupled with functional validation, identified PRDM1 (PR Domain Containing 1) as a key transcription factor regulating SLC30A9 expression. Silencing or knockout of PRDM1 resulted in a significant reduction in SLC30A9 promoter activity, as well as decreased SLC30A9 mRNA and protein levels in primary cervical cancer cells. Chromatin immunoprecipitation (ChIP) assays confirmed increased PRDM1 binding to the SLC30A9 promoter region in cervical cancer tissues. In vivo studies showed that SLC30A9 knockdown led to a remarkable decrease in the growth of xenografts formed by primary cervical cancer cells. These SLC30A9-silenced xenografts exhibited mitochondrial dysfunction, proliferation inhibition and apoptosis induction. These findings collectively suggest that PRDM1-driven SLC30A9 overexpression significantly contributes to the malignant phenotype of cervical cancer, possibly through promoting mitochondrial hyperfunction.

Cervical cancer incidence rates considering migration status in mainland China using Bayesian model—Estimation based on 2016 cancer registry data

AbstractIn mainland China, cancer registration relies on household‐registered populations, overlooking migrant populations. Estimating cervical cancer incidence among permanent residents, including migrants, offers a more accurate representation of the true burden. The data from 487 cancer registries across China in 2016 were analyzed using a Bayesian spatial regression model with the integrated nested Laplace approximation‐stochastic partial differential equation method. The study estimated cervical cancer incidence among household‐registered populations and adjusted for migrant populations using a weighting method based on interprovincial distribution and age stratification to derive the incidence of cervical cancer in the permanent residents. Data from the China Population Census, the China Migrants Dynamic Survey, and the Urban Statistical Yearbook were incorporated. The estimated crude incidence rate of cervical cancer among permanent residents was 17.4/100,000 in mainland China, with an age‐standardized incidence rate (ASIR) of 17.2/100,000. The largest disparities in cervical cancer crude incidence rate between permanent residents and household‐registered populations were observed in Guizhou (2.4/100,000, 95% CI 1.9–2.9/100,000), Zhejiang (−1.2/100,000, 95% CI −1.8 to −0.6/100,000) and Tianjin (−1.1/100,000, 95% CI −1.5 to −0.7/100,000). The number of the estimated cervical cancer incident cases was 8948. Guangdong saw an increase of 887 cases, while Henan had a decrease of 1430 cases. Guizhou had the highest ASIR (28.1/100,000), and Beijing had the lowest ASIR (11.0/100,000). The significance of this study is that it improves the accuracy of cervical cancer data in China. These findings provide evidence for developing cervical cancer prevention and control strategies, and offer insights for other countries and regions facing migration challenges.