Asthma is a highly heterogeneous chronic inflammatory airway disease whose pathophysiology is determined by a combination of genetic, environmental, and immune factors. As the largest interface between the host and the environment, airway epithelial cells serve not only as a physical barrier against exogenous stimuli but also as central cells in sensing environmental threats and initiating immune responses. Among their functions, the release of epithelial-derived alarmins is a key step in initiating type 2 inflammation. Under the long-term interaction of genetic susceptibility and environmental factors, persistent structural and functional alterations occur in the airway epithelium of asthma patients. These include disruption of the barrier integrity, skewed cell differentiation, aberrant repair programs, and dysregulated alarmin release. These alterations not only exacerbate airway inflammation but can also directly drive the process of airway remodeling through mechanisms such as epithelial-mesenchymal transition, ciliary dysfunction, mucus hypersecretion, and paracrine regulation of smooth muscle. Remodeling also involves biochemical and mechanical alterations, including dysregulated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), increased extracellular matrix (ECM) stiffness, and enhanced collagen crosslinking. Given the central role of the airway epithelium in asthma pathogenesis, targeting its alarmins and related signaling pathways holds promise for providing precise intervention strategies for patients with specific endotypes. This article systematically reviews the structural and functional changes in the asthmatic airway epithelium, analyzes the intrinsic links between barrier dysfunction, alarmin release, and airway pathological changes, and summarizes recent advances in interventions targeting the airway epithelium, aiming to provide a new theoretical basis for the precise diagnosis and treatment of asthma.
m5C modification plays a vital role in the progression of human cancers, including breast cancer (BC), but the function of NOP2/Sun RNA methyltransferase 2 (NSUN2), an RNA m5C modification enzyme, remains largely unclear. qRT-PCR, western blot and IHC assays were carried out to determine the expression of NSUN2, poly (ADP-ribose) polymerase 1 (PARP9) and Y box binding protein 1 (YBX1). EdU, flow cytometry, transwell, tube formation and sphere formation assays were conducted to evaluate cell proliferation, apoptosis, invasion, angiogenesis and stemness, respectively. ELISA was performed to examine the concentrations of inflammatory factors. RIP and pull-down assays were used to verify the interaction between NSUN2/YBX1 and PARP9. Murine xenograft model was constructed to explore the functions of NSUN2 and PARP9 in tumor growth in vivo. PARP9 silencing suppressed the proliferation, invasion, angiogenesis, stemness and immune escape, and promoted apoptosis in BC cells in vitro. Mechanically, NSUN2 functioned as an m5C writer that catalyzed m5C modification of PARP9 mRNA, while YBX1 acted as an m5C reader that recognized the modified transcript and enhanced its stability, thereby elevating PARP9 expression in BC cells. YBX1 could elevate PARP9 expression in BC cells. Moreover, NSUN2 knockdown restrained the malignant behaviors of BC cells, with PARP9 overexpression restored the effects. In addition, NSUN2 knockdown blocked tumorigenesis in vivo by regulating PARP9 expression. NSUN2-mediated m5C modification stabilizes PARP9 mRNA and is associated with enhanced BC progression and immune escape. The results broadened our understanding of the pathogenic mechanism of BC.
Carcinogenic factors facilitate cell carcinogenesis and the progression of cancer. In contrast, tumor suppressor factors inhibit abnormal cell proliferation and cancer development. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can either suppress or promote cancer initiation and progression. LINC01140, a recently identified lncRNA, exhibits abnormal expression in cancerous tissues. Downstream target genes can be regulated, directly or indirectly, via miRNAs (miR-452-5p, miR-139-5p, miR-140-5p, miR-33a, miR-4742-5p, miR-200b-3p, and miR-452-5p), functioning as either oncogenes or tumor suppressors and contributing to cancer progression. Dysregulated LINC01140 expression shows significant correlations with patient survival, diagnosis, and cancer stage. Consequently, this review aims to examine the expression patterns, functional roles, and clinical significance of LINC01140 across pan-cancer, highlighting it as a potential therapeutic target for cancer treatment.
Ferroptosis, a unique modality of cell death, possesses critical activity in tumorigenesis. This study defined the role of transcription factor (TF) forkhead box A1 (FOXA1) in modulating ferroptosis of cervical cancer (CC), a prevalent disease with high mortality rates in females. mRNA analysis was done by quantitative real-time PCR (qRT-PCR), and protein expression was analyzed by immunoblotting and immunohistochemistry (IHC). Colony formation and EdU proliferation assays were used to evaluate cell growth. Apoptosis was detected by flow cytometry. The contents of SOD, MDA, GSH, ROS and Fe2+ were measured by assay kits. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase assays were applied to analyzed the binding of FOXA1 to the SLC7A11 promoter. FOXA1 was an overexpressed factor in CC, which was related to prognosis of human CC. FOXA1 downregulation impaired CC cell in vitro proliferation, promoted apoptosis, and induced ferroptosis. FOXA1 was validated to bind to the promoter of SLC7A11 and enhance SLC7A11 transcription. Furthermore, the FOXA1/SLC7A11 cascade affected proliferation, apoptosis and ferroptosis of CC cells. In addition, FOXA1 downregulation impeded the in vivo tumorigenesis of C33A CC cells. Our study has identified FOXA1 as a crucial repressor of CC cell ferroptosis depending on its activation of SLC7A11 transcription. Developing inhibitors of FOXA1 is a promising way of harnessing ferroptosis for CC treatment.
Cutaneous squamous cell carcinoma (cSCC) is a prevalent type of skin cancer, and its development is strongly associated with impaired regulation of apoptosis. The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the tumor suppressor p53 play pivotal roles in controlling apoptotic signaling. Although Bcl-2 expression in cSCC has been reported to be heterogeneous, its role in mitochondria-associated membranes (MAMs)-mediated apoptosis remains unclear. This study aims to clarify how Bcl-2 and p53 regulate cSCC cell apoptosis by modulating the structure and function of MAMs. We constructed stable Bcl-2 overexpression (oe-Bcl-2) and Bcl-2/p53 co-overexpression (oe-Bcl-2 + oe-p53) A431 cell lines using lentiviral transduction. Transcriptome sequencing (RNA-seq) was performed, followed by pathway enrichment and protein–protein interaction (PPI) network analyses to screen for critical signaling routes. Cell apoptosis, growth, migratory capacity, and invasive potential were evaluated using flow cytometry, CCK-8, EdU incorporation, colony formation, and Transwell-based assays. Key MAMs functions, including Ca2+ flux, mitochondrial membrane potential (MMP), ROS, and ATP levels, were measured. Subcutaneous tumor models in nude mice were used for in vivo validation. RNA-seq analysis revealed that Bcl-2 regulates multiple apoptosis- and calcium signaling-related pathways, significantly affecting key MAM-associated proteins, including VDAC2, IP3R, SERCA2, as well as the p53 signaling pathway. Bcl-2 overexpression markedly enhanced proliferation and migration of A431 cells while reducing apoptosis. It also modulated mitochondrial membrane potential, ATP production, and ROS generation, suggesting that Bcl-2 exerts anti-apoptotic effects through MAMs. In contrast, Bcl-2 knockdown significantly suppressed proliferation and invasion while inducing apoptosis in A431 cells, further supporting its oncogenic role. Notably, p53 overexpression reversed these effects and significantly inhibited tumor growth in vivo. Our findings demonstrate that Bcl-2 promotes cSCC progression by modulating MAMs structure and function to inhibit p53-mediated mitochondrial apoptosis. The study identifies the novel Bcl-2-MAMs-p53 signaling axis that plays a pivotal role in determining cSCC cell fate, highlighting a promising target for therapeutic intervention.
Hepatocellular carcinoma (HCC) is a highly aggressive disease associated with a poor prognosis. The present study attempts to discover the potential of esculentoside A (EsA) in inhibiting HCC progression. Cell viability was assessed using the Cell Counting Kit-8 assays. At the same time, stemness and malignant behaviors were evaluated through sphere formation, Western blot (WB), flow cytometry, colony formation assays, and TUNEL. EsA treatment suppressed HCC cell proliferation, migration, invasion, and stemness in vitro and tumor growth in vivo. Bioinformatics identified retinoic acid receptor-related orphan receptor beta (RORB) as a potential target of EsA, and EsA induced RORB expression in HCC cells. EsA also inhibited Wnt signaling activity, as shown by TOP/FOP Flash assays and WB. Knockdown of RORB through lentivirus infection reversed the effects of EsA. At the same time, Wnt pathway inhibitor rescued the promotive role of RORB knockdown in HCC malignant behaviors, suggesting that EsA inhibited HCC progression via the RORB/Wnt axis. RORB expression was reduced and associated with higher Wnt signaling in tumor tissues from patients with HCC, and low RORB expression showed significant correlation with higher TNM staging in HCC patients. This study offers novel insights into the molecular mechanism of EsA in HCC.
Gastric cancer (GC) is a major global health challenge. This study explores the efficacy of linalool in GC and further elucidates its underlying mechanisms. Linalool inhibited the proliferation, migration, and invasion of GC cells and prevented transplanted tumor growth in nude mice. Linalool directly interacted with and stabilized the NR3C2 protein, inhibiting its proteasomal degradation. Functional rescue experiments demonstrated that knockdown of NR3C2 partially reversed the antitumor effects of linalool. Further studies revealed that NR3C2 transcriptionally activated NFKBIZ and inhibited NF-κB signaling, and restoring NFKBIZ expression reversed GC progression caused by NR3C2 deficiency. In clinical samples, the expression levels of NR3C2 and NFKBIZ were lower in GC tissues than in adjacent normal tissues, and the two markers were positively correlated in the tumor tissues. Furthermore, low expression of both NR3C2 and NFKBIZ was significantly associated with higher T stages and more advanced pTNM stages and was accompanied by NF-κB signaling activation and elevated levels of inflammatory cytokines in tumor tissues. Overall, linalool inhibits GC progression by upregulating NR3C2 and transcriptionally activating NFKBIZ, thereby suppressing NF-κB signaling. Low NR3C2/NFKBIZ expression is associated with adverse clinical and pathological features in GC.
Lung adenocarcinoma (LUAD) is a highly heterogeneous malignancy with poor clinical outcomes, underscoring the urgent need for robust prognostic biomarkers and therapeutically tractable regulatory molecules. Long non-coding RNAs (lncRNAs) have emerged as key modulators of tumor progression and immune regulation; however, the prognostic and functional significance of TMPO-AS1 in LUAD remains largely unexplored. Firstly, the top upregulated lncRNAs in LUAD were identified using the lnc2cancer3.0 database, and their prognostic significance was evaluated with the Kaplan–Meier Plotter. Differential expression of the selected lncRNA candidate was validated using TCGA-based platforms, including UALCAN, ENCORI and R-based statistical packages. TMPO-AS1–associated miRNAs were then predicted using the miRNet database, and their expression correlations, prognostic relevance, and differential expressions were assessed using the ENCORI, KM Plotter databases and R-based packages, respectively. A miRNA-centered heterogeneous gene model was constructed using the CancerMIRNome database, and gene–miRNA correlations were validated via ENCORI, followed by their survival analysis using the KM Plotter. Finally, immune cell infiltration associated with the identified genes was analyzed using the GSCA dataset. TMPO-AS1 was found to be significantly overexpressed in LUAD patients (HR = 2.16). The correlation analysis revealed hsa-let-7b-5p was significantly and negatively correlated with TMPO-AS1, and its overexpression was also linked with better prognosis. Survival analysis selectively highlighted TGFBR3, RNF144B, CD59, and MAT2B as the most significant positively associated genes, while AURKA and KIFC1 emerged as the most significant negatively associated genes. Immune infiltration analysis demonstrated that the miRNA-positively associated genes were negatively correlated with nTreg cells and positively correlated with NKT cells, whereas the miRNA-negatively associated genes showed an inverse correlation pattern. The study concludes that TMPO-AS1 is overexpressed in cases of LUAD, highlighting its potential as a molecular classifier for LUAD and a prognostic biomarker associated with poor clinical outcomes.
Circular RNA (circRNA) is a unique type of non-coding RNA molecule characterized by a closed circular structure, exceptional stability, and the ability to act as miRNA sponges, thereby relieving their inhibitory effects on downstream target genes, thus regulating cancer cell growth and metastasis. Circ_0000285 is one of the recently discovered circRNAs. It is aberrantly expressed in hepatocellular carcinoma, gastric cancer, bladder cancer, nasopharyngeal carcinoma, osteosarcoma, thyroid cancer, glioma, cervical cancer, and neuroblastoma, predominantly exhibiting upregulation. Abnormal expression of circ_0000285 is significantly associated with cancer cell growth, metastasis, and poor prognosis in cancer patients, a process mediated by circ_0000285 acting as sponges for miR-582-3p, miR-1278, miR-409-3p, miR-599, miR-127-5p, miR‑654-3p, and miR197-3p to promote the expression of downstream target genes or directly regulate target gene expression. Therefore, this review aims to summarize the expression, function, mechanisms, and association with poor prognostic features in cancer patients of circ_0000285, offering novel candidate target molecules for the treatment of cancer.
Colorectal cancer (CRC) is the third most common malignant tumor worldwide and is characterized by high incidence and mortality rates. In the chemotherapeutic treatment of CRC, antiangiogenic therapy is utilized throughout the entire disease course, particularly for highly metastatic tumors. However, studies have reported that resistance to current antiangiogenic therapies often develops, leading to suboptimal clinical outcomes. Vasculogenic mimicry (VM) represents a novel tumor blood supply mechanism that is distinct from traditional endothelial cell-dependent vasculature. VM channels are composed solely of tumor cells and extracellular basement membranes, emerge within malignant tumors requiring blood perfusion, and have been identified in numerous solid tumors. Research indicates that tumors exhibiting VM demonstrate greater proliferative, invasive, and metastatic potential, along with poorer prognosis, than those without VM. Additionally, studies suggest that VM contributes to the limited efficacy and resistance observed with antiangiogenic drugs in clinical practice. Thus, targeting VM is crucial in oncology, especially in CRC. Recent advances have been made in anti-VM drug therapy for CRC. Moving forward, combining VM-targeted strategies with conventional antiangiogenic therapies targeting endothelial cells may represent a promising new direction in CRC treatment. This review summarizes current insights into the mechanisms of VM in CRC and its therapeutic advancements, aiming to provide novel perspectives for clinical management.
BACKGROUND:MicroRNA-124-3p (miR-124-3p) has been widely reported as an important tumor-suppressive regulator in multiple malignancies. Nevertheless, its precise biological function in stomach adenocarcinoma (STAD) remains insufficiently clarified. METHODS:We applied large-scale bioinformatics interrogation of The Cancer Genome Atlas (TCGA) STAD cohort, combined with in vitro cellular assays and in vivo xenograft experiments, to explore both the biological significance and molecular mechanisms of miR-124-3p in STAD progression. RESULTS:MiR-124-3p expression was significantly downregulated in STAD tissues and correlated with advanced pathological stage, poor prognosis, and reduced survival outcomes. Functional investigations confirmed that miR-124-3p directly interacts with the 3'-UTR of the aryl hydrocarbon receptor (AHR) mRNA, suppressing its expression and inducing autophagy. This regulation led to impaired proliferation, migration, and invasiveness of STAD cells. Restoration of AHR expression reversed these tumor-suppressive effects. Moreover, in vivo delivery of miR-124-3p inhibited tumor growth and mitigated cancer-induced cachexia in nude mice. CONCLUSION:These findings establish miR-124-3p as a key suppressor of STAD progression via AHR-mediated autophagy, underscoring its promise as both a diagnostic biomarker and a therapeutic candidate.
BACKGROUND:Long noncoding RNAs (lncRNAs) are key regulators in cancer progression. Among them, KCNMB2 antisense RNA 1 (KCNMB2-AS1) has been identified as an oncogenic lncRNA in several tumor types; however, its role in clear-cell renal cell carcinoma (ccRCC) remains largely unexplored. This study aimed to elucidate the expression profile, functional significance, and underlying molecular mechanisms of KCNMB2-AS1 in ccRCC. METHODS:The expression of KCNMB2-AS1 in ccRCC tissues and cell lines was analyzed using publicly available datasets, quantitative real-time PCR, and Western blotting. Functional assays including Cell Counting Kit-8, colony formation, wound healing, and Transwell migration/invasion tests along with in vivo xenograft experiments were performed to assess its biological effects. Mechanistic studies, including luciferase reporter, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and rescue assays, were conducted to verify the regulatory interactions among KCNMB2-AS1, forkhead box protein 3 (FOXP3), microRNA-744-3p (miR-744-3p), and cluster of differentiation 1D (CD1D). RESULTS:KCNMB2-AS1 expression was markedly elevated in ccRCC tissues compared to adjacent normal tissues, and its high expression was significantly associated with advanced tumor stage, presence of distant metastasis, and poor overall survival. Silencing KCNMB2-AS1 markedly suppressed ccRCC cell proliferation, migration, and invasion in vitro, accompanied by reduced epithelial-mesenchymal transition marker expression. Consistent with these findings, xenograft experiments confirmed that KCNMB2-AS1 knockdown attenuated tumor growth in vivo, while its overexpression promoted aggressive tumor behavior. Mechanistically, FOXP3 directly bound to the promoter region of KCNMB2-AS1, activating its expression transcriptionally. KCNMB2-AS1 acted as a molecular sponge for miR-744-3p, thereby relieving its inhibitory effect on CD1D expression. Rescue assays demonstrated that restoring CD1D expression counteracted the inhibitory phenotypes resulting from KCNMB2-AS1 silencing. CONCLUSION:KCNMB2-AS1 serves as an oncogenic lncRNA in ccRCC, functioning through a FOXP3/KCNMB2-AS1/miR-744-3p/CD1D signaling axis, thereby revealing a novel molecular pathway that contributes to ccRCC progression.
Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer deaths. Standard therapeutic management is faced with challenges like treatment resistance and late-stage diagnosis, highlighting a need for better diagnosis. LncRNAs are crucial in CRC progression and may serve as non-invasive biomarkers. For the first time, this study explores LINC00332 potential as a therapeutic and diagnostic marker in CRC. Eighty fresh normal and tumor tissues were enrolled to evaluate the levels of LINC00332 expression using Real-time PCR method. LINC00332 ectopic expression was also done to evaluate its role in drug resistance and cell migration in HCT116 cells. Ectopic expression of LINC00332 significantly induced NOTCH and WNT pathways in HCT116 cells. LINC00332 promoted EMT process through up regulation of Vimentin, CDH2, Snail, ZEB2, Slug, MMP10, and MMP3 while down regulation of CDH1 and OCLUDIN in HCT116 cells. LINC00332 significantly induced the HCT116 cell migration and paclitaxel (PTX) resistance in HCT116 cells (p < 0.0001). There was significant up regulation of LINC00332 in CRC clinical samples compared to normal margins (p = 0.042). There was significant up regulation of LINC00332 in stage I/II tumors that was located in transverse and left colon in comparison to right colon (p = 0.03). Tumors with perineural invasion had significant LINC00332 up regulation compared with negative ones in CRC patients (p = 0.02). LINC00332 promotes PTX resistance and EMT in CRC via WNT and NOTCH pathways activation. It can also be suggested as a potential diagnostic marker in early-stage CRC patients. Targeting LINC00332 may enhance PTX response, warranting further studies for therapeutic application.
BUB1, a key mitotic checkpoint kinase, is often dysregulated in cancer, yet its regulatory mechanism remains unclear. This study investigates the BUB1-centered miRNA–lncRNA–mRNA (ceRNA) network, its role in cell cycle regulation and immune modulation. Prognostic significance and expression profiles were assessed using TCGA-based databases such as KM Plotter, UALCAN, OncoDB, ENCORI, GEPIA2, Lung Cancer Explorer, and TCGAnalyzeR. Transcription factors were identified via Enrichr, and a ceRNA network was constructed using miRNet. Binding affinity and folding energy between BUB1, miRNA, and lncRNA were predicted using miRWalk and RNA22v2. Molecular docking evaluated interactions with natural compounds, chemotherapeutics, and inhibitor. Immune subpopulations were visualized using the SPRING viewer and correlation analysis with the immune cells was conducted using the GSCA and TIMER2.0 databases. BUB1 overexpression correlated with poor LUAD prognosis, especially in smokers (HR = 1.76), with transcriptomic analysis showing a 2.46 log2-fold increase in BUB1 transcript levels in tumor. TF-E2F1 and lncRNA-TMPO-AS1 were positively correlated with BUB1 (R = 0.664 and R = 0.632, respectively), while miRNA hsa-let-7b-5p showed a negative correlation (R = − 0.366). TMPO-AS1 exhibited an inverse association with hsa-let-7b-5p, suggesting a molecular sponge formation, repressing its tumor-suppressive activity. Docking revealed strong binding affinity of hesperidin (− 9.4 kcal/mol) with BUB1. Additionally, BUB1 expression negatively correlated with CD4⁺ T cells, suggesting an immunosuppressive role. This study identifies the BUB1/E2F1/TMPO-AS1/hsa-let-7b-5p axis as a potential prognostic biomarker and therapeutic target in LUAD. Targeting hsa-let-7b-5p may modulate this network, offering opportunities for both diagnostic and prognostic interventions.
BACKGROUND: To uncover the mechanism of METTL3 and LncRNA DUXAP8 in esophageal squamous cell carcinoma (ESCC) progression. METHODS: LncRNA DUXAP8 expression was assessed by qRT-PCR. Its overexpression and knockdown in ESCC cells were evaluated for effects on viability and metastasis. WB analyzed PI3K/AKT signaling proteins. MeRIP and RIP assays explored METTL3-DUXAP8 interaction and m6A methylation. In vivo experiments validated the mechanism. RESULTS: DUXAP8 was upregulated in ESCC and enhanced cell proliferation, metastasis, and PI3K/AKT activation. It was confirmed that METTL3-DUXAP8 interaction and METTL3 mediated the m6A methylation of DUXAP8. The total level of DUXAP8 and its m6A methylation in TE-1 and KSYE-150 cell lines was decreased significantly by METTL3 knockdown, which inactivated the PI3K/AKT pathway and reduced cell proliferation and metastasis. Xenograft tumor mouse model confirmed that si-METTL3 can reverse DUXAP8-mediated ESCC proliferation via activating the PI3K/AKT pathway. CONCLUSION: METTL3 drives ESCC oncogenesis by binding and positively regulating DUXAP8 in an m6A-dependent manner and activating the PI3K/AKT pathway.
There is evidence that atherosclerosis is a “tumor-like” disease and has similar genetic mutations to lung adenocarcinoma. In addition, the treatment and progression of lung adenocarcinoma can contribute to the development of atherosclerosis. This highlights the importance of studying the mechanisms of crosstalk between these two diseases and developing tools for early diagnosis and prognosis. We obtained gene expression profiles of both diseases through the GEO and TCGA databases and screened for crosstalk genes on the basis of differential genes. On the one hand, we constructed a diagnostic model of AS with LUAD by screening the core genes through Lasso and SVM-RFE to advance the early diagnosis of AS in patients with LUAD and explored the association between the core genes and immune infiltration. On the other hand, we constructed a robust prognostic model of LUAD based on crosstalk genes, explored the potential mechanisms of prognostic model genes in the regulation of immune infiltration and predicted treatment differences in LUAD patients to advance clinical decision-making. In addition, we constructed a PPI network based on crosstalk genes and a TF-miRNA-mRNA network, and performed drug prediction and molecular docking validation based on core targets. In conclusion, we revealed the crosstalk between AS and LUAD based on multifaceted transcriptomic analysis, screened novel targets, advanced diagnosis and prognosis, explored potential drugs and treatments, and provided invaluable insights into the research and treatment of AS with LUAD.
Cancer, as one of the main causes of human deaths, has an adverse effect on the quality of life in cancer patients. Despite many advances in diagnostic and therapeutic methods, there is still a poor prognosis in cancer patients that can be associated with the late tumor diagnosis. Therefore, investigating the molecular pathology of cancer can help to introduce early diagnostic markers. MicroRNAs (miRNAs) have key roles in regulation of cell proliferation, migration, and apoptosis. Deregulations of miRNAs have been widely reported in various cancers. Regarding the high stability of miRNAs in body fluids, they can be used as the non-invasive diagnostic markers in tumor screening programs and early detection. Considering the aberrant expression of miR-339 in a wide range of tumors, we discussed the role of miR-339 during tumor progressions. MiR-339 mainly functions as a tumor suppressor by the modulation of apoptosis, transcription factors, and signaling pathways. This review can be an effective step towards suggesting miR-339 as a therapeutic target and diagnostic marker in cancer patients.
BACKGROUND:Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer, with high mortality and limited treatment approaches. This paper explores the function of TAL1 in NSCLC progression and glycolysis and its mechanism. METHODS:Bioinformatics analysis screened out TAL1 and the upstream and downstream molecules. MTT, EdU, wound healing assay, Transwell assay, and TUNEL were utilized to detect the malignant phenotype of A549 and H460 cells. Western blot analysis was conducted to detect the expression of the proliferation-associated protein (Ki67), EMT-associated proteins (E-cadherin, N-cadherin), and glycolysis-associated proteins (GLUT1, LDHA, and PDK1). Cellular metabolism assays detected changes in glucose metabolites. A xenograft model was constructed, and the mouse tumor weight and volumes were measured periodically. Dual-luciferase assays and ChIP assays were performed to authenticate the transcriptional regulation of TAL1 on PKM2 and the relationship between DNMT3B and TAL1. RESULTS:TAL1 was lowly expressed in NSCLC, and TAL1 overexpression prevented the proliferation, migration, and invasion and elevated apoptosis. TAL1 inhibited PKM2 transcription, and overexpression of PKM2 reversed the trend of overexpression of TAL1 and promoted glycolysis. DNMT3B inhibited TAL1 expression through methylation modification. DNMT3B overexpression facilitated NSCLC cell growth and promoted glycolysis, and further overexpression of TAL1 reversed this trend. In vivo experiments showed that overexpression of TAL1 inhibited NSCLC progression, while combined overexpression of PKM2 promoted NSCLC progression. Overexpression of DNMT3B promoted NSCLC progression, and combined knockdown of PKM2 inhibited NSCLC progression. CONCLUSION:DNMT3B activates glycolysis and promotes NSCLC progression by mediating methylation modification of TAL1 and inducing PKM2 transcription.
This study aims to develop a ceRNA network associated with the chromosomal passenger complex (CPC) and identify a prognostic signature in lung cancer, the most diagnosed globally, to better understand the molecular mechanisms underlying tumor progression. The study used R packages and publicly available databases to conduct multi-omics In-silico analyses on CPC. These tools facilitated gene expression profiling, prognostic assessment, exploration of miRNA (microRNA), lncRNA (long non-coding RNA), transcription factor interactions, and pathway enrichment analysis. Molecular docking tools were used to evaluate binding affinities of CPC proteins with tobacco carcinogens, selective Aurora kinase B inhibitors, FDA-approved chemotherapeutics, and natural compounds. Immune landscape analysis was conducted using the SPRING viewer to visualize immune cell subpopulations in NSCLC, validated by correlation analysis using the GSCA database. The study reveals that CPC genes—BIRC5, CDCA8, INCENP, and AURKB—are overexpressed in lung adenocarcinoma (LUAD) and are associated with poor overall survival, especially in smokers. A dysregulated ceRNA axis involving lncRNA TMPO-AS1 and miRNA-hsa-let-7b-5p was identified, along with transcription factor E2F1, which shows a strong correlation with the CPC genes. Notably, TMPO-AS1 and E2F1 are positively correlated, while hsa-let-7b-5p is negatively correlated with the CPCs, contributing to tumor progression. Downregulation of hsa-let-7b-5p is linked to poorer outcomes, highlighting its potential as a therapeutic target. Nicotine and NNK show stable binding, suggesting potential roles in activating the CPC pathway and contributing to LUAD progression. CPCs have a strong binding affinity with Hesperidin, a natural bioflavonoid, compared to known chemotherapeutic agents like docetaxel and paclitaxel. CPC genes are negatively correlated with CD4⁺ T cells, indicating a role in promoting an immunosuppressive tumor microenvironment. Lung adenocarcinoma patients have poorer prognosis due to higher levels of CPCs, TMPO-AS1, and E2F1. A sponge complex between TMPO-AS1 and hsa-let-7b-5p may contribute to the tumor progression, and targeting CPCs with natural compounds could offer therapeutic potential. Highlights
BACKGROUND:Overexpression or downregulation of long noncoding RNA (lncRNA) plays an essential role in the progression and chemotherapy-resistant of breast cancer (BRCA). LncPRESS1 is a lncRNA regulated by p53, suggesting its potential in participating in carcinogenesis. However, few evidences reported the role of LncPRESS1 in tumor development. METHODS:The clinical significance of LncPRESS1 was explored in BRCA and normal samples derived from the patients. Overexpression and knockdown of LncPRESS1 were performed by lentivirus. CCK-8 and colony formation were conducted to examined the proliferation ability of BRCA cells. Apoptosis was measured by PI/Annexin V staining and the activity of caspase 3/7. Xenografted tumorigenesis in nude mice was applied to explore the role of LncPRESS1 on BRCA progression and cisplatin response. RT-qPCR was used to detect the mRNA level, while immunoblotting was applied to check the protein level. RESULTS:In this study, we identified that LncPRESS1 was significantly upregulated in BRCA tissues as compared with normal tissues, and in the cancer tissues with late stage or node metastasis. LncPRESS1 abundance was not changed among the patients based on the expression of estrogen receptor, progesterone receptor, or epidermal growth factor 2. In vitro, LncPRESS1 suppressed the apoptosis, while enhanced the proliferation and cisplatin resistance in BRCA cells. Upregulation of LncPRESS1 was also observed in the patients who did not response to cisplatin treatment. In vivo, knockdown of LncPRESS1 suppressed the tumorigenesis of BRCA cells and enhanced the effectiveness of cisplatin. Mechanistically, LncPRESS1 activated glycolysis via upregulation of ENO1. Overexpression of LncPRESS1 dictated the sensitivity of BRCA cells to ENO1 inhibitor, ENOblock. Importantly, treatment of ENOblock reduced the resistance of cisplatin in BRCA cells with overexpression of LncPRESS1. CONCLUSION:In summary, we demonstrated that LncPRESS1 facilitated BRCA progression and cisplatin resistance via activation of ENO1-mediated glycolysis. Combination of ENO1 inhibitor and cisplatin was a promising therapeutic stragtegy for BRCA patients with overexpression of LncPRESS1.
