Axis In Non-small Cell Lung Cancer Research Articles

MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1

Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.

SETD1A-mediated Methylation of H3K4me3 Inhibits Ferroptosis in Non-small Cell Lung Cancer by Regulating the WTAPP1/WTAP Axis.

SETD1A is upregulated in non-small cell lung cancer (NSCLC) tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP axis in NSCLC. Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation, which is regulated by multiple cellular metabolic pathways, including REDOX homeostasis, iron metabolism, mitochondrial activity and metabolism of amino acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were measured in vitro, and NSCLC cell behaviors were assessed. SETD1A-mediated H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor growth in vivo were verified in nude mouse models. SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis. WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis. Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude mice through the WTAPP1/WTAP axis. SETD1A amplified WTAP expression through WTAPP1 upregulation by mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC cell proliferation and migration and inhibiting ferroptosis.

LncRNA KTN1-AS1 Drives Tumor Progression in Non-Small Cell Lung Cancer through microRNA-153-3p/KLF5 Axis

IntroductionThe most typical kind of lung cancer is non-small cell lung cancer (NSCLC). Surgery, targeted therapy, chemotherapy, and immunotherapy are all options for the treatment of NSCLC. LncRNA KTN1-AS1 is significantly increased in NSCLC, and it modulates the expression of microRNAs and downstream genes, promoting NSCLC progression.Material and methodsTCGA was employed to predict lncRNA KTN1-AS1 expression in NSCLC. The starBase was utilized to predict downstream microRNAs of KTN1-AS1. The RNA22 database was employed to predict corresponding binding sites. Subcellular localization of KTN1-AS1 was forecasted using the lncLocator database, and the results were validated by FISH. qRT-PCR was used to test KTN1-AS1, microRNA-153-3p, and KLF5 expression. CCK-8, flow cytometry, and Transwell were used to determine cell viability, proliferation, migration, and invasion. Western blot was used to test KLF5 and Ki67 protein levels, and dual-luciferase assay was used to assess bindings of KTN1-AS1 with microRNA-153-3p, and KLF5 with microRNA-153-3p.ResultsKTN1-AS1 was significantly upregulated in NSCLC cells. Silencing KTN1-AS1 significantly repressed the proliferation, migration, and invasion of NSCLC cells. KTN1-AS1 bound to microRNA-153-3p, and KLF5 was a direct target of microRNA-153-3p. Inhibition of microRNA-153-3p or overexpression of KLF5 restored the stimulatory impact of KTN1-AS1 knockdown on NSCLC cell proliferation and migration.ConclusionsKTN1-AS1 drove proliferation, migration, and invasion of NSCLC cells by regulating microRNA-153-3p/KLF5 axis. By studying the role of the KTN1-AS1/microRNA-153-3p/KLF5 axis in NSCLC, the possibility of targeting this axis as a therapeutic target in NSCLC can be explored.

Unveiling the STAT3-ACC1 axis: a key driver of lipid metabolism and tumor progression in non-small cell lung cancer.

Background and Objective: Lung cancer is a prevalent global malignancy, and investigating the metabolic reprogramming of tumor cells has significant therapeutic implications. This study aims to explore the molecular mechanism driving the progression of non-small cell lung cancer (NSCLC), with a specific emphasis on the STAT3-ACC1-FAS axis involved in fatty acid synthesis. Methods: The levels of Signal transducer and activator of transcription 3 (STAT3) and acetyl-CoA carboxylase 1 (ACC1) were determined in mouse NSCLC specimens and cell lines using Western blot and qPCR methods. Various assays such as CCK-8, colony formation, EDU, wound-healing, and transwell migration were employed to assess cancer cell proliferation, migration, and invasion. Additionally, a nude mouse xenograft model was utilized for in vivo tumor growth analysis. The interaction between STAT3 and ACC1 was examined through chromatin immunoprecipitation and dual-luciferase assays. Results: The study observed upregulation of STAT3 and ACC1 in NSCLC tissues. Notably, the suppression of STAT3 and ACC1 inhibited the in vitro progression and lipid synthesis of NSCLC cells. Furthermore, STAT3 enhanced lipid synthesis by upregulating ACC1 expression. Mechanistic assays revealed that this process occurred through direct activation of ACC1 transcription by STAT3. STAT3 played a vital role in regulating lipid metabolism and supporting NSCLC progression. Conclusion: The findings of this study underscore the significance of the STAT3-ACC1-FAS axis in NSCLC. The activation of ACC1 through STAT3-mediated transcription serves as a crucial mechanism for stimulating the progression of NSCLC tumors and promoting lipid synthesis. Consequently, targeting the STAT3-ACC1 axis may present a promising avenue for the diagnosis and treatment of NSCLC patients.

Engrailed 2 serves as a master regulator of the super-enhancer in the TNC gene locus in non-small cell lung cancer.

Engrailed 2 (EN2) is a homeodomain-containing protein that is dysregulated in many types of cancer. However, the role of EN2 in non-small cell lung cancer (NSCLC) and the mechanism underlying its biological function are largely unclear. Here, we showed that EN2 played an oncogenic function in NSCLC and greatly enhanced the malignant phenotype of NSCLC cells. Meanwhile, EN2 was able to boost the expression of a well-studied oncogenic Tenascin-C (TNC) gene, which in turn activated the AKT signaling pathway. Interestingly, we found that EN2 directly bound to the super-enhancer (SE) region in the TNC locus. The histone marker H3K27ac was also enriched in the region, indicating the activation of the SE. Treatment of the cells with JQ1, an inhibitor of SE activity, abrogated the effect of EN2 on the expression of TNC and phosphorylation of AKT-Ser473. Collectively, our work unveils a novel mode of EN2 function, in which EN2 governs the SE in the TNC locus, consequently activating the oncogenic TNC-AKT axis in NSCLC.

A circRNA-based ceRNA network shows its diagnostic value in non-small-cell lung cancer

BackgroundNumerous studies have reported the vital roles of circular RNA (circRNA)-based competitive endogenous RNA (ceRNA) regulatory networks in cancers. Here, we established a non-small-cell lung cancer (NSCLC)-related circRNA–miRNA–mRNA axis and estimated its diagnostic value in NSCLC. MethodsThe circ_0061235–miR-3180-5p–PPM1L axis was constructed by small RNA deep sequencing, bioinformatics databases, and preliminary testing. The serum levels of the selected circ_0061235, miR-3180-5p, and PPM1L were quantified using quantitative polymerase chain reaction. Receiver operating characteristic analyses were conducted to evaluate the diagnostic power. ResultsThe levels of circ_0061235, miR-3180-5p, and PPM1L showed close correlations according to the ceRNA regulation rule. They were significantly dysregulated in NSCLC and showed the diagnostic ability to discriminate between healthy and NSCLC, and remarkably, between benign lung tumors and NSCLC. Additionally, the down-regulated levels of hsa_circ_0061235, the up-regulated levels of miR-3180-5p, and the decreased levels of PPM1L were correlated to more aggressive features of NSCLC, such as lymph node metastasis, distant metastasis, and higher stages. Intriguingly, compared to the single circ_0061235, miR-3180-5p, PPM1L, and traditional tumor markers, the diverse combinations of circ_0061235, miR-3180-5p, and PPM1L showed much higher sensitivity and specificity to differentiate greater or lesser severity of NSCLC. GO annotation and KEGG pathway analyses revealed the underlying role of the circ_0061235–miR-3180-5p–PPM1L axis in NSCLC. ConclusionsWe established a specific circRNA–miRNA–mRNA network with higher sensitivity and specificity to diagnose NSCLC, particularly more aggressive NSCLC, providing a new strategy for further developing tumor biomarkers.

Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer

BackgroundThe gefitinib resistance mechanism in non-small cell lung cancer (NSCLC) remains unclear, albeit exosomal circular RNA (circRNA) is known to possibly play a vital role in it.MethodsWe employed high-throughput sequencing techniques to detect the expressions of exosomal circRNA both in gefitinib-resistant and gefitinib-sensitive cells in this study. The circKIF20B expression was determined in serum exosomes and tissues of patients by qRT-PCR. The structure, stability, and intracellular localization of circKIF20B were verified by Sanger sequencing, Ribonuclease R (RNase R)/actinomycin D (ACTD) treatments, and Fluorescence in situ hybridization (FISH). The functions of circKIF20B were investigated by 5-Ethynyl-20-deoxyuridine (EdU), flow cytometry, Cell Counting Kit-8 (CCK-8), oxygen consumption rate (OCR), and xenograft model. Co-culture experiments were performed to explore the potential ability of exosomal circKIF20B in treating gefitinib resistance. The downstream targets of circKIF20B were determined by luciferase assay, RNA pulldown, and RNA immunoprecipitation (RIP).ResultsWe found that circKIF20B was poorly expressed in the serum exosomes of gefitinib-resistant patients (n = 24) and the tumor tissues of patients with NSCLC (n = 85). CircKIF20B was negatively correlated with tumor size and tumor stage. Decreasing circKIF20B was found to promote gefitinib resistance by accelerating the cell cycle, inhibiting apoptosis, and enhancing mitochondrial oxidative phosphorylation (OXPHOS), whereas increasing circKIF20B was found to restore gefitinib sensitivity. Mechanistically, circKIF20B is bound to miR-615-3p for regulating the MEF2A and then altering the cell cycle, apoptosis, and mitochondrial OXPHOS. Overexpressing circKIF20B parental cells can restore sensitivity to gefitinib in the recipient cells by upregulating the exosomal circKIF20B expression.ConclusionsThis study revealed a novel mechanism of circKIF20B/miR-615-3p/MEF2A signaling axis involving progression of gefitinib resistance in NSCLC. Exosomal circKIF20B is expected to be an easily accessible and alternative liquid biopsy candidate and potential therapeutic target in gefitinib-resistant NSCLC.Graphical The schematic diagram of mechanism in this study. Exosomal circKIF20B inhibits gefitinib resistance and cell proliferation by arresting the cell cycle, promoting apoptosis, and reducing OXPHOS via circKIF20B/miR-615-3p/MEF2A axis in NSCLC.

Genome-wide epigenetic and mRNA-expression profiling followed by CRISPR/Cas9-mediated gene-disruptions corroborate the MIR141/MIR200C-ZEB1/ZEB2-FGFR1 axis in acquired EMT-associated EGFR TKI-resistance in NSCLC cells.

Epithelial-mesenchymal-transition (EMT) is an epigenetic-based mechanism contributing to the acquired treatment resistance against receptor tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor (EGFR)-mutations. Delineating the exact epigenetic and gene-expression alterations in EMT-associated EGFR TKI-resistance (EMT-E-TKI-R) is vital for improved diagnosis and treatment of NSCLC patients. We characterized genome-wide changes in mRNA-expression, DNA-methylation and the histone-modification H3K36me3 in EGFR-mutated NSCLC HCC827 cells in result of acquired EMT-E-TKI-R. CRISPR/Cas9 was used to functional examine key findings from the omics analyses. Acquired EMT-E-TKI-R was analyzed with three omics approaches. RNA-sequencing identified 2,233 and 1,972 up- and down-regulated genes, respectively, and among these were established EMT-markers. DNA-methylation EPIC array analyses identified 14,163 and 7,999 hyper- and hypo-methylated, respectively, differential methylated positions of which several were present in EMT-markers. Finally, H3K36me3 chromatin immunoprecipitation (ChIP)-sequencing detected 2,873 and 3,836 genes with enrichment and depletion, respectively, and among these were established EMT-markers. Correlation analyses showed that EMT-E-TKI-R mRNA-expression changes correlated better with H3K36me3 changes than with DNA-methylation changes. Moreover, the omics data supported the involvement of the MIR141/MIR200C-ZEB1/ZEB2-FGFR1 signaling axis for acquired EMT-E-TKI-R. CRISPR/Cas9-mediated analyses corroborated the importance of ZEB1 in acquired EMT-E-TKI-R, MIR200C and MIR141 to be in an EMT-E-TKI-R-associated auto-regulatory loop with ZEB1, and FGFR1 to mediate cell survival in EMT-E-TKI-R. The current study describes the synchronous genome-wide changes in mRNA-expression, DNA-methylation, and H3K36me3 in NSCLC EMT-E-TKI-R. The omics approaches revealed potential novel diagnostic markers and treatment targets. Besides, the study consolidates the functional impact of the MIR141/MIR200C-ZEB1/ZEB2-FGFR1-signaling axis in NSCLC EMT-E-TKI-R.

High level of LncRNA MAPKAPK5-AS1 predicts poor prognosis and contributes to the malignant proliferation and EMT of non-small cell lung cancer via sponging miR-490-3p from HMGB2.

Patients with non-small cell lung cancer (NSCLC) show a low survival rate, owing to the lack of early diagnostic method and high invasiveness. Long non-coding RNA MAPKAPK5-AS1 that regulates tumor genesis and progression through multiple signals, is upregulated and involved in the growth and apoptosis in lung adenocarcinoma (LUAD). To investigate whether MAPKAPK5-AS1 affected the malignant progression of NSCLC. The levels of MAPKAPK5-AS1, miR-490-3p and HMGB2 in lung cancer were first analyzed through StarBase website, and confirmed by a quantitative reverse transcriptase-PCR (qRT-PCR) assay. The biological functions of NSCLC cells were examined by CCK-8, 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays. The potential binding sequences lncRNA-miRNA and miRNA-mRNA were predicted by StarBase software and verified via dual luciferase reporter experiment. The effects of MAPKAPK5-AS1 on tumor growth were evaluated in a xenografted mice model. The expression of MAPKAPK5-AS1 was upregulated in tumor tissues from NSCLC patients. Patients with high expression of MAPKAPK5-AS1 had higher tumor size, advanced TNM stage, higher incidence of lymph node and distant metastasis, and shorter overall survival. Knockdown of MAPKAPK5-AS1 inhibited the proliferation, induced apoptosis and blocked epithelial mesenchymal transformation (EMT) of NSCLC cells. Mechanically, MAPKAPK5-AS1 could upregulate the HMGB2 level in NSCLC cells through competitively binding to miR-490-3p. MiR-490-3p inhibitor reversed the roles of MAPKAPK5-AS1 knockdown on tumor cell proliferation, apoptosis and EMT. Also, HMGB2 knockdown suppressed tumor cell malignant phenotypes. Furthermore, interference of MAPKAPK5-AS1 slowed NSCLC tumor growth in vivo. Knockdown of MAPKAPK5-AS1 inhibited the aggressive tumor phenotypes through miR-490-3p/HMGB2 axis in NSCLC. MAPKAPK5-AS1/miR-490-3p/HMGB2 might be potential biomarkers or therapeutic targets for NSCLC.

Platycodin D induces apoptosis through JNK1/AP-1/PUMA pathway in non-small cell lung cancer cells: A new mechanism for an old compound.

Platycodin D, a triterpenoid monomer, has been shown to possess an anti-tumor effect on various types of cancer. Although Platycodin D has been reported to suppress tumorigenesis, the detailed underlying mechanism remains elusive. Platycodin D treatment significantly reduced the cell viability, decreased the number of colonies, impaired the mitochondrial function, and induced apoptosis in non-small cell lung cancer (NSCLC) cells. To understand the mechanism by which platycodin D induces apoptosis, the expression levels of apoptosis-related proteins were examined, and we found that the expression of PUMA (p53 upregulated modulator of apoptosis) was upregulated upon platycodin D treatment. Knockdown of PUMA resulted in attenuation of platycodin D-induced apoptosis, indicating that PUMA up-regulation is essential for platycodin D to induce apoptosis. The induction of PUMA expression by platycodin D treatment was through activation of AP-1 since mutation of AP-1 binding site in the PUMA promoter abolished the PUMA promoter activity. In addition, the chromatin immunoprecipitation further demonstrated that platycodin D promoted AP-1 binding to PUMA promoter. Moreover, knockdown of JNK1, but not JNK2, significantly abolished the phosphorylation of c-Jun at Ser63 (a component of AP-1), decreased the platycodin D-induced expression of PUMA and cleaved caspase 3, indicating that platycodin D inhibits JNK1/AP-1 signaling pathway. Furthermore, immunohistochemical staining studies showed that tumors from the mice treated with platycodin D activated JNK by translocation of JNK into nuclei, increased phosphorylation of JNK and c-Jun at Ser63 in nuclei, and boosted the PUMA expression. Taken together, our in vitro and in vivo data revealed a novel mechanism by which platycodin D up-regulates PUMA to induce apoptosis through JNK1/AP-1 axis in NSCLC.

Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis

AbstractNon-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.

Mechanism of OTUD5 in non-small cell lung cancer cell proliferation, invasion, and migration.

Ovarian tumor protease deubiquitinase 5 (OTUD5) has been discussed as a regulator of cancer development. Herein, the current study set out to explore the molecular mechanism of OTUD5 in non-small cell lung cancer (NSCLC) cell proliferation, invasion, and migration. Firstly, the expression patterns of OTUD5, phosphatase and tensin homolog (PTEN), as well as microRNA (miR)-652-3p in cells were detected by qRT-PCR and Western blot. Cell viability, migration, and invasion were assessed with the help of cell-counting kit-8 and Transwell assays, in addition to the measurement of the ubiquitination and protein levels of PTEN. The binding relations between OTUD5 and PTEN, and miR-652-3p and OTUD5 were testified by co-immunoprecipitation or dual-luciferase assays. Cells were further treated with GSK2643943A (inhibitor of deubiquitinase) or miR-652-3p-inhibitor to explore the role of PTEN ubiquitination and miR-652-3p in NSCLC cells. OTUD5 and PTEN were both poorly-expressed, and miR-652-3p was highly-expressed in NSCLC cells. On the other hand, over-expression of OTUD5 suppressed NSCLC cell proliferation, invasion, and migration. OTUD5 deubiquitinated and stabilized PTEN, and miR-652-3p targeted and inhibited OTUD5 expression. Augmenting the ubiquitination levels of PTEN promoted NSCLC cell growth, whereas miR-652-3p inhibition promoted the tumor-suppressing effects of the OTUD5/ PTEN axis in NSCLC. Altogether, our findings highlighted that miR-652-3p restrained the role of OTUD5 in deubiquitinating PTEN to improve PTEN protein level, thereby promoting NSCLC cell proliferation, invasion, and migration.

CircRNA High Mobility Group At-hook 2 regulates cell proliferation, metastasis and glycolytic metabolism of nonsmall cell lung cancer by targeting miR-331-3p to upregulate High Mobility Group At-hook 2.

Increasing circular RNAs (circRNAs) have been identified as pivotal players in nonsmall cell lung cancer (NSCLC). The study will explore the function and mechanism of circRNA High Mobility Group AT-hook 2 (circHMGA2) in NSCLC. The circHMGA2, microRNA-331-3p (miR-331-3p) and HMGA2 expression analyses were performed via quantitative real-time PCR. Cell proliferation was assessed via Cell Counting Kit-8 and colony formation assays. Transwell migration/invasion assays were used for measuring cell metastasis. Glucose consumption and lactate production were determined for glycolytic evaluation. Western blot was used to detect the protein expression of HMGA2 and glycolytic markers. Target analysis was performed by dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Xenograft tumor assay in mice was conducted for the investigation of circHMGA2 in vivo . CircHMGA2 was overexpressed in NSCLC, and high circHMGA2 level might be related to NSCLC metastasis and poor prognosis. In-vitro assays suggested that NSCLC cell growth, metastasis and glycolysis were retarded by downregulation of circHMGA2. Upregulation of HMGA2 was shown to return the anticancer response of circHMGA2 knockdown in NSCLC cells. Through interacting with miR-331-3p, circHMGA2 could regulate the expression of HMGA2. In addition, circHMGA2/miR-331-3p and miR-331-3p/HMGA2 axes were affirmed in NSCLC regulation. In-vivo analysis indicated that circHMGA2 inhibition also reduced tumorigenesis and glycolysis of NSCLC via the miR-331-3p/HMGA2 axis. This study disclosed the oncogenic role of circHMGA2 and the regulatory circHMGA2/miR-331-3p/HMGA2 axis in NSCLC.

Dysregulation of Pseudogenes/lncRNA-Hsa-miR-1-3p-PAICS Pathway Promotes the Development of NSCLC.

Objective Non-small cell lung cancer (NSCLC) explains about 80 percent of whole lung cancers, and its 5-year survival rate is impoverished, as when people are first diagnosed, 68% of whom are identified at a dangerous stage. The molecular mechanisms of NSCLC are still being explored. Methods GSE18842 and GSE19804 were exerted to scan for diversely expressed genes (DEGs) in NSCLC, and then we used GEPIA for the validation of DEGs expression. The prognostic values were determined through Kaplan–Meier analysis. Three target prediction databases indicated potential microRNAs (miRNAs), while miRNet predicted hsa-miR-1-3p′s upstream long non-coding RNAs (lncRNAs) and pseudogenes. UALCAN was utilized to identify the co-expressed genes of PAICS, while enrichment analysis on them was managed with Enrichr. Results We initially found that the gene expression level of cyclin B1 (CCNB1), cyclin-dependent kinases1 (CDK1), and phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) had a notable increase in NSCLC. We predicted 6, 10, and 7 microRNAs to target CCNB1, CDK1, and PAICS, respectively. Among miRNA-mRNA (microRNA-messenger RNA) pairs, we deduced that the hsa-miR-1-PAICS axis was the most potential one to inhibit the occurrence of NSCLC. We also noted that the hsa-miR-1-3p-PAICS axis participated in regulating the process of mitosis with mechanical functions. Moreover, we identified 5 pseudogenes and 33 long non-coding RNAs (lncRNAs) that might inhibit the hsa-miR-1-3p-PAICS axis in NSCLC. Conclusions The pseudogene/lncRNA-hsa-miR-1-3p-PAICS is very important in NSCLC on the basis of this study, thus providing us with effective treatments and promising biomarkers for the diagnosis of NSCLC.

Different Roles of the Insulin-like Growth Factor (IGF) Axis in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains one of the deadliest malignant diseases, with high incidence and mortality worldwide. The insulin-like growth factor (IGF) axis, consisting of IGF-1, IGF-2, related receptors (IGF-1R, -2R), and high-affinity binding proteins (IGFBP 1-6), is associated with promoting fetal development, tissue growth, and metabolism. Emerging studies have also identified the role of the IGF axis in NSCLC, including cancer growth, invasion, and metastasis. Upregulation of IGE-1 and IGF-2, overexpression of IGF-1R, and dysregulation of downstream signaling molecules involved in the PI-3K/Akt and MAPK pathways jointly increase the risk of cancer growth and migration in NSCLC. At the genetic level, some noncoding RNAs could influence the proliferation and differentiation of tumor cells through the IGF signaling pathway. The resistance to some promising drugs might be partially attributed to the IGF axis. Therapeutic strategies targeting the IGF axis have been evaluated, and some have shown promising efficacy. In this review, we summarize the biological roles of the IGF axis in NSCLC, including the expression and prognostic significance of the related components, noncoding RNA regulation, involvement in drug resistance, and therapeutic application. This review offers a comprehensive understanding of NSCLC and provides insightful ideas for future research.

LINC00313/miR-4429 axis provides novel biomarkers for the diagnosis and prognosis of non-small cell lung cancer.

Increasing evidence suggests that the LncRNA/miRNA axis plays a key role in many types of tumorigenesis. However, the potential role and clinical value of LINC00313/miR-4429 in non-small cell lung cancer (NSCLC) remain elusive and need further study. The aim of this study was to investigate the role of LINC00313/miR-4429 axis in NSCLC. The expression of LINC00313 and miR-4429 in serum, tissues and cell lines of NSCLC patients were detected by reverse transcription-quantitative PCR. The diagnostic value was evaluated by receiver operating characteristic (ROC) curve analysis and the prognostic value was analyzed by Kaplan-Meier survival analysis and Cox regression. The expression of LINC00313 was significantly up-regulated while the expression of miR-4429 was down-regulated in NSCLC serum, tissue and cell lines. A negative correlation was found between LINC00313 and miR-4429 in patients with NSCLC. ROC curves showed that LINC00313 and miR-4429 had high diagnostic value and Kaplan-Meier curve results showed that high expression of LINC00313 and low expression of miR-4429 predicted poor prognosis. In summary, our data show that the ectopic expression of LINC00313 and miR-4429 has promising clinical significance in the diagnosis and prognosis of NSCLC. The LINC00313/miR-4429 axis may provide novel biomarker for NSCLC treatment.

Restraint of chaperonin containing T-complex protein-1 subunit 3 has antitumor roles in non-small cell lung cancer via affection of YAP1

The implication of chaperonin containing T-complex protein-1 subunit 3 (CCT3) in carcinogenesis has been observed in a diverse malignancies. However, the relevance of CCT3 in non-small cell lung cancer (NSCLC) has not been well addressed. This research is dedicated to investigating the expression pattern and functional role of CCT3 in NSCLC. An elevation in CCT3 levels was observed in NSCLC tissue, which was linked to a reduced overall survival rate. The inhibition of CCT3 by shRNA-mediated gene silencing induced suppressive effects on the transformative phenotypes of NSCLC cells, including the inhibition of cell proliferation and invasion, and the induction of cell cycle arrest and apoptosis. Further investigation revealed that the silencing of CCT3 led to the suppression of Yes-associated protein 1 (YAP1), and decreased the expression of YAP1 target genes in NSCLC cells. The activation of YAP1 via forced expression of constitutively active YAP1 mutant reversed CCT3-restraint-evoked antitumor effects in NSCLC cells. Crucially, NSCLC cells with CCT3 silencing also exhibited weakened oncogenicity in nude mice associated with the down-regulation of YAP1 activation in xenografts. To sum up, these observations of our work show that the inhibition of CCT3 produces antitumor effects in NSCLC via the suppression of YAP1. This study unveils a possible role CCT3/YAP1 axis in NSCLC and suggests CCT3 as a candidate anticancer target.

FOXM1/lncRNA TYMSOS/miR-214-3p-Mediated High Expression of NCAPG Correlates With Poor Prognosis and Cell Proliferation in Non-Small Cell Lung Carcinoma.

Lung cancer is the most common cancer with high mortality. Increasing evidence has demonstrated that nonstructural maintenance of chromosomes condensin I complex subunit G (NCAPG) plays a crucial role in the progression of human cancers. However, the biological function and underlying mechanism of NCAPG in non–small cell lung cancer (NSCLC) are still unclear. Here, we utilized diverse public databases to analyze the expression of NCAPG in pan-cancer. We found that NCAPG was highly expressed in various human cancers, especially in NSCLC. NCAPG expression was significantly positively correlated with poor clinical-pathological features, poor prognosis, tumor mutational burden, DNA microsatellite instability, and immune cell infiltration in NSCLC. In addition, our results showed that depletion of NCAPG significantly inhibited NSCLC cell proliferation, migration, and self-renewal abilities, yet these could be reversed by adding microRNA (miRNA)-214-3p. Knockdown of long noncoding RNA (lncRNA) thymidylate synthetase opposite strand (TYMSOS) also inhibits the NSCLC cell proliferation, migration, and self-renewal abilities. In summary, our findings demonstrated that the crucial roles of the FOXM1/lncRNA-TYMSOS/miRNA-214-3p/NCAPG axis in NSCLC may shed light on how NCAPG may act as a therapeutic target for NSCLC.

The LMCD1-AS1/miR-526b-3p/OSBPL5 axis promotes cell proliferation, migration and invasion in non-small cell lung cancer

PurposeTo explore the specific role and regulatory mechanism of oxysterol binding protein like 5 (OSBPL5) in non-small cell lung cancer (NSCLC).Methods and results Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that OSBPL5 expression was notably elevated in NSCLC tissues and cell lines, and Kaplan–Meier analysis manifested that high OSBPL5 expression was closely related to the poor prognosis of NSCLC patients. Besides, according to the results from western blot analysis, cell counting kit-8, EdU and Transwell assays, knockdown of OSBPL5 suppressed NSCLC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. Additionally, by performing qRT-PCR analysis, luciferase reporter and RNA pull-down assays, we verified that OSBPL5 was a downstream target of miR-526b-3p and long noncoding RNA (lncRNA) LMCD1-AS1 served as a sponge for miR-526b-3p. Moreover, from rescue assays, we observed that OSBPL5 overexpression offset LMCD1-AS1 knockdown-mediated inhibition in cell proliferation, migration, invasion and EMT in NSCLC.ConclusionsThis paper was the first to probe the molecular regulatory mechanism of OSBPL5 involving the LMCD1-AS1/miR-526b-3p axis in NSCLC and our results revealed that the LMCD1-AS1/miR-526b-3p/OSBPL5 axis facilitates NSCLC cell proliferation, migration, invasion and EMT, which may offer a novel therapeutic direction for NSCLC.

MiR-199a-3p/5p regulate tumorgenesis via targeting Rheb in non-small cell lung cancer.

Lung cancer is one of the deadliest cancers, in which non-small cell lung cancer (NSCLC) accounting for 85% and has a low survival rate of 5 years. Dysregulation of microRNAs (miRNAs) can participate in tumor regulation and many major diseases. In this study, we found that miR-199a-3p/5p were down-expressed in NSCLC tissue samples, cell lines, and the patient sample database. MiR-199a-3p/5p overexpression could significantly suppress cell proliferation, migration ability and promote apoptosis. Through software prediction, ras homolog enriched in brain (Rheb) was identified as a common target of miR-199a-3p and miR-199a-5p, which participated in regulating mTOR signaling pathway. The same effect of inhibiting NSCLC appeared after down-regulating the expression of Rheb. Furthermore, our findings revealed that miR-199a can significantly inhibit tumor growth and metastasis in vivo, which fully demonstrates that miR-199a plays a tumor suppressive role in NSCLC. In addition, miR-199a-3p/5p has been shown to enhance the sensitivity of gefitinib to EGFR-T790M in NSCLC. Collectively, these results prove that miR-199a-3p/5p can act as cancer suppressor genes to inhibit the mTOR signaling pathway by targeting Rheb, which in turn inhibits the regulatory process of NSCLC. Thus, to investigate the anti-cancer effect of pre-miR-199a/Rheb/mTOR axis in NSCLC, miR-199a-3p and miR-199a-5p have the potential to become an early diagnostic marker or therapeutic target for NSCLC.