• RNA
• diagnosis
• prostate cancer
• splicing
• treatment

• prostate cancer
• oncogenes
• cancer stem cells

• Male
• Humans
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/metabolism
• Hyaluronan Receptors/metabolism
• Hyaluronan Receptors/genetics
• Epithelial-Mesenchymal Transition/genetics
• Transcriptional Activation
• Animals
• Mice
• Cell Line, Tumor
• Octamer Transcription Factor-3/metabolism
• Octamer Transcription Factor-3/genetics
• Prostatic Neoplasms, Castration-Resistant/pathology
• Prostatic Neoplasms, Castration-Resistant/genetics
• Prostatic Neoplasms, Castration-Resistant/metabolism
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Nanog Homeobox Protein/genetics
• Nanog Homeobox Protein/metabolism
• Receptors, Cytoplasmic and Nuclear/metabolism
• Receptors, Cytoplasmic and Nuclear/genetics
• Gene Expression Regulation, Neoplastic
• Orphan Nuclear Receptors/metabolism
• Orphan Nuclear Receptors/genetics
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism

• 14110918 Research Grants Council, University Grants Committee (RGC, UGC)
• 81872283 and 82273341 National Natural Science Foundation of China (National Science Foundation of China)
• Guangdong Basic and Applied Basic Research Foundation (2024A1515011645), Science and Technology Project of Shenzhen (GJHZ20220913144209018) Research Foundation of Shenzhen Hospital of Southern Medical University (No. 22H3ATF02)

• alternative splicing
• cancer
• epithelial-mesenchymal transitions

• Humans
• Alternative Splicing/genetics
• Epithelial-Mesenchymal Transition/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• RNA Splicing Factors/genetics

• BB/J007293/2 Biotechnology and Biological Sciences Research Council

Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. HA, also gain attention due to consideration as a primary ligand of CD44 receptor. The CD44, complex transmembrane receptor protein, due to alternative splicing in the transcription process, various CD44 isoforms predominantly exist. The overexpression of distinct CD44 isoforms (CD44v) standard (CD44s) depends on the tumour type and stage. The receptor proteins, CD44 engage in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. HA-CD44 interaction trigger survival pathways that result in cell proliferation, invasion ultimately complex metastasis. The interaction and binding of ligand-receptor HA-CD44 regulate the downstream cytoskeleton pathways involve in cell survival or cell death. Thus, targeting HA, CD44 (variant and standard) isoform, and HA-CD44 binding consider as an attractive and useful approach towards cancer therapeutics. The use of various inhibitors of HA, hyaluronidases (HYALs), and utilizing targeted Nano-delivery of anticancer agents and antibodies against CD44, peptides gives promising results in vitro and in vivo. However, they are in clinical trials with favourable and unfavourable outcomes, which reflects the need for various modifications in targeting agents and a better understanding of potential targets in tumour progression pathways.

• Apoptosis
• CD44
• Cancer pathways
• Cell proliferation
• Hyaluronan
• Nanotechnology
• Targeted therapeutics
• Tumor progression

To evaluate the role of epithelial splicing regulatory protein 1 (ESRP1) expression in survival prognoses and disease progression for prostate cancer (PC) using The Cancer Genome Atlas (TCGA) dataset and to validate it using patients’ prostatectomy specimens.

A preliminary investigation into the clinical significance of ESRP1 in PC was conducted using TCGA PC PRAD dataset and then using immunohistochemistry in 514 PC patients’ tissue microarrays of radical prostatectomy specimens. The interpretation of immunohistochemistry was done using its intensity (high vs. low) or the semi-quantitative expression value (H-score, 0–300). The prognostic significance of ESRP1 expression was analyzed for biochemical recurrence (BCR), recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) using the Cox proportional-hazards model (p < 0.05).

In the publicly available prostate adenocarcinoma dataset, ESRP1 expression was significantly higher in the tumor samples compared to the normal samples (p < 0.001). Survival analysis showed that the tumor samples in the ESRP1-high group had significantly worse BCR-free survival and RFS compared to the ESRP1-low group (p < 0.05), whereas OS was not (p=0.08). These results were largely consistent with the 514 patients’ clinical data during a median 91.2 months of follow-up. After adjusting for significant prognostic clinicopathological factors, the multivariable models showed that the ESRP1 was a significantly risk factor for CSS (Hazard ratio 3.37, p = 0.034) and for BCR (HR 1.34, p=0.049) without any significance for OS (p=0.464).

The higher ESRP1 expression appeared increased risk of disease progression and cancer-specific death in PC.

• ESRP1 gene
• biochemical recurrence (BCR)
• clinical validation
• prostate cancer
• prostate cancer-specific mortality
• survival analysis

• EMT
• FOSL2
• Hepatocellular carcinoma
• PCBP1
• hsa_circ_0003998
• microRNA-143-3p

• oncolytic viro-immunotherapy, CAR T cell, BiTE molecule, cytokine, checkpoint inhibitor, CD44 variant 6

The breast cancer is one of the most common cancer affecting millions of lives worldwide. Though the prevalence of breast cancer is worldwide; however, the developing nations are having a comparatively higher percentage of breast cancer cases and associated complications. The molecular etiology behind breast cancer is complex and involves several regulatory molecules and their downstream signaling. Studies have demonstrated that the CD44 remains one of the major molecule associated not only in breast cancer but also several other kinds of tumors. The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well. The Carbon nanotubes (CNTs) have shown tremendous scope in delivering the drug by targeting a particular receptor and molecules. Functionalized CNTs including both SWCNTs and MWCNTs are a pioneer in drug delivery with higher efficacy. The present work emphasized mainly on the potential of CNTs including both SWCNTs and MWCNTs in drug delivery for anti-cancerous therapy. The review provides a comprehensive overview of the development of various CNTs and their validation for effective drug delivery. The work focus on drug delivery approaches for breast cancer, precisely targeting CD44 molecule.

• Anti-cancerous therapy
• BBB, Blood–Brain Barrier
• Breast cancer
• CD 44, Cluster of Differentiation
• CD44
• DNA, Deoxyribonucleic acid
• Delivery
• Drug
• HA, hyaluronic acid
• HNSCC, Head and neck squamous cell carcinoma
• MMPs, Matrix metalloproteinase
• MWCNTs, Multiwalled Carbon Nanotubes
• Multiwalled carbon nanotubes
• PDT, Photodynamic Therapy
• PTT, Photothermal Therapy
• SWCNTs, Single-walled Carbon Nanotubes
• siRNA, Small Interfering RNA

• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Male
• Neoplastic Stem Cells/pathology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology

• Z99 HD999999 Intramural NIH HHS
• Z01 HD001501 Intramural NIH HHS
• ZIA HD001501 Intramural NIH HHS
• P30 GM103392 NIGMS NIH HHS
• U54 GM115516 NIGMS NIH HHS
• P20 GM121301 NIGMS NIH HHS

• Cancer
• Cancer stem cells
• Clinical outcome
• Drug resistance
• Targeted therapy

• EMT
• ESRP1
• RNA binding proteins
• alternative splicing
• hnRNPM

• Alternative Splicing
• Binding Sites
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/mortality
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition/genetics
• Exons
• Female
• Gene Expression Regulation
• Gene Expression Regulation, Neoplastic
• Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism
• Humans
• Nucleotide Motifs
• Prognosis
• Protein Binding
• RNA-Binding Proteins/metabolism
• Reproducibility of Results

• U01 HG009417 NHGRI NIH HHS
• R01 GM110146 NIGMS NIH HHS
• F30 CA196118 NCI NIH HHS
• R01 HG006264 NHGRI NIH HHS
• R01 CA182467 NCI NIH HHS
• US National Institutes of Health Ruth L. Kirschstein National Research Service Award
• US National Institutes of Health

• Cancer metastasis
• Cancer stem cells
• Collective cell migration
• Epithelial-mesenchymal transition
• Hybrid epithelial/mesenchymal
• Phenotypic plasticity

Prostate adenocarcinoma (PRAD) is one of the most common types of malignancy in males and at present, effective prognostic indicators are limited. The development of PRAD has been associated with abnormalities in alternative splicing (AS), a requisite biological process of gene expression in eukaryotic cells; however, the prognostic value of AS products and splicing events remains to be elucidated. In the present study, the data of splicing events and the clinical information of PRAD patients were obtained from The Cancer Genome Atlas (TCGA)SpliceSeq and TCGA databases, respectively. A prognostic index (PI) was generated from disease-free survival-associated splicing events (DFS-SEs), which were identified by univariate/multivariate Cox regression analysis. A total of 6,909 DFS-SEs were identified in PRAD. The corresponding genes for the DFS-SEs were significantly enriched in mitochondria and their associated pathways according to Gene Ontology annotation and in the pathways of fatty acid metabolism, oxidative phosphorylation and Huntington's disease according to a Kyoto Encyclopedia of Genes and Genomes pathway analysis. The PI for mutually exclusive exons had the greatest ability to predict the probability of five-year disease-free survival of patients with PRAD, with an area under the time-dependent receiver-operating characteristic curve of 0.7606. Patients with PRAD, when divided into a 'low' and a 'high' group based on their median PI for exon skip values, exhibited a marked difference in disease-free survival (low vs. high, 3,588.45±250.51 vs. 1,531.08±136.50 days; P=7.43×10⁻⁹). A correlation network between DFS-SEs of splicing factors and non-splicing factors was constructed to determine the potential mechanisms in PRAD, which included the potential regulatory interaction between the splicing event of splicing factor RNA binding motif protein 5-alternate terminator (AT)-64957 and the splicing event of non-splicing factor heterochromatin protein 1 binding protein 3-AT-939. In conclusion, the PIs derived from DFS-SEs are valuable prognostic factors for patients with PRAD, and the function of splicing events in PRAD deserves further exploration.

• Alternative splicing
• cancer
• cancer-specific isoforms
• metastasis
• metastasis-initiating potential
• transcriptional isoforms

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

• CD44
• Cancer
• Cancer therapy
• Epithelial to mesenchymal transition (EMT)
• Signaling transduction
• Tumorigenicity

Here, Huang et al. investigated the role of RNA secondary structure in splicing regulation and show that RNA elements with G-quadruplex-forming capacity promote exon inclusion. Analysis of RNA-binding protein footprints revealed that G quadruplexes are enriched in hnRNPF-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome, thus providing new insights into the regulation of alternative splicing.

It is generally thought that splicing factors regulate alternative splicing through binding to RNA consensus sequences. In addition to these linear motifs, RNA secondary structure is emerging as an important layer in splicing regulation. Here we demonstrate that RNA elements with G-quadruplex-forming capacity promote exon inclusion. Destroying G-quadruplex-forming capacity while keeping G tracts intact abrogates exon inclusion. Analysis of RNA-binding protein footprints revealed that G quadruplexes are enriched in heterogeneous nuclear ribonucleoprotein F (hnRNPF)-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome. Moreover, hnRNPF regulates an epithelial–mesenchymal transition (EMT)-associated CD44 isoform switch in a G-quadruplex-dependent manner, which results in inhibition of EMT. Mining breast cancer TCGA (The Cancer Genome Atlas) data sets, we demonstrate that hnRNPF negatively correlates with an EMT gene signature and positively correlates with patient survival. These data suggest a critical role for RNA G quadruplexes in regulating alternative splicing. Modulation of G-quadruplex structural integrity may control cellular processes important for tumor progression.

• EMT
• RNA G quadruplex
• alternative splicing
• hnRNPF
• splicing factor

Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.

• cancer stem cells
• cell-fate decisions
• epithelial-mesenchymal transition
• multistability
• partial EMT

• BREAST CANCER
• CD24
• CD44
• ESRP1
• GRHL2
• ZEB1
• ZEB2

• Biomarkers
• Cadherins/metabolism
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation
• Cell Transformation, Neoplastic/genetics
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Transcriptome
• Vimentin/metabolism