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Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing is evolving into an essential tool in the field of biological and medical research. Notably, the development of catalytically deactivated Cas9 (dCas9) enzyme has substantially broadened its traditional boundaries in gene editing or perturbation. The conjugation of dCas9 with various molecular effectors allows precise control over transcriptional processes, epigenetic modifications, visualization of chromosomal dynamics, and several other applications. This expanded repertoire of CRISPR-Cas9 applications has emerged as an invaluable molecular tool kit that empowers researchers to comprehensively interrogate and gain insights into health and diseases. This review delves into the advancements in Cas9 protein engineering, specifically on the generation of various dCas9 tools that have significantly enhanced the CRISPR-based technology capability and versatility. We subsequently discuss the multifaceted applications of dCas9, especially in interrogating the regulation and function of genes that involve in supporting cancer pathogenesis. In addition, we also delineate the designing and utilization of dCas9-based tools as well as highlighting its current constraints and transformative potentials in cancer research.
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Edición Génica , Neoplasias , Sistemas CRISPR-Cas/genética , Proteína 9 Asociada a CRISPR/genética , Epigénesis Genética , Neoplasias/genéticaAsunto(s)
Carcinoma de Células Renales , Colesterol , Subunidad alfa del Factor 1 Inducible por Hipoxia , Transducción de Señal , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Humanos , Colesterol/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genéticaRESUMEN
The leading indicator for successful outcomes in in-vitro fertilization (IVF) is the quality of gametes in oocytes and sperm. Thus, advanced research aims to highlight the parameter in assessing these qualities - DNA fragmentation in sperm and oocyte development capacity (ODC) via evaluation of microenvironments involving its maturation process. Regarding oocytes, most evidence reveals the role of cumulus cells as non-invasive methods in assessing their development competency, mainly via gene expression evaluation. Our review aims to consolidate the evidence of GDF-9 derivatives, the HAS2, GREM1, and PTGS2 gene expression in cumulus cells used as ODC markers in relevant publications and tailored to current IVF outcomes. In addition to that, we also added the bioinformatic analysis in our review to strengthen the evidence aiming for a better understanding of the pathways and cluster of the genes of interest - HAS2, GREM1, and PTGS2 in cumulus cell level. Otherwise, the current non-invasive method can be used in exploring various causes of infertility that may affect these gene expressions at the cumulus cell level. Nevertheless, this method can also be used in assessing the ODC in various cohorts of women or as an improvement of markers following targeted tools or procedures by evaluating the advancement of these gene expressions following the targeted intervention.
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Células del Cúmulo , Semen , Humanos , Masculino , Femenino , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Células del Cúmulo/metabolismo , Oocitos/metabolismo , Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Hialuronano Sintasas/metabolismoRESUMEN
Colorectal cancer (CRC) is ranked as the second leading cause of mortality worldwide, mainly due to metastasis. Epithelial to mesenchymal transition (EMT) is a complex cellular process that drives CRC metastasis, regulated by changes in EMT-associated gene expression. However, while numerous genes have been identified as EMT regulators through various in vivo and in vitro studies, little is known about the genes that are differentially expressed in CRC tumour tissue and their signalling pathway in regulating EMT. Using an integration of systematic search and bioinformatic analysis, gene expression profiles of CRC tumour tissues were compared to non-tumour adjacent tissues to identify differentially expressed genes (DEGs), followed by performing systematic review on common identified DEGs. Fifty-eight common DEGs were identified from the analysis of 82 tumour tissue samples obtained from four gene expression datasets (NCBI GEO). These DEGS were then systematically searched for their roles in modulating EMT in CRC based on previously published studies. Following this, 10 common DEGs (CXCL1, CXCL8, MMP1, MMP3, MMP7, TACSTD2, VIP, HPGD, ABCG2, CLCA4) were included in this study and subsequently subjected to further bioinformatic analysis. Their roles and functions in modulating EMT in CRC were discussed in this review. This study enhances our understanding of the molecular mechanisms underlying EMT and uncovers potential candidate genes and pathways that could be targeted in CRC.
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Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Humanos , Transición Epitelial-Mesenquimal/genética , Neoplasias Colorrectales/patología , Transducción de Señal/genética , Expresión Génica , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
Pre-eclampsia, which is part of the spectrum of hypertensive pregnancy disorders, poses a significant health burden, contributing to maternal and infant morbidity and mortality. Pre-eclampsia is widely associated with persistent adverse effects on the cardiovascular health of women with a history of pre-eclampsia. Additionally, there is increasing evidence demonstrating that offspring of pre-eclamptic pregnancies have altered cardiac structure and function, as well as different vascular physiology due to the decrease in endothelial function. Therefore, early detection of the likelihood of developing pre-eclampsia-associated cardiovascular diseases is vital, as this could facilitate the undertaking of the necessary clinical measures to avoid disease progression. The utilisation of microRNAs as biomarkers is currently on the rise as microRNAs have been found to play important roles in regulating various physiological and pathophysiological processes. In regard to pre-eclampsia, recent studies have shown that the expression of microRNAs is altered in postpartum women and their offspring who have been exposed to pre-eclampsia, and that these alterations may persist for several years. This review, therefore, addresses changes in microRNA expression found in postpartum women and offspring exposed to pre-eclampsia, their involvement in cardiovascular disease, and the potential role of microRNAs to be used as predictive tools and therapeutic targets in future cardiovascular disease research.
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Enfermedades Cardiovasculares , Hipertensión , MicroARNs , Preeclampsia , Embarazo , Humanos , Femenino , Enfermedades Cardiovasculares/genética , MicroARNs/genética , Factores de Riesgo , Periodo Posparto , Factores de Riesgo de Enfermedad CardiacaRESUMEN
The homeobox A10 (HOXA10) gene is known to be related to endometriosis; however, due to a lack of knowledge/evidence in the pathogenesis of endometriosis, the mechanisms that link HOXA10 to endometriosis still need to be clarified. This review addresses the difference in the expression of the HOXA10 gene in endometriotic women versus non-endometriotic women across populations by country and discusses its influences on women's fertility. An organized search of electronic databases was conducted in Scopus, ScienceDirect, PubMed, and Web of Science. The keywords used were (HOXA10 OR "homeobox A10" OR PL OR HOX1 OR HOX1H OR HOX1.8) AND ("gene expression") AND (endometriosis). The initial search resulted in 623 articles, 10 of which were included in this review. All ten papers included in this study were rated fair in terms of the quality of the studies conducted. The expression of the HOXA10 gene was found to be downregulated in most studies. However, one study provided evidence of the downregulation and upregulation of HOXA10 gene expression due to the localization of endometriotic lesions. Measuring the expression of the HOXA10 gene in women is clinically essential to predicting endometriosis, endometrial receptivity, and the development of pinopodes in the endometrium during the luteal phase.
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Bencenoacetamidas , Endometriosis , Humanos , Femenino , Genes Homeobox , Endometriosis/genética , Bases de Datos Factuales , Proteínas Homeobox A10RESUMEN
In vitro oocyte maturation (IVM) has been used worldwide. Despite the long-term implementation, the uptake of this procedure to complement current in vitro fertilization (IVF) remains low. The main reason is likely due to the non-synchronization of protocol and definition criteria, leading to difficulty in collective proper outcome data worldwide and, thus, lack of understanding of the exact IVM procedure. The review aims to consolidate the current clinical practice of IVM by dissecting relevant publications to be tailored for a current spectrum of clinical practice. Nevertheless, the background theories of oocyte maturation were also explored to provide a comprehensive understanding of the basis of IVM theories. Additional discussion of other potential uses of IVM in the future, such as in ovarian tissue cryopreservation known as OTO-IVM for fertility preservation and among women with diminished ovarian reserve, was also explored. Otherwise, future collaboration among all IVM centers is paramount for better collection of clinical data to provide valid recommendations for IVM in clinical practice, especially in molecular integrity and possible DNA alteration if present for IVM offspring outcome safety purposes.
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Preservación de la Fertilidad , Enfermedades del Ovario , Humanos , Femenino , Fertilización In Vitro/métodos , Técnicas de Maduración In Vitro de los Oocitos/métodos , Preservación de la Fertilidad/métodos , Criopreservación/métodosRESUMEN
Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy.
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Stem cells such as induced pluripotent stem cells, embryonic stem cells, and hematopoietic stem and progenitor cells are growing in importance in disease modeling and regenerative medicine. The applications of CRISPR-based gene editing to create a mélange of disease and nondisease stem cell lines have further enhanced the utility of this innately versatile group of cells in the studies of human genetic disorders. Precise base edits can be achieved using a variety of CRISPR-centric approaches, particularly homology-directed repair and the recently developed base editors and prime editors. Despite its much-touted potential, editing single DNA bases is technically challenging. In this review, we discuss the strategies for achieving exact base edits in the creation of various stem cell-based models for use in elucidating disease mechanisms and assessing drug efficacy, and the unique characteristics of stem cells that warrant special considerations.
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Edición Génica , Células Madre Pluripotentes Inducidas , Humanos , Sistemas CRISPR-Cas/genética , Células Madre Pluripotentes Inducidas/metabolismo , Línea Celular , Células Madre Embrionarias/metabolismoRESUMEN
Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease's metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facilitating immunosurveillance evasion. Additionally, the secretome has been shown to play a crucial role in drug resistance development, making it an attractive target for cancer therapy. Understanding the intricate role of the cancer cell secretome in breast cancer progression will provide new insights into the underlying mechanisms of this disease and aid in the development of more innovative therapeutic interventions. Hence, this review provides a nuanced analysis of the impact of the cancer cell secretome on breast cancer progression, elucidates the complex reciprocal interaction with the components of the tumor microenvironment and highlights emerging therapeutic opportunities for targeting the constituents of the secretome.
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Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGFB-overexpressing ccRCC cells was able to re-activate mTORC1 activity in KLF6-targeted cells. In conclusion, cancer cell-derived PDGFB can mediate mTORC1 signalling pathway activation in ccRCC, further consolidating the link between the KLF6-PDGFB axis and the mTORC1 signalling pathway activity in ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Proteínas Proto-Oncogénicas c-sis/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Línea Celular Tumoral , Becaplermina/metabolismo , Neoplasias Renales/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
Endometriosis is an inflammatory chronic systemic disease resulting in pelvic pain and infertility. However, despite a high prevalence of endometriosis, disease identification is still insufficient, and a high percentage of misdiagnosing was observed. Hence, a comprehensive study needs to be done to improve our understanding of the pathogenesis of endometriosis. Aberrant hypermethylation of HOXA10 has been reported to play a role in endometriosis. Thus, a comprehensive literature search was conducted to identify the DNA methylation level of HOXA10 among endometriosis patients across populations. The literature search was done using PubMed, Scopus, EBSCOhost, and Science Direct applying (HOXA10 OR "homeobox A10" OR "HOXA-10" OR HOX1) AND ("DNA methylation" OR methylation) AND (endometriosis OR endometrioma) as keywords. From 491 retrieved studies, five original articles investigating the DNA methylation level of HOXA10 from endometrium tissues among endometriosis women were included. All five included studies were classified as high-quality studies. High HOXA10 DNA methylation level was observed in the endometrium tissue of women with endometriosis in all the included studies. The secretory phase was identified as the best sampling time for HOXA10 DNA methylation study in endometriosis, and the most studied DNA methylation site is the promoter region of the HOXA10. However, more studies are needed to expose the HOXA10 mechanism in the pathogenesis of endometriosis.
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Pathogenic infections have significant roles in the pathogenesis of colorectal cancer (CRC). These infections induce the secretion of various damage-associated molecular patterns (DAMPs) including interleukin-1 alpha (IL-1α) and high mobility group box-1 (HMGB1). Despite their implication in CRC pathogenesis, the mechanism(s) that modulate the secretion of IL-1α and HMGB1, along with their roles in promoting CRC tumourigenesis remain poorly understood. To understand the secretory mechanism, HT-29 and SW480 cells were stimulated with infectious mimetics; polyinosinic:polycytidylic acid [Poly(I:C)], lipopolysaccharide (LPS) and pro-inflammatory stimuli; tumour necrosis factor-alpha (TNF-α). IL-1α and HMGB1 secretion levels upon stimulation were determined via ELISA. Mechanism(s) mediating IL-1α and HMGB1 secretion in CRC cells were characterized using pharmacological inhibitors and CRISPR-Cas9 gene editing targeting relevant pathways. Recombinant IL-1α and HMGB1 were utilized to determine their impact in modulating pro-tumourigenic properties of CRC cells. Pharmacological inhibition showed that Poly(I:C)-induced IL-1α secretion was mediated through endoplasmic reticulum (ER) stress and RIPK1 signalling pathway. The secretion of HMGB1 was RIPK1-dependent but independent of ER stress. RIPK1-targeted CRC cell pools exhibited decreased cell viability upon Poly(I:C) stimulation, suggesting a potential role of RIPK1 in CRC cells survival. IL-1α has both growth-promoting capabilities and stimulates the production of pro-metastatic mediators, while HMGB1 only exhibits the latter; with its redox status having influence. We demonstrated a potential role of RIPK1-dependent signalling pathway in mediating the secretion of IL-1α and HMGB1 in CRC cells, which in turn enhances CRC tumorigenesis. RIPK1, IL-1α and HMGB1 may serve as potential therapeutic targets to mitigate CRC progression.
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The endoplasmic reticulum (ER) is a multi-layered organelle that is essential for the synthesis, folding, and structural maturation of almost one-third of the cellular proteome. It houses several resident proteins for these functions including the 21 members of the protein disulfide isomerase (PDI) family. The signature of proteins belonging to this family is the presence of the thioredoxin domain which mediates the formation, and rearrangement of disulfide bonds of substrate proteins in the ER. This process is crucial not only for the proper folding of ER substrates but also for maintaining a balanced ER proteostasis. The inclusion of new PDI members with a wide variety of structural determinants, size and enzymatic activity has brought additional epitomes of how PDI functions. Notably, some of them do not carry the thioredoxin domain and others have roles outside the ER. This also reflects that PDIs may have specialized functions and their functions are not limited within the ER. Large-scale expression datasets of human clinical samples have identified that the expression of PDI members is elevated in pathophysiological states like cancer. Subsequent functional interrogations using structural, molecular, cellular, and animal models suggest that some PDI members support the survival, progression, and metastasis of several cancer types. Herein, we review recent research advances on PDIs, vis-à-vis their expression, functions, and molecular mechanisms in supporting cancer growth with special emphasis on the anterior gradient (AGR) subfamily. Last, we posit the relevance and therapeutic strategies in targeting the PDIs in cancer.
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Breast cancer is the leading cause of cancer-related deaths in women. The aggressive breast cancer subtype is commonly linked to the genetic alterations in the TP53 tumor suppressor gene, predominantly the missense mutations. Robust experimental models are needed to gain better insights into these mutations' molecular properties and implications in tumorigenesis. The generation of such models harboring the alterations is feasible with the CRISPR-based gene editing technology. Moreover, the development of new CRISPR applications, particularly DNA base and prime editing, has considerably improved the precision and versatility of gene editing. Here, we employed the prime editing tool to revert a TP53 missense C > T mutation (L194F) in a T47D luminal A breast cancer cell line. In parallel, this prime editing tool was also utilized to introduce the L194F mutation in HEK293T cells. To assess the prime editing efficiency in both cell lines, we first performed Sanger sequencing in the prime-edited cells pool and single cell-derived clones. However, the Sanger sequencing approach did not detect any base substitution in these cell lines. Next, by employing the more sensitive amplicon target sequencing, we managed to identify the expected substitution in these T47D and HEK293T cells, albeit the editing efficiency was low. In light of these findings, we discussed the technical aspects and provided suggestions for improve the prime editing workflow and efficiency for future experiments.
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Neoplasias de la Mama , Sistemas CRISPR-Cas , Neoplasias de la Mama/genética , Sistemas CRISPR-Cas/genética , Femenino , Células HEK293 , Humanos , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Flujo de TrabajoRESUMEN
A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encoded protein (SEP) which comprises ≤ 100 amino acids. Traditionally dismissed by genome annotation pipelines as meaningless noise, sORFs were found to possess coding potential with ribosome profiling (RIBO-Seq), which unveiled sORF-based transcripts at various genome locations. Nonetheless, the existence of corresponding microproteins that are stable and functional was little substantiated by experimental evidence initially. With recent advancements in multi-omics, the identification, validation, and functional characterisation of sORFs and microproteins have become feasible. In this review, we discuss the history and development of an emerging research field of sORFs and microproteins. In particular, we focus on an array of bioinformatics and OMICS approaches used for predicting, sequencing, validating, and characterizing these recently discovered entities. These strategies include RIBO-Seq which detects sORF transcripts via ribosome footprints, and mass spectrometry (MS)-based proteomics for sequencing the resultant microproteins. Subsequently, our discussion extends to the functional characterisation of microproteins by incorporating CRISPR/Cas9 screen and protein-protein interaction (PPI) studies. Our review discusses not only detection methodologies, but we also highlight on the challenges and potential solutions in identifying and validating sORFs and their microproteins. The novelty of this review lies within its validation for the functional role of microproteins, which could contribute towards the future landscape of microproteomics.
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Sistemas de Lectura Abierta , Proteínas , Proteómica , Biología Computacional , Sistemas de Lectura Abierta/genética , Proteínas/genética , Proteómica/métodosRESUMEN
The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.
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The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/ß-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.
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CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
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Empalme Alternativo , Receptores de Hialuranos/genética , Neoplasias/patología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/metabolismo , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10,000 people globally. The cell surface proteins or surfaceome serve as information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation in surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in a cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have 'direct' access to drugs, they are appealing targets for cancer therapy. However, a comprehensive GBM surfaceome landscape has not been fully defined yet. Thus, this study aimed to define GBM-associated surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. METHODS: We integrated the RNA-Seq data from TCGA GBM (n = 166) and GTEx normal brain cortex (n = 408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by an integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-confidence GBM surfaceome signature. RESULTS: Of the 2381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes was validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. CONCLUSIONS: In summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.