LncRNA PVT1 links estrogen receptor alpha and the polycomb repressive complex 2 in suppression of pro-apoptotic genes in hormone-responsive breast cancer

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 8, 2025

RNA-based therapeutics highlighted novel approaches to target either coding or noncoding molecules for multiple diseases treatment. In breast cancer (BC), a multitude of deregulated long RNAs (lncRNAs) have been identified as potential therapeutic targets also in the context antiestrogen resistance, and RNA binding activity estrogen receptor α (ERα) points additional candidates interfere with estrogenic signaling. A set lncRNAs was selected among ERα-associated BC cell nuclei due their roles processes such transcriptional regulation epigenetic chromatin modifications. Native immunoprecipitation nuclear ERα-interacting coupled NGS (RIP-Seq) performed MCF-7 cells, leading identification essential interacting multi-molecular regulatory complexes. Among these, PVT1, FGD5-AS1 EPB41L4A-AS1 were further investigation. Functional assays transcriptome analysis following lncRNA knock-down indicated PVT1 master modulator some most relevant hallmarks, proliferation, apoptosis, migration response hypoxia. addition, targeted experiments key factor composition PRC2-ERα network involved downregulation tumor suppressor genes, including BTG2.

Язык: Английский

---

Altered ribosomal profile in acquired resistance and reversal associates with pathological response to chemotherapy in inflammatory breast cancer

npj Breast Cancer, Год журнала: 2024, Номер 10(1)

Опубликована: Июль 29, 2024

Abstract Therapeutic resistance presents a significant hurdle in combating inflammatory breast cancer (IBC), adding to the complexity of its management. To investigate these mechanisms, we conducted comprehensive analysis using transcriptomic and proteomic profiling preclinical model alone with correlates treatment response IBC patients. This included SUM149 cell lines derived from treatment-naïve patients, along acquired drug (rSUM149) others state reversal (rrSUM149), aiming uncover networks. We identified specific ribosomal proteins associated acquiring resistance. These correlated elevated levels molecular markers such as pERK, CDK1, XIAP, SOD2. While rrSUM149 cells largely normalized expression profile, VIPER revealed persistent alterations process-related (AGO2, Exportin 1, RPL5), suggesting their continued involvement Moreover, genes linked processes were significantly enriched ( P < 0.001) among overexpressed patients n = 87) who exhibited pathological complete (pCR) neoadjuvant chemotherapy. Given common hyperactivation MAPK tumors, including rSUM149, evaluated Merestinib, multikinase inhibitor clinical trials. It effectively targeted pERK peIF4E pathways, suppressed downstream targets, induced death drug-resistant rSUM149 cells, showed synergistic effects another tyrosine kinase (Lapatinib) parental cells. underscores impact on protein synthesis signaling, crucial for translational dependence In summary, our study elucidates adaptive changes therapy pauses, guiding precision medicine approaches this challenging type.

Язык: Английский

---

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Июнь 8, 2023

Chemotherapy resistance remains a major challenge in the treatment of gynecologic malignancies. Increasing evidence suggests that circular RNAs (circRNAs) play significant role conferring chemoresistance these cancers. In this review, we summarize current understanding mechanisms by which circRNAs regulate chemotherapy sensitivity and We also discuss potential clinical implications findings highlight areas for future research. CircRNAs are novel class RNA molecules characterized their unique structure, confers increased stability to degradation exonucleases. Recent studies have shown can act as miRNA sponges, sequestering miRNAs preventing them from binding target mRNAs. This lead upregulation genes involved drug pathways, ultimately resulting decreased chemotherapy. several specific examples been implicated cancers, including cervical cancer, ovarian endometrial cancer. applications circRNA-based biomarkers predicting response guiding decisions. Overall, review provides comprehensive overview state knowledge regarding By elucidating underlying sensitivity, work has important improving patient outcomes developing more effective therapeutic strategies challenging

Язык: Английский

---

RNA-binding proteins in breast cancer: Biological implications and therapeutic opportunities

Critical Reviews in Oncology/Hematology, Год журнала: 2024, Номер 195, С. 104271 - 104271

Опубликована: Янв. 23, 2024

RNA-binding proteins (RBPs) refer to a class of that participate in alternative splicing, RNA stability, polyadenylation, localization and translation RNAs, thus regulating gene expression post-transcriptional manner. Dysregulation RNA-RBP interaction contributes various diseases, including cancer. In breast cancer, disorders RBP function influence the biological characteristics tumor cells. Targeting RBPs has fostered development innovative therapies for However, RBP-related mechanisms cancer are not completely clear. this review, we summarize regulatory their signaling crosstalk Specifically, emphasize potential certain as prognostic factors due effects on proliferation, invasion, apoptosis, therapy resistance Most importantly, present comprehensive overview latest therapeutic strategies novel targets have proven be useful treatment

Язык: Английский

---

The emerging role of circular RNAs in cisplatin resistance in ovarian cancer: From Molecular mechanism to future potential

Non-coding RNA Research, Год журнала: 2024, Номер 9(4), С. 1280 - 1291

Опубликована: Май 20, 2024

Ovarian cancer (OC) is the most common cause of death in female cancers. The prognosis OC very poor due to delayed diagnosis and identification patients advanced stages, metastasis, recurrence, resistance chemotherapy. As chemotherapy with platinum-based drugs such as cisplatin (DDP) main treatment cases, DDP an important obstacle achieving satisfactory therapeutic efficacy. Consequently, knowing different molecular mechanisms involved necessary achieve new approaches. According numerous recent studies, non-coding RNAs (ncRNAs) could regulate proliferation, differentiation, apoptosis, chemoresistance many cancers, including OC. Most these ncRNAs are released by tumor cells into human fluid, allowing them be used tools for diagnosis. CircRNAs ncRNA family members that have a role initiation, progression, regulation various In current study, we investigated roles several circRNAs their signaling pathways on progression also during

Язык: Английский

---

Genomic analysis uncovers that cold-inducible RNA binding protein is associated with estrogen receptor in breast cancer

Genes & Genomics, Год журнала: 2024, Номер 46(8), С. 899 - 907

Опубликована: Июнь 7, 2024

Язык: Английский

---

RNA-binding protein transcripts as potential biomarkers for detecting Primary Sclerosing Cholangitis and for predicting its progression to Cholangiocarcinoma

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Июнь 6, 2024

Primary Sclerosing Cholangitis (PSC) is a persistent inflammatory liver condition that affects the bile ducts and commonly diagnosed in young individuals. Despite efforts to incorporate various clinical, biochemical molecular parameters for diagnosing PSC, it remains challenging, no biomarkers characteristic of disease have been identified hitherto. PSC linked with an uncertain prognosis, there pressing need explore multiomics databases establish new biomarker panel early detection PSC’s gradual progression into Cholangiocarcinoma (CCA) development effective therapeutic interventions. Apart from non-coding RNAs, other components Ribonucleoprotein (RNP) complex, such as RNA-Binding Proteins (RBPs), also hold great promise due their versatile expression pathological conditions. In present review, update on RBP transcripts show dysregulated CCA provided. Moreover, by utilizing bioinformatic data mining approach, we give insight those exhibit differential gall bladder, well body fluids, are promising predicting prognosis PSC. Expression were bioinformatically extracted public repositories usingTCGA Bile Duct Cancer dataset specific NCBI GEO datasets both CCA; more specifically, RBPs annotations obtained World database. Interestingly, our comprehensive analysis shows elevated non-canonical RBPs, FANCD2 , microtubule dynamics regulator, ASPM fluids patients compared respective controls, same trend being observed bladder cancer tissues. Consequently, manipulation tissue might be considered strategy mitigate onset patients, warrants further experimental investigation. The performed herein may helpful identification non-invasive its CCA. conclusion, future clinical research should investigate depth full potential human pathologies.

Язык: Английский

---

Using the structural diversity of RNA: protein interfaces to selectively target RNA with small molecules in cells: methods and perspectives

Frontiers in Molecular Biosciences, Год журнала: 2023, Номер 10

Опубликована: Ноя. 16, 2023

In recent years, RNA has gained traction both as a therapeutic molecule and target in several human pathologies. this review, we consider the approach of targeting using small molecules for research purposes. Given primary challenge presented by low structural diversity RNA, discuss potential RNA: protein interactions to enhance sequence specificity drug candidates. We review available tools inherent challenges approach, ranging from adapted bioinformatics vitro cellular high-throughput screening functional analysis. further two critical steps RNA/protein interactions: first, integration silico analyses improve efficacy identifying scaffolds with high affinity, second, increasing likelihood on-target compounds cells through combination approaches assays. anticipate that development new class prevent physio-pathological mechanisms could significantly expand arsenal effective compounds.

Язык: Английский

---

ESRP1-driven alternative splicing of CLSTN1 inhibits the metastasis of gastric cancer

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Дек. 19, 2023

Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement cancer. Here, we found that ESRP1, a RBP specific epithelial cells, important regulating cells. ESRP1 negatively correlated with distant and lymph node And demonstrated inhibit migration invasion vitro vivo. Mechanistically, promotes exon 11 alternative splicing CLSTN1 pre-mRNA. The post-splicing short stabilizes Ecadherin/β-catenin binding structure, β-catenin protein ubiquitination degradation, thereby inhibiting Our study highlights role extends its mechanism. These results provide possibility for to become therapeutic targets

Язык: Английский

---

Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13127 - 13127

Опубликована: Авг. 23, 2023

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This has been progressively recognized as a relevant therapeutic for several pathologies, like cancer, neurodegeneration, well inflammation. Inhibitors mRNA binding to HuR might thus be beneficial against variety diseases. Here, we present the rational identification structurally novel inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, RNA–protein pulldown assays, demonstrate that 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits dose-dependent inhibition effect in experiments. Importantly, chemical scaffold is new with respect currently known inhibitors, opening up avenue design pharmaceutical agents targeting this important protein.

Язык: Английский

---