Malignant Behavior Research Articles

SPP1 promotes tumor progression in esophageal carcinoma by activating focal adhesion pathway.

Recurrence and metastasis are the major obstacles affecting the therapeutic efficacy and clinical outcomes for patients with esophageal carcinoma (ESCA). Secreted phosphoprotein 1 (SPP1) is considered as a hub gene in ESCA and is negatively associated with disease-free survival (DFS) in ESCA. However, the exact roles and underlying mechanisms remain elusive. This study aims to examine the roles of SPP1 on ESCA, and elucidate the potential mechanisms. Bioinformatics were used to analyze the expression of SPP1 in ESCA tissues, and its relations with clinicopathological characteristics and clinical prognosis in patients with ESCA based on The Cancer Genome Atlas (TCGA) dataset. Loss-of-function was conducted to examine the roles of SPP1 on malignant behaviors of ESCA cells by cell counting kit-8 (CCK8), plate clone, wound healing, and transwell assays. Gene set enrichment analysis (GSEA) was conducted to screen the pathways associated with SPP1 in ESCA. Then, the enriched pathway and the underlying mechanism were elucidated by western blotting, cell adhesion, and cell spreading assays. Lastly, Y15 [a specific inhibitor of focal adhesion kinase (FAK)] was used to examine its potential to inhibit tumor growth in ESCA cells. SPP1 was upregulated in ESCA tissues compared to the adjacent nontumorous tissues, which was closely associated with clinical stage, lymph node metastasis, histological subtype, and p53 mutation. A high expression of SPP1 indicated a poor clinical prognosis in patients with ESCA. The knockdown of SPP1 inhibited cell proliferative, migratory, and invasive capacities in ESCA cells. GSEA indicated that the focal adhesion pathway was closely related with SPP1 in ESCA. Further studies confirmed that the knockdown of SPP1 suppressed cell adhesion ability and reduced the expression of p-FAK and p-Erk in ESCA cells. In addition, Y15 inhibited FAK autophosphorylation and dramatically inhibited cell proliferation, migration, and invasion in ESCA cells. SPP1 promotes tumor progression in ESCA by activating FAK/Erk pathway, and FAK is a potential therapeutic target to overcome tumor recurrence and metastasis of ESCA.

LINC00665 promotes the progression and immune evasion of lung cancer by facilitating the translation of TCF7 protein through dependence on IRES

ObjectiveTo investigate the influence of LINC00665 on the development and immune evasion of lung cancer.MethodsTumor tissues and corresponding adjacent tissues were collected from 84 lung cancer patients, categorized into non-metastatic (n = 58) and metastatic (n = 26) groups. LINC00665 expression in lung cancer and metastatic lung cancer tissues was assessed via qRT-PCR. Pearson correlation analysis was conducted to examine the correlation between LINC00665 and immune-modulating cytokines (TGF-β, IL-10, IL-1β, IFN-γ, IL-2, TNF-α). A549 and H1299 cells, with relatively high LINC00665 expression, were used for in vitro studies. Cells were transfected with LINC00665-targeting shRNA, and changes in proliferation, apoptosis, migration, invasion, and NK cell cytotoxicity were assessed. Downstream molecular mechanisms of LINC00665 were investigated using GEO database analysis, highlighting the association with HHLA2. LINC00665’s role in promoting HHLA2 expression via binding with TCF7 was explored. In low LINC00665-expressing A549/H1299 cells, overexpression of HHLA2 was performed to evaluate effects on malignant behavior and NK cell sensitivity. A xenograft model was established for in vivo validation through tumor volume and weight measurements, Ki-67 immunoreactivity analysis, and flow cytometry analysis of CD107a + NK cells.ResultsLINC00665, TCF7 mRNA, and HHLA2 mRNA expression levels were significantly higher in lung cancer tissues than adjacent tissues, with non-metastatic lung cancer showing higher expression than metastatic lung cancer. In metastatic lung cancer, LINC00665 positively correlated with immune-suppressive cytokines (TGF-β, IL-10, IL-1β) and negatively correlated with anti-tumor cytokines (IFN-γ, IL-2, TNF-α). LINC00665 knockdown significantly inhibited lung cancer cell growth and metastasis, promoting sensitivity to NK cells. Further analysis revealed that LINC00665 recruits transcription factor TCF7 to upregulate HHLA2 expression in lung cancer cells, thereby facilitating lung cancer development and immune escape.ConclusionLINC00665, through recruitment of TCF7 and upregulation of HHLA2, inhibits NK cell cytotoxicity, promoting the development and immune evasion of lung cancer.

Mediation of circ_0007142 on miR-128-3p/S100A14 pathway to stimulate the progression of cervical cancer.

A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC progression. The expression of circ_0007142, microRNA-128-3p (miR-128-3p), S100 calcium-binding protein A14 (S100A14), and epithelial mesenchymal transition (EMT)-related markers was measured by qRT-PCR and Western blot. Cell proliferative, migratory, and invasion abilities were evaluated using cell counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and transwell assays, respectively. The interaction among circ_0007142, miR-128-3p and S100A14 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo experiment was implemented to investigate the effect of circ_0007142 on tumor growth. CC tissues and cells displayed high expression of circ_0007142 and S100A14, and low expression of miR-128-3p in comparison to the controls. Knockdown of circ_0007142 resulted in the inhibition of cell proliferation, migration invasion, and EMT in vitro. In support, circ_0007142 deficiency hindered tumor growth and EMT in vivo. In rescue experiments, downregulation of miR-128-3p relieved circ_0007142 absence-mediated anticancer impacts. MiR-128-3p overexpression-induced inhibitory effects on cell growth and metastasis were attenuated by S100A14 overexpression. Importantly, circ_0007142 regulated S100A14 expression by sponging miR-128-3p. Circ_0007142 knockdown suppressed CC cell malignant behaviors by miR-128-3p/S100A14 pathway, providing a possible circRNA-targeted therapy for CC.

The combination of SHP099 inhibits the malignant biological behavior of L-OHP/5-FU-resistant colorectal cancer cells by regulating energy metabolism reprogramming

Background and objectiveColorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC. MethodsHT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 106 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells. ResultsCompared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC. ConclusionThe combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.

Tumoral EIF4EBP1 regulates the crosstalk between tumor-associated macrophages and tumor cells in MRTK

Malignant renal rhabdoid tumor (MRTK) is an aggressive and rare malignancy primarily affecting infants and young children. The intricate interactions within the Tumor Microenvironment (TME) are crucial in shaping MRTK's progression. This study elucidates the significance of tumor-associated macrophages(TAMs) within this milieu and their interplay with eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) in tumor cells, collectively contributing to MRTK's malignant advancement. Through comprehensive analysis of clinical samples and the TARGET database, EIF4EBP1 emerges as a central macrophage-associated gene with robust prognostic implications. Elevated EIF4EBP1 expression correlates with poor prognosis and heightened infiltration of TAMs. Functional validation demonstrates that EIF4EBP1 knockdown in G401 cells significantly attenuates self-proliferation, migration, and invasion. Moreover, EIF4EBP1 regulates macrophage recruitment and M2 polarization through the ERK/P38 MAPK-MIF axis. Notably, M2 macrophages reciprocally foster the malignant behavior of MRTK tumor cells. This study unveils the pivotal role of EIF4EBP1 in propelling MRTK's malignant progression, unraveling a complex regulatory network involving EIF4EBP1 and TAMs. These findings underscore EIF4EBP1 as a promising biomarker and highlight its therapeutic potential in MRTK management.

FOXCUT regulates the malignant phenotype of triple-negative breast Cancer via the miR-337-3p/ANP32E Axis

BackgroundThe lack of specific molecular targets and the rapid spread lead to a worse prognosis of triple-negative breast cancer (TNBC). Therefore, identifying new therapeutic and prognostic biomarkers helps to develop effective treatment strategies for TNBC. MethodsThrough preliminary bioinformatics analysis, FOXCUT was found to be significantly overexpressed in breast cancer, especially in TNBC. Tissue samples were collected from 15 TNBC patients, and qRT-PCR was employed to validate the expression of FOXCUT in both TNBC patient tissues and TNBC cell lines. We also carried out the GSEA analysis and KEGG enrichment analysis of FOXCUT. Additionally, the effects of FOXCUT knockdown on TNBC cell malignant behaviors, and aerobic glycolysis were assessed by methods including CCK-8, Transwell, western blot, and Seahorse XF 96 analyses. Moreover, utilizing databases predicting interactions between ceRNAs, corresponding lncRNA-miRNA binding relationships, and miRNA-mRNA interactions were predicted. These predictions were subsequently validated through RNA immunoprecipitation and dual-luciferase reporter assays. ResultsFOXCUT exhibited high expression in both TNBC tissues and cell lines, fostering cell malignant behaviors and glycolysis. FOXCUT was found to sponge miR-337-3p, while miR-337-3p negatively regulated the expression of ANP32E. Consequently, FOXCUT ultimately facilitated the malignant phenotype of TNBC by upregulating ANP32E expression. ConclusionThis study elucidated the role of FOXCUT in elevating aerobic glycolysis levels in TNBC and driving malignant cancer cell development via the miR-337-3p/ANP32E regulatory axis.

CircNUP98 promotes the malignant behavior of glioma cells through the miR-520f-3p/ELK4 axis.

Glioma, a formidable form of brain cancer, poses significant challenges in terms of treatment and prognosis. Circular RNA nucleoporin 98 (circNUP98) has emerged as a potential regulator in various cancers, yet its role in glioma remains unclear. Here, we elucidate the functional role of circNUP98 in glioma cell proliferation, invasion, and migration, shedding light on its therapeutic implications. Glioma cells were subjected to si-NUP98 transfection, followed by assessments of cell viability, proliferation, invasion, and migration. Subcellular localization of circNUP98 was determined, and its downstream targets were identified. We delineated the binding relationships between circNUP98 and microRNA (miR)-520f-3p, as well as between miR-520f-3p and ETS transcription factor ELK4 (ELK4). The expression levels of circNUP98/miR-520f-3p/ELK4 were quantified. Our findings demonstrated that circNUP98 was upregulated in glioma cells, and its inhibition significantly attenuated glioma cell proliferation, invasion, and migration. Mechanistically, circNUP98 functioned as a sponge for miR-520f-3p, thereby relieving the inhibitory effect of miR-520f-3p on ELK4. Moreover, inhibition of miR-520f-3p or overexpression of ELK4 partially rescued the suppressive effect of circNUP98 knockdown on glioma cell behaviors. In summary, our study unveils that circNUP98 promotes glioma cell progression via the miR-520f-3p/ELK4 axis, offering novel insights into the therapeutic targeting of circNUP98 in glioma treatment.

MiR-200a-3p promotes the malignancy of endometrial carcinoma through negative regulation of epithelial-mesenchymal transition

BackgroundmiR-200a-3p is involved in the progression of malignant behavior in various tumors, and its mechanism of action in endometrial cancer is speculated to be related to epithelial-mesenchymal transition (EMT). Therefore, this study explored the metastatic mechanism of miR-200a-3p and EMT in endometrial cancer, with the aim of identifying potential therapeutic targets.MethodsqRT-PCR was used to analyze miR-200a-3p expression in HEC-1B and Ishikawa cell lines. The cell proliferation assay, transwell assay, and cell scratch test were used to assess changes in the malignant phenotypes of cells after regulating miR-200a-3p expression. Changes in EMT-related protein zinc finger E-box binding homeobox 1 (ZEB1) were detected after regulating miR-200a-3p expression. An endometrial carcinoma transplantation mouse tumor model was constructed, and multiple EMT-related proteins were examined.ResultsThe expression of miR-200a-3p and ZEB1 in the endometrial cancer cell lines was higher than in normal endometrial epithelial cell lines (P < 0.05). After silencing miR-200a-3p, the expression of EMT-related protein ZEB1 increased, indicating a negative correlation. Simultaneously, the proliferation, invasion, and metastasis of endometrial cancer cells were significantly enhanced. After miR-200a-3p overexpression, the corresponding malignant phenotype was reversed (P < 0.05). In in vivo experiments, the degree of tumor malignancy and the expression level of EMT-related proteins were significantly reduced in the miR-200a-3p mimic group (P < 0.05).ConclusionThis study found that miR-200a-3p is a promising target, regulating the EMT process and promoting endometrial cancer progression.

The emerging roles of circHECTD1 in human diseases and the specific underlying regulatory mechanisms

Circular RNAs (circRNAs) are a class of single-stranded closed-loop RNAs that have become a popular research subject in biology. Compared to linear RNAs, they are more stable, more conserved, and more widely distributed, and they play crucial biological functions in many diseases. CircHECTD1, a newly identified member of the circRNA family, is widely distributed in humans. Recent studies have shown that circHECTD1 is abnormally expressed in various human diseases, including glioma, hepatocellular carcinoma, gastric cancer, acute ischaemic stroke, silicosis, acute lung injury, ulcerative colitis, atherosclerosis, and hypertrophic scarring. In malignant tumours, circHECTD1 is thought to be an oncogene that promotes malignant tumour behaviours and influences tumour prognosis. In nontumour diseases, it plays a dual role, promoting disease in silicosis, stroke, and other diseases, while alleviating the disease process in ulcerative colitis, acute lung injury, and atherosclerosis. This article provides a review of the regulatory roles and mechanisms of action of circHECTD1 in different diseases. We also discuss and prospectively evaluate the clinical potential of circHECTD1 as a diagnostic biomarker and a therapeutic target for related diseases, providing new insights for developing new therapeutic strategies.

LncRNA PGM5-AS1 inhibits non-small cell lung cancer progression by targeting miRNA-423-5p/SLIT2 axis

Non-small cell lung cancer (NSCLC) is a common and aggressive primary malignancy worldwide. Dysregulation of long non-coding RNAs (lncRNAs) has been shown to play an essential regulatory role in multiple cancers. However, the role of PGM5-AS1 in NSCLC remains unclear. Here, we found that PGM5-AS1 was down-regulated in NSCLC tissues and cells. Furthermore, reduced PGM5-AS1 expression levels were associated with larger tumor size, positive lymph node metastasis, advanced TNM stage and worse prognosis. We found that overexpression of PGM5-AS1 inhibited cell proliferation and metastasis, and induced apoptosis and G0/G1 cell cycle arrest in NSCLC cell lines. Using dual luciferase gene reporter and RNA immunoprecipitation assays, we confirmed that miR-423-5p interacted with PGM5-AS1, and that their expression levels were negatively correlated in NSCLC tissues. miR-423-5p was also found to reverse PGM5-AS1-induced malignant biological behavior. Moreover, we identified slit guidance ligand 2 (SLIT2) as a target gene of miR-423-5p. Using a dual luciferase gene reporter assay, we confirmed the regulatory relationship between SLIT2 and miR-423-5p and demonstrated that their expression levels were negatively correlated. Our rescue experiments showed that SLIT2 knockdown reversed miR-423-5p-mediated effects. Overall, this study identifies PGM5-AS1 as a potential prognostic biomarker for NSCLC and shows that PGM5-AS1 suppresses NSCLC development by regulating the miR-423-5p/SLIT2 axis.

Androgen-responsive FOXP4 is a target for endometrial carcinoma

Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.

Hyper-methylation and DNMT3A mediated LTC4S downregulation promoted lung adenocarcinoma tumorigenesis via mTORC1 signaling pathway

BackgroundLung adenocarcinoma is a malignancy characterized by high mortality rates and unfavorable prognosis. However, the role of Leukotriene C4 Synthase (LTC4S) in lung cancer remains uninvestigated. MethodsThe expression and prognostic value of LTC4S in LUAD were analyzed using the GEPIA online database. Subsequently, the function of LTC4S in lung cancer cells was examined through gain-of function experiments, using assays to evaluate tumor malignant behavior. Subcutaneous xenograft experiments in vivo was used for investigating the functions of LTC4S. Then, tumor hallmark pathways were analyzed by GSEA. Western blot assay was used to validate the impact of LTC4S on mTORC1 pathway. Finally, the correlation of mRNA and methylation of LTC4S were analyzed by cBioPortal. qRT-PCR, ChIP-qPCR and ChIP-Atlas were used to verify the regulation factors of LTC4S low expression in LUAD cells. ResultsLTC4S presented significant decreased expression and favorable prognostic significance in LUAD. LTC4S was correlated with clinical stages in LUAD, which showed decreased expression gradually and significantly along with TNM stages. LTC4S-co-expressed genes were closely related to Ras signaling pathway, and MAPK signaling pathway. Overexpression of LTC4S inhibited cancer malignant phenotype and tumor growth in vitro and vivo. GSEA analysis and Western blot assay suggested low expression of LTC4S activated mTORC1 signaling pathway in LUAD. Moreover, the DNA methylation level of LTC4S in LUAD tissue was markedly elevated compared to normal tissue. The hypermethylation of the LTC4S promoter by DNMT3A leads to the decreased expression of LTC4S in LUAD. ConclusionsIn conclusion, low expression of LTC4S serves as an unfavorable prognostic marker and the critical function of LTC4S in controlling the progression of LUAD. This highlights the promise for exploring the clinical benefits of manipulating LTC4S in LUAD targeted therapies.

Circ_0004771 regulates malignant biological behaviors and has clinical significance in oral squamous cell carcinoma.

The incidence of oral squamous cell carcinoma (OSCC) is increasing, and more effective treatment protocols must rapidly be developed to prevent the death of patients and ensure favorable outcomes. CircRNAs are a unique class of noncoding ribonucleic acid (RNA) molecules unaffected by RNA exonucleases. CircRNAs have more stable expression than linear RNAs and are not readily degraded; therefore, they are the newest focus of RNA research. Here, we analyze the mechanism of hsa_circ_0004771 (circ_0004771) in OSCC to provide a clinical reference. Circ_0004771 expression was measured in peripheral blood, cancerous tissues and adjacent tissues of OSCC patients. Patients were followed up for 3 years. The diagnostic value of circ_0004771 for OSCC occurrence, prognosis, recurrence and survival was analyzed with receiver operating characteristic (ROC) curves. OSCC cells were lentivirally transduced with a circ_0004771-silencing or an empty vector to evaluate alterations in cell growth, invasion, and apoptosis. Apoptosis-related and epithelial-mesenchymal transition (EMT)-related protein expression was quantified. BALB/c nude mice were used for tumorigenesis experiments to evaluate tumor growth in vivo after silencing circ_0004771. Circ_0004771 expression was higher in peripheral blood and cancerous tissue of OSCC patients than in control peripheral blood and paracancerous tissue, respectively, exhibiting excellent predictive value for OSCC occurrence, prognosis, recurrence and survival. Silencing circ_0004771 decreased the growth, invasiveness, and EMT capacity and increased the apoptosis of OCC cells. In mice implanted with OSCC cells transduced with the circ_0004771-silencing lentiviral vector, the tumor growth capacity was obviously decreased. Silencing circ_0004771 inhibits the malignant growth of OSCC.

CircIQCH Contributes to the Progression of Breast Cancer by Elevating NFIB Through Decoying miR-139-5p.

Circular RNAs (circRNAs) are implicated in the progression of breast cancer (BC). However, the explorations on circRNA IQ motif containing H (circIQCH) in BC progression remain limited. Functional experiments were conducted using in vitro and murine xenograft model assays, respectively. Dual-luciferase reporter assay and RIP assay detected the associations among circIQCH, miR-139-5p, and nuclear factor IB (NFIB). CircIQCH was upregulated in BC, and the silencing of circIQCH repressed BC cell growth, metastasis, and autophagy, arrested cell cycle, promoted cell apoptosis in vitro, and blocked tumor growth in vivo. CircIQCH positively modulated NFIB expression by sponging miR-139-5p. Moreover, the deletion of miR-139-5p abated the action of circIQCH deficiency on BC cell malignant behaviors. Overexpression of miR-139-5p repressed the malignant characteristics of BC cells, while these impacts were abolished by elevating NFIB. Collectively, CircIQCH functioned as an oncogene in BC through upregulating NFIB expression by sponging miR-139-5p.

EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer.

Lobaplatin shows antitumor activity against a wide range of tumors, including triple-negative breast cancer (TNBC), and has been linked to cancer stem cell pool. Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

Identification and validation of the role of ZNF281 in 5-fluorouracil chemotherapy of gastric cancer

BackgroundThe early diagnosis of gastric cancer (GC) and overcoming chemotherapy resistance is challenging. The aberrant expression of zinc finger protein 281 (ZNF281) and the over-activation of the Wnt/β-catenin pathway are oncogenic factors and confer tumor chemoresistance. ZNF281 modulates the Wnt/β-catenin pathway to influence malignant tumor behavior. However, the role of ZNF281 in GC chemotherapy and the relationship with the Wnt/β-catenin pathway have not been elucidated by researchers.MethodsWe explored differences in ZNF281 expression in Pan-cancer and normal tissues, the effect of its expression on prognosis of patients treated with 5-fluorouracil (5-FU). Cox regression was utilized to determine whether ZNF281 is an independent prognostic factor. Enrichment analysis was performed to explore the mechanism underlying ZNF281’s role in 5-FU treatment. We assessed the relationship between ZNF281 and the tumour microenvironment (TME) and combined bulk-RNA and single-cell RNA data to analyse the relationship between ZNF281 and immune infiltration. In vitro experiments verified the effects of ZNF281 knockdown on proliferation, invasion, migration, apoptosis, DNA damage of GC cells with 5-FU treated and the Wnt/β-catenin pathway proteins.ResultsZNF281 was highly expressed in seven cancers and correlates with the prognosis. It is an independent prognostic factor in 5-FU treatment. ZNF281 correlates with TME score, CD8T cell abundance. ZNF281 is primarily associated with DNA repair and the Wnt/β-catenin pathway. ZNF281 knockdown enhanced the effect of 5-FU on phenotypes of GC cells.ConclusionWe identified and verified ZNF281 as one of the potential influencing factors of 5-FU treatment in GC and may be associated with the Wnt/β-catenin pathway. Low ZNF281 may contribute to improved 5-FU sensitivity in GC patients.

RNF144A-AS1 stabilizes TAF15 and promotes malignant biological behaviors of skin cutaneous melanoma.

LncRNAs have been demonstrated to regulate biological processes in malignant tumors. In our previous study, we identified the immune-related LncRNA RNF144A-AS1 as a potential regulator in SKCM. However, its precise function and regulatory mechanism remain unclear. In this study, we observed upregulation of RNF144A-AS1 in SKCM and found that knockdown of RNF144A-AS1 suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition abilities of melanoma cells. Mechanistically, as a high-risk prognostic factor, RNF144A-AS1 regulated biological processes of SKCM by interacting with TAF15 through an RNA-binding protein-dependent (RBP-dependent) manner. Furthermore, we confirmed that TAF15 activated downstream transcriptional regulation of YAP1 to modulate malignant behaviors in melanoma cells. In vivo experiments revealed that knockdown of RNF144A-AS1 inhibited tumorigenic capacity of melanoma cells and exhibited promising therapeutic effects. Collectively, these findings highlight the significance of the RNF144A-AS1/TAF15/YAP1 axis in promoting malignant behaviors in SKCM and provide novel insights into potential prognostic biomarkers and therapeutic targets for this disease.

Nicotine-induced activation of cholinergic receptor nicotinic alpha 5 subunit mediates the malignant behaviours of laryngeal squamous epithelial cells by interacting with RABL6

Nicotine, a crucial constituent of tobacco smoke, can bind to and activate nicotinic acetylcholine receptors (nAChRs), thereby regulating various biological functions. However, the specific mechanisms through which nicotine mediates nAChRs to regulate the metastasis of laryngeal squamous cell carcinoma (LSCC) remain elusive. In this study, smoking status was found to be closely associated with metastasis in patients with LSCC. In addition, nicotine exposure potentiated the hematogenous and lymphatic metastatic capacity of LSCC cells. Nicotine activates membrane-bound CHRNA5, promoting cell migration and invasion, EMT and cell–ECM adhesion in LSCC. Furthermore, this study demonstrated that the Ras superfamily protein RABL6 directly interacted with CHRNA5, which preferentially binds to the RABL6-39-279aa region, and this interaction was enhanced by nicotine. Nicotine-mediated activation of CHRNA5 enhanced its interaction with RABL6, triggering the JAK2/STAT3 signalling pathway and eventually augmenting the metastatic potential of LSCC cells. This study reveals a novel mechanism through which nicotine-mediated CHRNA5–RABL6 interaction promotes the metastasis of LSCC. The findings of this study may help to develop effective strategies for improving the outcome of patients with LSCC in clinical settings.

Bidirectional activation of stem-like programs between metastatic cancer and alveolar type 2 cells within the niche

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer

BackgroundBreast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.MethodsRNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.ResultsUsing RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.ConclusionsOur study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.