IUBMB Life

Elevated microRNA‐130b‐5p or silenced ELK1 inhibits self‐renewal ability, proliferation, migration, and invasion abilities, and promotes apoptosis of cervical cancer stem cells

AbstractCervical cancer (CC) is the most familiar gynecological malignancy. With the poor prognosis of CC patients, this study explored the effect of microRNA (miR)‐130b‐5p targeting ELK1 expression on self‐renewal ability and stemness of CC stem cells. The tissues of patients with CC or cervical benign lesions were collected. MiR‐130b‐5p and ELK1 expression was detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. Human CC cell line Hela was cultured and the induced CC stem cells were introduced with miR‐130b‐5p mimic or silenced ELK1 to figure their roles in self‐renewal ability, stemness, colony formation, proliferation, migration, invasion abilities, and apoptosis of CC stem cells. Tumor growth was detected in nude mice in vivo. The targeting relationship between miR‐130b‐5p and ELK1 was analyzed using bioinformatic prediction and dual luciferase reporter gene assay. Decreased miR‐130b‐5p and elevated ELK1 existed in CC tissues of patients. Up‐regulated miR‐130b‐5p decreased ELK1 expression in CC stem cells. Elevated miR‐130b‐5p or silenced ELK1 inhibited self‐renewal ability and stemness, colony formation, proliferation, migration and invasion abilities, promoted apoptosis of CC stem cells, as well as decreased the weight and volume of tumor in nude mice. ELK1 was found to be targeted by miR‐130b‐5p. Overexpression ELK1 effectively reversed the cellular phenotypic changes and tumor formation in vivo caused by up‐regulation of miR‐130b‐5p. We conclude that up‐regulated miR‐130b‐5p or silenced ELK1 inhibits CC stem cell growth.

RNPS1 functions as an oncogenic splicing factor in cervical cancer cells

AbstractNumerous recent studies suggest that cancer‐specific splicing alteration is a critical contributor to the pathogenesis of cancer. RNA‐binding protein with serine‐rich domain 1, RNPS1, is an essential regulator of the splicing process. However, the defined role of RNPS1 in tumorigenesis still remains elusive. We report here that the expression of RNPS1 is higher in cervical carcinoma samples from The Cancer Genome Atlas (TCGA‐cervical squamous cell carcinoma and endocervical adenocarcinoma) compared to the normal tissues. Consistently, the expression of RNPS1 was high in cervical cancer cells compared to a normal cell line. This study shows for the first time that RNPS1 promotes cell proliferation and colony‐forming ability of cervical cancer cells. Importantly, RNPS1 positively regulates migration‐invasion of cervical cancer cells. Intriguingly, depletion of RNPS1 increases the chemosensitivity against the chemotherapeutic drug doxorubicin in cervical cancer cells. Further, we characterized the genome‐wide isoform switching stimulated by RNPS1 in cervical cancer cell. Mechanistically, RNA‐sequencing analysis showed that RNPS1 regulates the generation of tumor‐associated isoforms of key genes, particularly Rac1b, RhoA, MDM4, and WDR1, through alternative splicing. RNPS1 regulates the splicing of Rac1 pre‐mRNA via a specific alternative splicing switch and promotes the formation of its tumorigenic splice variant, Rac1b. While the transcriptional regulation of RhoA has been well studied, the role of alternative splicing in RhoA upregulation in cancer cells is largely unknown. Here, we have shown that the knockdown of RNPS1 in cervical cancer cells leads to the skipping of exons encoding the RAS domain of RhoA, consequently causing decreased expression of RhoA. Collectively, we conclude that the gain of RNPS1 expression may be associated with tumor progression in cervical carcinoma. RNPS1‐mediated alternative splicing favors an active Rac1b/RhoA signaling axis that could contribute to cervical cancer cell invasion and metastasis. Thus, our work unveils a novel role of RNPS1 in the development of cervical cancer.

Histone deacetylase 10 exerts antitumor effects on cervical cancer via a novel microRNA‐223/TXNIP/Wnt/β‐catenin pathway

AbstractDysfunction of histone deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened‐out miRNA target. Microarray analysis and RT‐qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR‐223, upregulated in CC, was regulated by HDAC10 through histone acetylation, while miR‐223 inhibited the effects of HDAC10 overexpression in CC. miR‐223 targeted the 3′‐UTR of thioredoxin interacting protein (TXNIP) and suppressed its expression, leading to increased CC development in vitro and in vivo. TXNIP overexpression impaired Wnt/β‐catenin pathway activity in CC cells.

Multi‐Omics Analysis Reveals That the MAZ / HDGF Regulatory Axis Drives High‐Grade Serous Ovarian Cancer Progression by Modulating Glycolysis and M2 Macrophage Polarization

ABSTRACT Super‐enhancers (SEs) are large clusters of enhancers that drive high‐level expression of genes critical for normal development and tumorigenesis. However, their precise roles in high‐grade serous ovarian carcinoma (HGSOC) remain unclear. This study integrated SE‐derived regulatory networks with proteomic profiles to identify key pro‐tumorigenic signaling in HGSOC progression. Weighted gene co‐expression network analysis (WGCNA) and machine learning were used to screen SE‐driven core oncoproteins. The influence on cell phenotypes was evaluated by detecting invasion, proliferation, apoptosis, glucose consumption, lactate generation, and tube formation. M2 macrophage polarization was assessed by detecting CD163 + cell proportion and TGF‐β1 and IL‐10 secretion. The MAZ/HDGF interaction was confirmed by luciferase and ChIP‐qPCR assays. Xenograft studies were used to evaluate the in vivo function. HDGF was overexpressed and was identified as a core SE‐driven oncoprotein in HGSOC. Silencing of HDGF inhibited the invasion, proliferation, and glycolysis of HGSOC cells, promoted their apoptosis, and attenuated HUVEC tube formation and M2 macrophage polarization. Mechanistically, MAZ transcriptionally activated HDGF through promoter binding. Moreover, HDGF re‐expression counteracted the suppressive effects of MAZ knockdown on HGSOC cell malignant behaviors, HUVEC tube formation, M2 macrophage polarization, and the growth of xenograft tumors. In conclusion, our study unveils the MAZ/HDGF axis as a novel SE‐mediated oncogenic pathway in HGSOC, providing previously unrecognized insights into SE‐driven oncogenesis and highlighting potential targets for HGSOC treatment.

Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway

AbstractMelatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)‐trisphosphate kinase (PI3K), p‐PI3K, Akt, p‐Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl‐XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin‐1 phosphorylation. Beclin‐1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP‐activated protein kinase (AMPK), Wnt/β‐catenin, mitogen‐activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.

Circ_0109046 promotes the malignancy of endometrial carcinoma cells through the microRNA‐105/SOX9/Wnt/β‐catenin axis

AbstractEmerging evidence suggests the important involvements of circular RNAs (circRNAs) in cancer progression. This study focuses on the function of Circ_0109046 on the malignancy of endometrial carcinoma (EC) cells and the molecules involved. First, high expression of Circ_0109046 was found in EC tissues compared to the adjacent tissues, and it predicted unfavorable prognosis in patients. Similarly, high expression of Circ_0109046 was confirmed in EC cells relative to that in normal endometrial epithelial cells. Silencing of Circ_0109046 in AN3‐CA cells inhibited proliferation and aggressiveness but increased apoptosis of cells. Circ_0109046 was mainly sub‐localized in cytoplasm, and it mediated SOX9 expression through sponging microRNA (miR)‐105. The proliferation and aggressiveness of EC cells suppressed by Circ_0109046 downregulation was recovered upon SOX9 overexpression. SOX9 activated the Wnt/β‐catenin pathway. Furthermore, downregulation of Circ_0109046 reduced the growth of xenograft tumors in nude mice. This study evidenced that Circ_0109046 upregulates SOX9 expression through sponging miR105, leading to activation of Wnt/β‐catenin signaling and the malignant growth of EC. This study may offer novel understanding in EC treatment.

Unveiling Gamma‐Interferon‐Inducible Lysosomal Thiol Reductase (IFI30) as a Regulator of Macrophage Polarization and Prognostic Biomarker by Multi‐Transcriptome Analysis in Cervical Cancer

ABSTRACTCervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRNA signature model based on tumor immune infiltration characteristics of cervical cancer. By employing RNA sequencing technologies at both tissue and single‐cell resolutions, a survival predictive gene signature was constructed for cervical cancer through the application of machine learning methods. To further validate the key prognostic genes identified in the prognostic signature, we performed additional experiments, including tissue microarray (TMA) analysis and in vitro assays. Our developed signature model comprised nine genes, which ranks at the top tier when compared to previously published mRNA signature models. Gamma‐interferon‐inducible lysosomal thiol reductase (IFI30) emerged as a critical prognostic marker, validated externally through immunohistochemistry (IHC) and multiplex immunohistochemistry staining (mIHC) on cervical cancer TMAs. Notably, IFI30 exhibited pronounced expression in macrophages compared to other cell types within the tumor microenvironment (TME). We further investigated the potential role of IFI30 in regulating macrophage polarization. Specifically, a reduced expression of IFI30 in macrophages co‐cultured with HeLa cells induced a polarization transition from the M2 to the M1 phenotype. In conclusion, we have successfully established a prognostic model on the basis of tumor immune infiltration characteristic of cervical cancer, highlighting IFI30 as a pivotal prognostic marker potentially involved in macrophage polarization. Future investigation is required to explore the underlying mechanisms for the advancement of therapeutic strategies in cervical cancer.

Effect of Saponin from Tupistra chinensis Baker on proliferation and apoptosis of ovarian cancer cells by Wnt/β‐Catenin pathway

AbstractThe present study aimed to investigate the molecular mechanism and the effect of Saponin from Tupistra chinensis Baker (STCB) on the proliferation and apoptosis of ovarian cancer cells. To investigate the inhibitory effect of STCB on the proliferation of ovarian cancer cells, SKOV3 cells were cultured and the methyl thiazolyl tetrazolium assay was used. Flow cytometry was also used to analyze the cell cycle distribution and apoptotic rate. Ki‐67, cyclin D1, cleaved caspase‐3, cleaved caspase‐9, β‐catenin, and c‐Myc protein expressions were detected by western blot. Ovarian cancer cells were treated with STCB and Wnt pathway activator lithium chloride (LiCl). These methods were also used to determine the proliferation, cell cycle distribution, and apoptosis of ovarian cancer cells. In STCB‐treated group, the proliferation inhibition and apoptosis rate, the proportion of G0‐G1 phase, and the expression level of cleaved caspase‐3 and 9 of ovarian cancer cells were significantly increased. Similarly, the expression of Ki‐67, cyclin D1, β‐catenin, and c‐Myc were significantly decreased (p < .05). The results also showed that in STCB‐LiCl‐treated group, while the proliferation inhibition rate of ovarian cancer cells, the proportion of G0‐G1 cells, the expression level of cleaved caspase‐3 and 9, and the apoptosis rate (p < .05) were significantly decreased, the expression level of Ki‐67, cyclin D1, β‐catenin, and c‐Myc was significantly increased. STCB induced G0‐G1 phase arrest, inhibited cell proliferation, and promoted apoptosis of ovarian cancer cells by inhibiting Wnt/β‐catenin pathway.

Chitosan is a potential inhibitor of ovarian cancer: Molecular aspects

AbstractAlthough ovarian cancer has a lower prevalence than breast cancer, its mortality rate is three times higher, which is reported to increase in the coming years. As the early stages of ovarian cancer do not have any obvious symptoms, in most of the cases, this cancer is diagnosed at advanced stages with a poor prognosis. Moreover, in many patients who are diagnosed with advanced stage, relapse of the disease and drug resistance are observed. Over the past years, these women have been treated with chemotherapy and cytoreductive surgeries. However, the chemotherapy could affect the healthy tissues in addition to the malignancies. Therefore, discovering new diagnostic and therapeutic options seems to be a crucial need. Unlike the common invasive and/or nonspecific treatments, nanomedicine is trying to find a new way for cancer imaging, diagnosis, and drug delivery method. Nanoparticles (NPs), which has recently drawn attention, can be used in order to reduce the toxicity and frequent dosing of drugs, tumor‐specific delivery, and early diagnosis for malignancies. Chitosan as an NP and product of chitin deacetylation has multiple characteristics, including biocompatibility, biodegradability, and safety. In this review, we cover the studies concerned with the role of chitosan in finding solutions to overcome the problems faced in ovarian cancer treatments. Furthermore, we highlight how chitosan is being used in delivering chemotherapy drugs, gene therapy, and imaging methods for both detection and image‐guided therapies.