ABSTRACT
Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/ß-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.
Subject(s)
RNA, Long Noncoding , Signal Transduction , Stomach Neoplasms , Humans , RNA, Long Noncoding/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Signal Transduction/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression Regulation, NeoplasticABSTRACT
Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs) and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. Curcumin, baicalein, oleanolic acid, shikonin, oxymatrine, arctigenin, liensinine, fangchinoline, and dioscin are a few examples of natural compounds that have demonstrated promising anticancer activities against GBC through the regulation of important signaling pathways. The lncRNAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC, are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR activate oncogenes such as DNMT1, Wnt/ß-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor proteins NF-κB, EZH2, and miR-421. Clinically, specific lncRNAs can serve as diagnostic or prognostic biomarkers based on overexpression correlating with advanced TNM stage, metastasis, chemoresistance, and poor survival. Therapeutically, targeting aberrant lncRNAs with siRNA or antisense oligos disrupts their oncogenic signaling and inhibits GBC progression. Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.
ABSTRACT
The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51-14.57), P = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets' expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren't altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis.
Subject(s)
Colorectal Neoplasms , Genetic Predisposition to Disease , Insulin-Like Growth Factor Binding Protein 3 , MicroRNAs , Obesity , Polymorphism, Single Nucleotide , RNA, Long Noncoding , Sirtuin 1 , Humans , RNA, Long Noncoding/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Male , MicroRNAs/genetics , Obesity/complications , Obesity/genetics , Middle Aged , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 3/blood , Sirtuin 1/genetics , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Gene Expression Regulation, Neoplastic , Aged , Case-Control Studies , Risk FactorsABSTRACT
Gallbladder cancer (GBC) is one of the most aggressive types of biliary tree cancers and the commonest despite its rarity. It is infrequently diagnosed at an early stage, further contributing to its poor prognosis and low survival rate. The lethal nature of the disease has underlined a crucial need to discern the underlying mechanisms of GBC carcinogenesis which are still largely unknown. However, with the continual evolution in the research of cancer biology and molecular genetics, studies have found that non-coding RNAs (ncRNAs) play an active role in the molecular pathophysiology of GBC development. Dysregulated long non-coding RNAs (lncRNAs) and their interaction with intracellular signaling pathways contribute to malignancy and disease development. LncRNAs, a subclass of ncRNAs with over 200 nucleotides, regulate gene expression at transcriptional, translational, and post-translational levels and especially as epigenetic modulators. Thus, their expression abnormalities have been linked to malignancy and therapeutic resistance. lnsRNAs have also been found in GBC patients' serum and tumor tissue biopsies, highlighting their potential as novel biomarkers and for targeted therapy. This review will examine the growing involvement of lncRNAs in GBC pathophysiology, including related signaling pathways and their wider clinical use.
Subject(s)
Gallbladder Neoplasms , RNA, Long Noncoding , Humans , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/diagnosis , Gallbladder Neoplasms/pathology , RNA, Long Noncoding/genetics , Biomarkers, Tumor/genetics , Signal Transduction/genetics , RNA, UntranslatedABSTRACT
Colorectal cancer (CRC) is one of the most frequent cancers in incidence and mortality. Despite advances in cancer biology, molecular genetics, and targeted treatments, CRC prognosis and survival have not kept pace. This is usually due to advanced staging and metastases at diagnosis. Thus, great importance has been placed upon understanding the molecular pathophysiology behind the development of CRC, which has highlighted the significance of non-coding RNA's role and associated intracellular signaling pathways in the pathogenesis of the disease. According to recent studies, long non-coding RNAs (lncRNA), a subtype of ncRNAs whose length exceeds 200 nucleotides, have been found to have regulatory functions on multiple levels. Their actions at the transcription, post-transcriptional, translational levels, and epigenetic regulation have made them prime modulators of gene expression. Due to their role in cellular cancer hallmarks, their dysregulation has been linked to several illnesses, including cancer. Furthermore, their clinical relevance has expanded due to their possible detection in blood which has cemented them as potential future biomarkers and thus, potential targets for new therapy. This review will highlight the importance of lncRNAs and related signaling pathways in the development of CRC and their subsequent clinical applications.
Subject(s)
Colorectal Neoplasms , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Epigenesis, Genetic , Colorectal Neoplasms/therapy , Colorectal Neoplasms/drug therapy , RNA, Untranslated/genetics , Signal Transduction/genetics , Gene Expression Regulation, Neoplastic/geneticsABSTRACT
The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.
Subject(s)
Adenocarcinoma/secondary , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adult , Aged , Biomarkers, Tumor/genetics , Case-Control Studies , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Genotype , Humans , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Transcriptome , Tumor Cells, Cultured , Young AdultABSTRACT
BACKGROUND: This study aimed to evaluate the relationship of serum vitronectin and integrin alpha V beta 3 (αvß3) levels with various clinicopathological parameters of breast cancer and to assess the diagnostic value of these markers alone or in combination with the conventional breast cancer biomarker CA15.3. METHODS: This study included 50 early diagnosed stage I - II primary breast cancer patients, 20 patients with fibroadenoma benign lesions, and 20 apparently normal healthy controls. Integrin αVß3, vitronectin, and CA15.3 levels were measured using ELISA technique. RESULTS: Serum levels of integrin αVß3 and vitronectin were significantly higher in the malignant group than those in the benign group and the control group with (p < 0.001). Significant positive correlation between integrin αvß3 and vitronectin concentrations was found. Both markers showed significant statistically difference with lymph node, histological grade, tumor stage, and tumor size (p < 0.05). Integrin αvß3 exhibited the highest sensitivity (70%) and specificity (68%), then vitronectin with 67% and 68%, respectively, followed by CA15.3 showing the least sensitivity and specificity (65% and 62%, respectively). All assessed parameters revealed comparable area under the receiver-operating characteristic curve (AUC) 95% confidence interval (CI) range of 0.581 - 0.822. CONCLUSIONS: Integrin αvß3 is a promising biomarker alone or in combination with vitronectin and CA15.3 for diagnosis and prognosis of early stage breast cancer.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/diagnosis , Early Detection of Cancer , Integrin alphaVbeta3/blood , Vitronectin/blood , Adult , Breast Neoplasms/blood , Female , Humans , Middle Aged , Mucin-1/blood , Prognosis , ROC CurveABSTRACT
Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation.