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Abstract Mounting evidence has found that tumor microenvironment (TME) plays an important role in the tumor progression of lung adenocarcinoma (LUAD). However, the roles of tumor microenvironment-related genes in immunotherapy and clinical outcomes remain unclear. In this study, 6 TME-related genes (PLK1, LDHA, FURIN, FSCN1, RAB27B, and MS4A1) were identified to construct the prognostic model. The established risk scores were able to predict outcomes at 1, 3, and 5 years with greater accuracy than previously known models. Moreover, the risk score was closely associated with immune cell infiltration and the immunoregulatory genes including T cell exhaustion markers. In conclusion, the TME risk score can function as an independent prognostic biomarker and a predictor for evaluating immunotherapy response in LUAD patients, which provides recommendations for improving patients’ response to immunotherapy and promoting personalized tumor immunotherapy in the future.

Abstract YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem cell self-renewal, and embryonic development. YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA. The cellular levels of YTHDF1 are precisely regulated by a complicated transcriptional, post-transcriptional, and post-translational network. Very solid evidence supports the pivotal role of YTHDF1 in embryonic development and human cancer progression. In this review, we discuss how YTHDF1 influences both the physiological and pathological biology of the central nervous, reproductive and immune systems. Therefore we focus on some relevant aspects of the regulatory role played by YTHDF1 as gene expression, complex cell networking: stem cell self-renewal, embryonic development, and human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, and prognosis. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy.

Abstract The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.

Dual-specificity phosphatase 10 (DUSP10) correlates with inflammation, cytokine secretion, cell proliferation, survival, and apoptosis. However, its role in glioma is unclear. Herein, we sought to examine the expression and the underlying carcinogenic mechanisms of DUSP10 action in glioma. DUSP10 expression in glioma was significantly higher than that in normal brain tissues. High DUSP10 expression indicated adverse clinical outcomes in glioma patients. Increased DUSP10 expression correlated significantly with clinical features in glioma. Univariate Cox analysis showed that high DUSP10 expression was a potential independent marker of poor prognosis in glioma. Furthermore, DUSP10 expression in glioma correlated negatively with its DNA methylation levels. DNA methylation level of DUSP10 also correlated negatively with poor prognosis in glioma. More importantly, DUSP10 expression correlated positively with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells in glioma. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that DUSP10 participated in signaling pathways involved in focal adhesion, TNF cascade, Th17 cell differentiation, and NF-kappa B cascade. Finally, we uncovered that DUSP10 was dramatically upregulated in glioblastoma (GBM) cells and that the knockdown of DUSP10 inhibited glioma cell proliferation and migration. Our findings suggested that DUSP10 may serve as a potential prognostic biomarker in glioma.

Abstract Background Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved. Methods Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism. Result Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis. Conclusions Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

BackgroundGliomas account for 75% of all primary malignant brain tumors in adults and result in high mortality. Accumulated evidence has declared the minichromosome maintenance protein complex (MCM) gene family plays a critical role in modulating the cell cycle and DNA replication stress. However, the biological function and clinic characterization of nine MCM members in low-grade glioma are not yet clarified.MethodsIn this study, we utilized diverse public databases, including The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt, Human Protein Atlas (HPA), Linkedomics, cbioportal, Tumor and Immune System Interaction Database (TISIDB), single-sample GSEA (ssGSEA), Tumor Immune Estimation Resource (TIMER), Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal databases to explore the mRNA and protein expression profiles, gene mutation, clinical features, diagnosis, prognosis, signaling pathway, tumor mutational burden (TMB), immune subtype, immune cell infiltration, immune modulator and drug sensitivity of nine MCMs. Afterward, qRT-PCR was utilized to detect the expression of the MCM family in glioblastoma multiforme (GBM) cell lines. The one-, three-, or five-year survival rate was predicted by utilizing a nomogram established by cox proportional hazard regression.ResultsIn this study, we found that nine MCMs were consistently up-regulated in glioma tissues and glioma cell lines. Elevated nine MCMs expressions were significantly correlated with a higher tumor stage, isocitrate dehydrogenase (IDH) mutates, 1p/19q codeletion, histological type, and primary therapy outcome. Survival analyses showed that higher expression of MCM2-MCM8 (minichromosome maintenance protein2-8) and MCM10 (minichromosome maintenance protein 10) were linked with poor overall survival (OS) and progression-free survival (PFS) in glioma patients. On the other hand, up-regulated MCM2-MCM8 and MCM10 were significantly associated with shorter disease-specific survival (DSS) in glioma patients. Univariate and multivariate analyses revealed that MCM2 (minichromosome maintenance protein2), MCM4 (minichromosome maintenance protein 4), MCM6 (minichromosome maintenance protein 6), MCM7 (minichromosome maintenance protein 7) expression and tumor grade, 1p/19q codeletion, age, and primary therapy outcome were independent factors correlated with the clinical outcome of glioma patients. More importantly, a prognostic MCMs model constructed using the above five prognostic genes could predict the overall survival of glioma patients with medium-to-high accuracy. Furthermore, functional enrichment analysis indicated that MCMs principal participated in regulating cell cycle and DNA replication. DNA copy number variation (CNV) and DNA methylation significantly affect the expression of MCMs. Finally, we uncover that MCMs expression is highly correlated with immune cell infiltration, immune modulator, TMB, and drug sensitivity.ConclusionsIn summary, this finding confirmed that MCM4 is a potential target of precision therapy for patients with glioma.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs are covalently close, endogenous RNAs without 5′ end caps or 3′poly (A) tails and have been characterized by high stability, abundance, and conservation as well as display cell/tissue/developmental stage-specific expressions. Numerous studies have confirmed that circRNAs act as microRNA (miRNA) sponges, RNA-binding protein, and transcriptional regulators; some circRNAs even act as translation templates that participate in multiple pathophysiological processes. Growing evidence have confirmed that circRNAs are involved in the pathogenesis of lung cancers through the regulation of proliferation and invasion, cell cycle, autophagy, apoptosis, stemness, tumor microenvironment, and chemotherapy resistance. Moreover, circRNAs have emerged as potential biomarkers for lung cancer diagnosis and prognosis and targets for developing new treatments. In this review, we will summarize recent progresses in identifying the biogenesis, biological functions, potential mechanisms, and clinical applications of these molecules for lung cancer diagnosis, prognosis, and targeted therapy.

Extra spindle pole bodies-like 1 (ESPL1), a cysteine endopeptidase, plays a vital role in chromosome inheritance. However, the association of ESPL1 with prognosis and immune infiltration in lung adenocarcinoma (LUAD) has not yet been explored. Here, we analyzed the expression level, prognostic values, diagnostic value, and immune infiltration level in LUAD using various databases. Immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) assays were used to detect the expression of ESPL1 in LUAD tissues and cell lines. In this study, we found that ESPL1 was upregulated in LUAD and a higher expression of ESPL1 was correlated with unfavorable prognosis in LUAD. Meanwhile, Cox hazard regression analysis results suggested that ESPL1 may be an independent prognostic factor for LUAD. Moreover, we demonstrated that ESPL1 expression was significantly correlated with immune infiltration of Th2 and dendritic cells in LUAD. We also confirmed that DNA copy number amplification and DNA hypo-methylation were positively correlated with ESPL1 expression in LUAD. Additionally, DNA copy number amplification was significantly associated with adverse clinical outcomes in LUAD. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) confirmed that ESPL1 was mainly involved in the DNA replication and glycolysis signaling pathway. Finally, we revealed that ESPL1 was highly expressed in LUAD tissues and cell lines. Knockdown of ESPL1 significantly inhibited cell migration and the invasion abilities of LUAD. Our study comprehensively confirmed that ESPL1 expression may serve as a novel prognostic biomarker for both the clinical outcome and immune cell infiltration in LUAD.

BackgroundLung cancer has the highest death rate among cancers globally. Accumulating evidence has indicated that cancer-related inflammation plays an important role in the initiation and progression of lung cancer. However, the prognosis, immunological role, and associated regulation axis of inflammatory response-related gene (IRRGs) in non-small-cell lung cancer (NSCLC) remains unclear.MethodsIn this study, we perform comprehensive bioinformatics analysis and constructed a prognostic inflammatory response-related gene (IRRGs) and related competing endogenous RNA (ceRNA) network. We also utilized the Pearson’s correlation analysis to determine the correlation between IRRGs expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor-immune infiltration, and the drug sensitivity in NSCLC. Growth curve and Transwell assay used to verify the function of SNHG17 on NSCLC progression.ResultsFirst, we found that IRRGs were significantly upregulated in lung cancer, and its high expression was correlated with poor prognosis; high expression of IRRGs was significantly correlated with the tumor stage and poor prognosis in lung cancer patients. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that these IRRGs are mainly involved in the inflammatory and immune response-related signaling pathway in the progression of NSCLC. We utilized 10 prognostic-related genes to construct a prognostic IRRGs model that could predict the overall survival of lung adenocarcinoma (LUAD) patients possessing high specificity and accuracy. Our evidence demonstrated that IRRGs expression was significantly correlated with the TMB, MSI, immune-cell infiltration, and diverse cancer-related drug sensitivity. Finally, we identified the upstream regulatory axis of IRRGs in NSCLC, namely, lncRNA MIR503HG/SNHG17/miR-330-3p/regulatory axis. Finally, knockdown of SNHG17 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and migration. Our findings confirmed that SNHG17 is a novel oncogenic lncRNA and may be a biomarker for the prognosis and diagnosis of LUAD.ConclusionDNA hypomethylation/lncRNA MIR503HG/SNHG17/microRNA-330-3p/regulatory axis may be a valuable biomarker for prognosis and is significantly correlated with immune cell infiltration in lung cancer.

Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3) is an adaptor protein expressed mainly in lymphocytes, and plays significant roles in T-cell proliferation and cell survival. However, its expression level, clinical significance, and correlation with tumor-infiltrating immune cells across cancers remain unclear. In this study, we comprehensively examined the expression, dysregulation, and prognostic significance of SASH3, and the correlation with clinicopathological parameters and immune infiltration in pan-cancer. The mRNA and protein expression status of SASH3 were determined by TCGA, GTEx, and UALCAN. Kaplan–Meier analysis utilized the prognostic values of SASH3 in diverse cancers. The association between SASH3 expression and gene mutation, DNA methylation, immune cells infiltration, immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed using data from the TCGA database. High expression of SASH3 was not only linked to poor OS in ESCC, LAML, LGG, and UVM, but also associated with better OS in CESC, HNSC, LUAD, SARC, SKCM, THYM, and UCEC. As for DSS, a high level of SASH3 correlated with adverse DSS in ESCC, LGG, and UVM, and lowly expressed SASH3 was associated with shorter OS in CESC, HNSC, LUAD, SARC, SKCM, and UCEC. The results of Cox regression and nomogram analyses confirmed that SASH3 was an independent factor for LUAD prognosis. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) results showed that SASH3 was involved in natural killer cell-mediated cytotoxicity, Th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, NF-kappa B signaling pathway, B-cell receptor signaling pathway, and Toll-like receptor signaling pathway. SASH3 expression was correlated with TMB in 28 cancer types and associated with MSI in 22 cancer types, while there was a negative correlation between SASH3 expression and DNA methylation in diverse human cancer. The high DNA methylation level of SASH3 was correlated with better OS in KIRC and UVM, and associated with poor OS in SKCM. Moreover, we uncover that SASH3 expression was positively associated with the stroma score in 27 cancer types, the microenvironment score, and immune score in 32 cancer types, 38 types of immune cells in 32 cancer types, the 45 immune stimulators, 24 immune inhibitors, 41 chemokines, 18 receptors, and 21 major histocompatibility complex (MHC) molecules in 33 cancer types. Finally, forced SASH3 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and cell migration. Our findings confirmed that SASH3 may be a biomarker for the prognosis and diagnosis of human cancer.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC087588.2 (ENSG00000274976) is a novel lncRNA that is abnormally expressed in diverse cancer types, including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and the potential biological function of AC087588.2 LUAD remain elusive. In this study, we found that AC087588.2 was upregulated and associated with a poor prognosis in LUAD. In addition, univariate and multivariate Cox regression analysis indicated that AC087588.2 could be an independent prognostic factor for LUAD. Functionally, the knockdown of AC087588.2 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a ceRNA network that included hsa-miR-30a-5p and four mRNAs (ANLN, POLR3G, EHBP1, and ERO1A) specific to AC087588.2 in LUAD. The Kaplan–Meier survival analysis showed that lower expression of hsa-miR-30a-5p and higher expression of ANLN, POLR3G, EHBP1, and ERO1A were associated with adverse clinical outcomes in patients with LUAD. This finding provided a comprehensive view of the AC087588.2-mediated ceRNA network in LUAD, thereby highlighting its potential role in the diagnosis and prognosis of LUAD.

BackgroundStriatin-interacting protein 2 (STRIP2), also called Fam40b, has been reported to regulate tumor cell growth. But the role of STRIP2 in lung adenocarcinoma (LUAD) has not been discovered clearly. Thus, the aim of our study is to explore the function and underlying mechanism of STRIP2 in LUAD.MethodsExpression of STRIP2 was determined using the Cancer Genome Atlas (TCGA), GTEx, Ualcan, and the Human Protein Altas databases. The Correlation of STRIP2 and survival was detected by PrognoScan and Kaplan–Meier plotter databases. Besides, the correlation between STRIP2 expression and tumor immune infiltration as well as immune checkpoints were analyzed by the ssGSEA method. The biological function of STRIP2 and its co-expression genes was determined by gene ontology (GO) and Genes and Genomes (KEGG), respectively. Finally, the expression level and biological function of STRIP2 in LUAD were determined by qPCR, CCK8, transwell, and wound healing assays.ResultsThis manuscript revealed a significantly increased expression of mRNA and protein of STRIP2 in lung adenocarcinoma compared with the adjacent normal tissues. GEO and Kaplan–Meier plotter databases showed higher STRIP2 expression levels were correlated with poor prognosis survival of LUAD. Moreover, Cox regression analysis suggested that a higher STRIP2 level served as an independent risk factor in predicting deteriorative overall survival (OS) for LUAD patients. SsGSEA results showed STRIP2 expression level was positively correlated with infiltrating levels of Th2 cells in LUAD. Lastly, GO analysis indicated the biological processes were enriched in nuclear division and positive regulation of the cell cycle. KEGG signaling pathway analysis showed STRIP2 was correlated with the MAPK signaling pathway and the TNF signaling pathway. The GSEA database showed that STRIP2 was positively associated with the epithelial–mesenchymal transition, cell cycle, and TNF signaling pathway. The QRT-PCR assay showed that STRIP2 was upregulated in LUAD cell lines. Cell proliferation and migration were inhibited in LUAD by knockdown of STRIP2. Moreover, we confirmed that the TMPO-AS1/let-7c-5p/STRIP2 network regulates STRIP2 overexpression in LUAD and is associated with poor prognosis.ConclusionOur findings indicated that STRIP2 acted as a crucial oncogene in LUAD and was correlated with unfavorable survival and tumor infiltration inflation.

Abstract N6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Shugoshin-like protein 1 (SGO1) has been characterized in its function in correct cell division and its role in centrosome cohesion in the nucleus. However, the underlying biological function and potential mechanisms of SGO1 driving the progression of lung adenocarcinoma remain unclear. In this study, we found that SGO1 was increased in LUAD tissues and cell lines. Upregulation of SGO1 expression was correlated with poor overall survival (OS), disease-free survival (DSS), and progression-free survival (PFS) in patients with LUAD. ROC curve analysis suggested that the AUC value of SGO1 was 0.983. Correlation analysis showed that SGO1 expression was related to immune infiltration in LUAD. Meanwhile, a potential ceRNA network was constructed to identify the lncRNA-MIR4435-2HG/miR-125a-5p/SGO1 regulatory axis in LUAD. Finally, we determine that SGO1 regulated the cell proliferation and cell apoptosis of lung adenocarcinoma in vitro. In conclusion, our data suggested that SGO1 could be a novel prognostic biomarker for lung adenocarcinoma.

PurposeLung adenocarcinoma (LUAD) is the most common type of cancer and the leading cause of cancer-related death worldwide, resulting in a huge economic and social burden. MiRNA-195-5p plays crucial roles in the initiation and progression of cancer. However, the significance of the miRNA-195-5p/polypyrimidine tract-binding protein 1 (miRNA-195-5p/PTBP1) axis in the progression of lung adenocarcinoma (LUAD) remains unclear.MethodsData were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The starBase database was employed to examine the expression of miRNA-195-5p, while the Kaplan–Meier plotter, UALCAN, and Gene Expression Profiling Interactive Analysis (GEPIA) databases were utilized to analyze the tumor stage and prognostic value of miRNA and PTBP1. Quantitative reverse transcription-polymerase chain reaction assay was conducted to detect the expression levels of miRNA-195-5p in LUAD cell lines and tissues. The effects of miRNA-195-5p on cell proliferation and migration were examined using the cell growth curve, clone information, transwell assays, and wound healing assays.ResultsWe found that miRNA-195-5p was down-regulated in LUAD cancer and cell lines. Importantly, its low levels were related to the tumor stage, lymph node metastasis, and poor prognosis in LUAD. Overexpression of miR-195-5p significantly inhibited cell growth and migration promotes cell apoptosis. Further study revealed that PTBP1 is a target gene of miRNA-195-5p, and overexpression of miRNA-195-5p inhibited the progression of LUAD by inhibiting PTBP1 expression. MiRNA-195-5p expression was related to immune infiltration in lung adenocarcinoma. Moreover, PTBP1 was negatively correlated with diverse immune cell infiltration and drug sensitivity.ConclusionOur findings uncover a pivotal mechanism that miRNA-195-5p by modulate PTBP1 expression to inhibit the progression of LUAD. MiRNA-195-5p could be a novel diagnostic and prognostic molecular marker for LUAD.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC099850.3 is a novel lncRNA that is abnormally expressed in diverse cancer types including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and potential biological function of AC099850.3 LUAD remain elusive. In this study, we found that AC099850.3 was highly expressed in LUAD and associated with an advanced tumor stage, poor prognosis, and immune infiltration. Receiver operating curve analysis revealed the significant diagnostic ability of AC099850.3 (AUC=0.888). Functionally, the knockdown of AC099850.3 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a competitive endogenous RNAs (ceRNA) network that included hsa-miR-101-3p and 4 mRNAs (ESPL1, AURKB, BUB3, and FAM83D) specific to AC099850.3 in LUAD. Kaplan–Meier survival analysis showed that a lower expression of miR-101-3p and a higher expression of ESPL1, AURKB, BUB3, and FAM83D, were associated with adverse clinical outcomes in patients with LUAD. This finding provided a comprehensive view of the AC099850.3-mediated ceRNA network in LUAD, thereby highlighting its potential role in the diagnosis and prognosis of LUAD.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. LncRNA-AL139385.1 (ENSG00000275880) is a novel lncRNA that is abnormally expressed in various cancer types including LUAD. However, the underlying biological function and potential mechanisms of AL139385.1 driving the progression of LUAD remain unclear. In this study, we investigated the role of AL139385.1 in LUAD and found that DNA hypomethylation was positively correlated with AL139385.1 expression in LUAD. Moreover, we uncover that the expression of AL139385.1 in LUAD tissues was significantly higher than that of AL139385.1 expression in adjacent normal tissues. Kaplan–Meier survival analysis showed that patients with higher AL139385.1 expression correlated with adverse overall survival and progression-free survival. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) value of AL139385.1 was 0.808. Correlation analysis showed that AL139385.1 expression was associated with immune infiltration in LUAD. We also found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of AL139385.1 significantly inhibited cell proliferation and migration abilities of LUAD. Finally, we constructed a ceRNA network that includes hsa-miR-532-5p and four mRNAs (GALNT3, CYCS, EIF5A, and ITGB4) specific to AL139385.1 in LUAD. Subsequent Kaplan–Meier survival analysis suggested that polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), cytochrome c, somatic (CYCS), eukaryotic translation initiation factor 5A (EIF5A), and integrin subunit beta 4 (ITGB4), were potential prognostic biomarkers for patients with LUAD. In conclusion, this finding provides possible mechanisms underlying the abnormal upregulation of AL139385.1 as well as a comprehensive view of the AL139385.1-mediated competing endogenous RNAs (ceRNA) network in LUAD, thereby highlighting its potential role in diagnosis and therapy.

Family with sequence similarity 72B (FAM72B) has been characterized in the regulation of neuronal development. Nevertheless, the prognostic value of FAM72B expression and its function in the immune microenvironment of lung adenocarcinoma (LUAD) currently remains elusive. In this study, by adopting bioinformatics methodology and experimental verification, we found that FAM72B was upregulated in lung cancer tissues and cell lines, and a higher FAM72B level predicted an unfavorable clinical outcome in LUAD patients. The knockdown of FAM72B significantly inhibited cell proliferation, cell migration, and induced cell apoptosis in LUAD. The receiver operating characteristic curve suggested that FAM72B had a high predictive accuracy for the outcomes of LUAD. Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses confirmed that FAM72B-related genes were involved in cell proliferation and immune-response signaling pathway. Moreover, upregulated FAM72B expression was significantly associated with immune cell infiltration in the LUAD tumor microenvironment. Meanwhile, a potential ceRNA network was constructed to identify the lncRNA-AL360270.2/TMPO-AS1/AC125807.2/has-let-7a/7b/7c/7e/7f/FAM72B regulatory axis that regulates FAM72B overexpression in LUAD and is associated with a poor prognosis. We also confirmed that AL360270.2, TMPO-AS1, and AC125807.2 were significantly upregulated in LUAD cell lines than in human bronchial epithelial cells. In conclusion, FAM72B may serve as a novel biomarker in predicting the clinical prognosis and immune status for lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. NCAPG2 (non-SMC condensin II complex subunit G2) has been shown to be upregulated in various human cancers. Nevertheless, the underlying biological function and potential mechanisms of NCAPG2 driving the progression of LUAD remain unclear. In this study, we investigated the role of NCAPG2 in LUAD and found that the expression of NCAPG2 in LUAD tissues was significantly higher than that of NCAPG2 expression in adjacent normal tissues. Kaplan–Meier survival analysis showed that patients with higher NCAPG2 expression correlated with unfavorable clinical outcomes. Receiver operating characteristic (ROC) curve analysis showed that the AUC value of NCAPG2 was 0.914. Correlation analysis showed that NCAPG2 expression was associated with immune infiltration in LUAD. Finally, we found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of NCAPG2 inhibited cell proliferation, cell migration, and cell invasion of LUAD in vitro. More importantly, we established the AL035458.2/hsa-miR-181a-5p axis as the most likely upstream ncRNA-related pathway of NCAPG2 in LUAD. In conclusion, our data demonstrated that ncRNA-mediated high expression of NCAPG2 was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for LUAD.

Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of lung adenocarcinoma (LUAD). LncRNA-AP000695.2 (ENSG00000248538) is a long non-coding RNA (lncRNA) that is widely increased in many tumor types including lung adenocarcinoma (LUAD). However, the aberrant expression profile, clinical significance, and biological function of AP000695.2 in human lung adenocarcinoma (LUAD) need to be further investigated. This study mines key prognostic AP000695.2 and elucidates its potential role and molecular mechanism in regulating the proliferation and metastasis of LUAD. Here, we discovered that AP000695.2 was significantly upregulated in lung adenocarcinoma tissues compared with healthy adjacent lung tissue and higher in LUAD cell lines than in normal human bronchial epithelial cell lines. A higher expression of AP000695.2 was positively correlated with aggressive clinicopathological characteristics, and AP000695.2 served as an independent prognostic indicator for the overall survival, disease-free survival, and progression-free survival in patients with LUAD. Receiver operating curve (ROC) analysis revealed the significant diagnostic ability of AP000695.2 (AUC = 0.838). Our in vivo data confirmed that AP000695.2 promotes the proliferation, migration, and invasion of LUAD cells. GSEA results suggested that AP000695.2 co-expressed genes were mainly enriched in immune-related biological processes such as JAK-STAT signaling pathway and toll-like receptor signaling pathway. Single-sample GSEA analysis showed that AP000695.2 is correlated with tumor-infiltrating immune cells in lung adenocarcinoma. Our findings confirmed that AP000695.2 was involved in the progression of lung adenocarcinoma, providing a novel prognostic indicator and promising diagnostic biomarker in the future.

LncRNA-AC02278.4 (ENSG00000248538) is a long non-coding RNA (lncRNA) found to be highly expressed in multiple human cancers including lung adenocarcinoma (LUAD). However, the underlying biological function and potential mechanisms of AC02278.4 driving the progression of LUAD remain unclear. In this study, we investigated the role of AC02278.4 in LUAD and found that AC02278.4 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of lncRNA-AC02278.4 was correlated with advanced clinical parameters. Receiver operating characteristic (ROC) curve analysis revealed the significant diagnostic ability of AC02278.4 [area under the ROC curve (AUC) = 0.882]. In addition, gene set enrichment analysis (GSEA) enrichment showed that AC02278.4 expression was correlated with immune response-related signaling pathways. Finally, we determined that AC02278.4 regulated cell proliferation and migration of LUAD in vitro. Our clinical sample results also confirmed that AC02278.4 was highly expressed in LUAD and correlated with adverse clinical outcomes. In conclusion, our data demonstrated that AC02278.4 was correlated with progression and immune infiltration and could serve as a prognostic biomarker for LUAD.

Gliomas account for 75% of all primary malignant brain tumors in adults and are associated with high mortality. Emerging evidence has demonstrated that baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) plays a critical role in cell apoptosis and the progression of diverse cancers. However, no studies have yet focused on the immunological function and mechanisms of upstream BIRC5 regulation in the progression of low-grade gliomas (LGG). Here, we evaluated BIRC5 expression and clinical characteristics in people with LGG using the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, Gene Expression Omnibus, Rembrandt, and Gravendeel databases. We used Kaplan–Meier statistics and receiver operating characteristic (ROC) curves to analyze the prognostic value of BIRC5 in LGG. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment terms were also explored to identify functional roles of BIRC5. The Tumor Immune Estimation Resource (TIMER) and Tumor Immune System Interaction (TISIDB) databases were used to examine the correlation between BIRC5 expression and immune cell infiltration in LGG. The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) databases were used to examine the potential drugs targeting BIRC5. We used transwell and wound healing assays to determine the biological functions of BIRC5 in glioma cell migration. Our results demonstrated that BIRC5 was highly expressed in LGG and the expression level correlated with tumor grade, prognosis, histological subtype, isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q chromosomal co-deletion, chemotherapy status, and O[6]-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. GO and KEGG analysis showed that BIRC5 is primarily involved in cell proliferation and immune response-related signaling pathways. We also found that BIRC5 was significantly correlated with m6A modification and diverse drug sensitivity. TIMER and TISIDB database analysis showed that BIRC5 expression is associated with infiltration of diverse immune cells and immune modulation in LGG. BIRC5 knockdown inhibited LGG cell migration. Collectively, our results demonstrate that BIRC5 is correlated with cell migration and immune infiltration in LGG and may be a useful prognostic biomarker.

BackgroundHyaluronan-mediated motility receptor (HMMR) plays a pivotal role in cell proliferation in various cancers, including lung cancer. However, its function and biological mechanism in lung adenocarcinoma (LUAD) remain unclear.MethodsData on HMMR expression from several public databases were extensively analyzed, including the prognosis of HMMR in the Gene Expression Profiling Interactive Analysis (GEPIA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using DAVID and gene set enrichment analysis (GSEA) software. The correlation between HMMR expression and immune cell infiltration was analyzed in the Tumor Immune Estimation Resource (TIMER) database, and the gene and protein networks were examined using the GeneMANIA and STRING databases. Experimentally, the expression of HMMR in LUAD and lung cancer cell lines was determined using immunohistochemistry and quantitative RT-PCR assays. Besides, the function of HMMR on cancer cell proliferation and migration was examined using cell growth curve and colony formation, Transwell, and wound healing assays.ResultsIn this study, we found that HMMR was elevated in LUAD and that its high expression was associated with poor clinicopathological features and adverse outcomes in LUAD patients. Furthermore, our results demonstrated that the expression of HMMR was positively correlated with immune cell infiltration and immune modulation. Interestingly, diverse immune cell infiltration affects the prognosis of LUAD. In the functional assay, depletion of HMMR significantly repressed the cancer cell growth and migration of LUAD. Mechanically, we found that that the DNA methylation/TMPO-AS1/let-7b-5p axis mediated the high expression of HMMR in LUAD. Depletion of TMPO-AS1 and overexpression of let-7b-5p could result in the decreased expression of HMMR in LUAD cells. Furthermore, we found that TMPO-AS1 was positively correlated with HMMR, yet negatively correlated with let-7b-5p expression in LUAD.ConclusionsOur findings elucidated that the DNA methylation/TMPO-AS1/let-7b-5p axis mediated the high expression of HMMR, which may be considered as a biomarker to predict prognosis in LUAD.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer, accounting for approximately 85% of pulmonary malignancies. Emerging evidence has demonstrated that ferroptosis plays a central role in both immunities as well as tumor proliferation. However, the clinical significance, immunological function, and upstream modulatory mechanism of ferroptosis-related genes in LUAD remain unclear. Here, we utilized various bioinformatics data to identify differentially expressed (DEGs) and prognosis-related ferroptosis (FRGs) genes in LUAD. Based upon identified DEGs, FRG, and ceRNA modulatory networks were constructed. Pearson’s correlation analysis was used to evaluate the correlation between FRGs and the tumor mutational burden, microsatellite instability, tumor-infiltrating immunity, cellular checkpoint control, and drug sensitivity in LUAD. A loss-of-function analysis was performed to verify the function of CISD1 in LUAD progression. Our findings revealed that certain FRGs (CISD1, ATP5MC3, PGD, SLC7A11, ACSL3, and FANCD2) are significantly upregulated in LUAD and that their elevated expression is associated with both advanced tumor stage and unfavorable prognosis. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results revealed these FRGs to be primarily involved in ferroptosis and glutathione metabolism in LUAD. We constructed a prognostic FRG-based model capable of accurately predicting LUAD patient overall survival with high specificity. The upstream lncRNA GSEC/miRNA-101-3p regulatory axis involving CISD1, ATP5MC3, and PGD was identified to be relevant in tumor progression. We also found GSEC, CISD1, ATP5MC3, and PGD to be upregulated, with miRNA-101-3p downregulated, in the setting of LUAD. Immunohistochemical analysis revealed CISD1, ATP5MC3, and PGD overexpression in LUAD tissue samples; CISD1 knockdown was noted to significantly inhibit LUAD proliferation and migration. In summary, this study characterizes relevant functional roles of the lncRNA GSEC/miR-101-3p axis in the setting of LUAD and suggests diagnostic and therapeutic biomarkers potentially useful in the clinical management of this illness.

A growing number of studies have focused on investigating microRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and immunological role of miR-125b-5p in non-small cell lung cancer (lung adenocarcinoma, LUAD) have not been determined. The present study aimed to examine the function of miR-125b-5p on cell proliferation and the outcomes of LUAD patients. We utilized diverse public databases in the analysis of the expression, prognosis, diagnostic value, and immune role of miR-125b-5p in non-small cell lung cancer. The growth curve, colony formation, flow cytometry, and Transwell and invasion assays were utilized to determine the function of miR-125b-5p in LUAD progression. In this study, we found that miR-125b-5p was decreased in LUAD and correlated with poor prognosis. Pathway analyses revealed that miR-125b-5p was mainly involved in cell proliferation and immune regulation. Moreover, in vitro experiments indicated that the overexpression of miR-125b-5p significantly inhibited cell proliferation, migration, and invasion and induced cell apoptosis of LUAD. Finally, we discovered that miR-125b-5p correlated with immune cell infiltration. In summary, these results demonstrated that miR-125b-5p serves as a prognostic marker and a therapeutic target for LUAD.

Platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) plays a critical role in cancer initiation, metastasis, and progression; however, it remains unknown how PAFAH1B3 impacts cancer diagnosis and prognosis or regulates the immune response to different types of cancer. In this study, PAFAH1B3 was elevated in human pan-cancer, and this correlated with greater pathology and poor prognosis, in particular for non-small cell lung cancer (NSCLC) and liver hepatocellular carcinoma (LIHC). In addition, PAFAH1B3 expression was positively associated with tumor mutational burden (TMB), microsatellite instability (MSI), immune cell infiltration, immune-modulatory related gene expression, and diverse cancer drug sensitivity in human cancer. Increased PAFAH1B3 expression correlated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of NSCLC and LIHC, and has potential as an independent risk factor for overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) during LIHC. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PAFAH1B3 is primarily involved in immune regulation. More importantly, results demonstrated that PAFAH1B3 was upregulated in liver cancer cells lines and that knockdown of this gene significantly inhibited cell proliferation, migration, and invasion in liver hepatocellular carcinoma (LIHC). In summary, this study elucidates the clinical significance and biological function of PAFAH1B3 during liver hepatocellular carcinoma (LIHC) and may serve as a potential biomarker for the diagnosis and prognosis of various cancer types.

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.

IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the Rho family of guanosine-5′-triphosphatases (GTPases). IQGAP3 plays a crucial part in the development and progression of several types of cancer. However, the prognostic, upstream-regulatory, and immunological roles of IQGAP3 in human cancer types are not known. We found that IQGAP3 expression was increased in different types of human cancer. The high expression of IQGAP3 was correlated with tumor stage, lymph node metastasis, and a poor prognosis in diverse types of human cancer. The DNA methylation of IQGAP3 was highly and negatively correlated with IQGAP3 expression in diverse cancer types. High DNA methylation in IQGAP3 was correlated with better overall survival in human cancer types. High mRNA expression of IQGAP3 was associated with tumor mutational burden, microsatellite instability, immune cell infiltration, and immune modulators. Analyses of signaling pathway enrichment showed that IQGAP3 was involved in the cell cycle. IQGAP3 expression was associated with sensitivity to a wide array of drugs in cancer cells lines. We revealed that polypyrimidine tract–binding protein 1 (PTBP1) and an IQGAP3-associated lncRNA (IQGAP3AR)/let-7c-5p axis were potential regulations for IQGAP3 expression. We provided the first evidence to show that an IQGAP3AR/let-7c-5p/IQGAP3 axis has indispensable roles in the progression and immune response in different types of human cancer.

BackgroundThe crucial roles played by lncRNA-AC068228.1 in primary malignant cancer remain poorly understood. This study aimed at examining the clinical significance and evaluating the biological function of AC068228.1 in lung adenocarcinoma (LUAD).MethodsWe used data obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Gene Expression Omnibus (GEO) database to examine the expression of AC068228.1 in LUAD patients, and the prognostic and diagnostic value of those levels. Functional experiments were conducted to determine the function of AC068228.1 on LUAD cells. Signaling pathway enrichment analysis of AC068228.1 was conducted using the clusterProfiler and Gene Set Enrichment Analysis (GSEA) software. We analyzed the correlation between AC068228.1 expression and immune infiltration level in LUAD using the single-sample gene set enrichment analysis (ssGSEA) method by the R package GSVA.ResultsAC068228.1 expression was significantly elevated in LUAD tissues compared with normal tissues. Higher expression of AC068228.1 was strongly correlated with adverse clinical outcomes and was identified as an independent prognostic marker for LUAD patients. GSEA and infiltration analysis confirmed that AC068228.1 expression was significantly correlated with immune cells infiltrating in LUAD. Knockdown of AC068228.1 inhibited the cell proliferation and cell migration of LUAD.ConclusionsAC068228.1 was upregulated in LUAD and was significantly correlated with adverse clinical outcomes. Meanwhile, it was associated with immune cell infiltration and could be used as a promising diagnostic and prognostic biomarker for LUAD patients.

BackgroundNon-SMC condensin I complex subunit G (NCAPG) is expressed in various human cancers, including gliomas. However, its biological function in glioma remains unclear. The present study was designed to determine the biological functions of NCAPG in glioma and to evaluate the association of NCAPG expression with glioma progression.MethodsClinical data on patients with glioma were obtained from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Gene Expression Omnibus (GEO), and the Rembrandt and Gravendeel databases. The correlations among NCAPG expression, pathological characteristics, and clinical outcome were evaluated. In addition, the correlations of NCAPG expression with immune cell infiltration and glioma progression were analyzed.ResultsNCAPG expression was higher in gliomas than in adjacent normal tissues. Higher expression of NCAPG in gliomas correlated with poorer prognosis, unfavorable histological features, absence of mutations in the isocitrate dehydrogenase gene (IDH), absence of chromosome 1p and 19q deletions, and responses to chemoradiotherapy. Univariate and multivariate Cox analysis demonstrated, in addition to patient age, tumor grade, absence of IDH mutations, and absence of chromosome 1p and 19q deletions, NCAPG expression was independently prognostic of overall survival, disease-free survival, and progression-free survival in patients with glioma. In addition, high expression of NCAPG correlated with tumor infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Gene set enrichment analysis (GSEA) indicated that high NCAPG expression was associated with cell proliferation and immune response-related signaling pathways. NCAPG knockdown in glioma cell lines significantly reduced cell survival, proliferation, and migration.ConclusionNCAPG expression correlates with glioma progression and immune cell infiltration, suggesting that NCAPG expression may be a useful prognostic biomarker for glioma.

MiRNA-30a-5p is a microRNA found to be decreased in various human cancers, including lung adenocarcinoma (LUAD). However, the molecular mechanisms of miRNA-30a-5p involve in the progression of LUAD remains unclear. In this study, we found that miRNA-30a-5p expression was significantly decreased in LUAD cells lines, LUAD tissues, and peripheral blood serum. Besides, LUAD patients with decreased miRNA-30a-5p expression exhibit worse clinical outcomes compared to the patients with higher miRNA-30a-5p expression, decreased expression of miRNA-30a-5p was associated with advanced clinical outcomes. Receiver operating characteristic (ROC) curve analysis of miRNA-30a-5p showed an area under the curve (AUC) value of 0.902, indicating its prognostic value in LUAD. Moreover, immune infiltration and gene set enrichment analysis (GSEA) enrichment analyze demonstrated that miRNA-30a-5p expression was associated with immune cell infiltrated in LUAD. Finally, we found that miRNA-30a-5p inhibits cell proliferation, migration, and self-renewal abilities of LUAD in vitro. In summary, this is the first report that miRNA-30a-5p correlated with progression and immune infiltration, which shed some lights on potential prognostic and therapeutic biomarker for LUAD.

Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region of RETSAT is highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16 in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future.

Growing evidence has demonstrated that UBE2C plays a critical role in cancer progression, but there is no study focusing on the prognosis, upstream regulation mechanism, and immunological roles of UBE2C across diverse tumor types. In this study, we found that UBE2C was elevated in this human pan-cancer analysis, and high expression of UBE2C was correlated with poor prognosis. In addition, UBE2C expression was markedly associated with tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and diverse drug sensitivities. Finally, we showed that the METTL3/SNHG1/miRNA-140-3p axis could potentially regulate UBE2C expression. N(6)-Methyladenosine (m6A) modifications improved the stability of methylated SNHG1 transcripts by decreasing the rate of RNA degradation, which lead to upregulation of SNHG1 in non-small cell lung cancer (NSCLC). In vitro functional experiments showed that SNHG1, as a competing endogenous RNA, sponges miR-140-3p to increase UBE2C expression in NSCLC cell lines. Our study elucidates the clinical importance and regulatory mechanism of the METTL3/SNHG1/miRNA-140-3p/UBE2C axis in NSCLC and provides a prognostic indicator, as well as a promising therapeutic target for patients with NSCLC.

Lung cancer is the most common tumor with severe morbidity and high mortality. Increasing evidence has demonstrated that SNX20 plays crucial roles in the progression of human cancer. However, the functions and mechanism of SNX20 in LUAD are still barely known. Here, we employ the TCGA, GEO and CCLE databases to examine the expression of SNX20 in human varies cancer, the results shown that SNX20 is down-regulated in lung Adenocarcinoma, SNX20 level was significantly positive correlated with poor prognosis and lung cancer immune cell infiltration. We found that over-expression of SNX20 significantly restrain NSCLC cell proliferation and migration. Subsequently, we discover a network regulating SNX20 in LUAD, further study found that the decreased of the SNX20 likely caused by DNA hypermethylation. Furthermore, we identified that SNX20AR/miRNA-301a-3p mediated decreased of SNX20 correlated with lung cancer progression and cancer immune infiltration in LUAD. Our findings suggested that ncRNAs play a crucial role in the regulatory network of SNX20. Collectively, our findings demonstrate the suppressor roles of the SNX20AR/miRNA-301a-3p/SNX20 axis in Lung Adenocarcinoma, represent that SNX20 have the potential of as an effective therapeutic target in future.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. LncRNA-AL139385.1 (ENSG00000275880) is a novel lncRNA that is abnormally expressed in various cancer types including LUAD. However, the underlying biological function and potential mechanisms of AL139385.1 driving the progression of LUAD remain unclear. In this study, we investigated the role of AL139385.1 in LUAD and found that DNA hypomethylation was positively correlated with AL139385.1 expression in LUAD. Moreover, we uncover that the expression of AL139385.1 in LUAD tissues was significantly higher than that of AL139385.1 expression in adjacent normal tissues. Kaplan-Meier survival analysis showed that patients with higher AL139385.1 expression correlated with adverse overall survival and progression-free survival. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) value of AL139385.1 was 0.808. Correlation analysis showed that AL139385.1 expression was associated with immune infiltration in LUAD. We also found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of AL139385.1 significantly inhibited cell proliferation and migration abilities of LUAD. Finally, we constructed a ceRNA network that includes hsa-miR-532-5p and four mRNAs (GALNT3, CYCS, EIF5A, and ITGB4) specific to AL139385.1 in LUAD. Subsequent Kaplan-Meier survival analysis suggested that polypeptide Nacetylgalactosaminyltransferase 3 (GALNT3), cytochrome c, somatic (CYCS), eukaryotic translation initiation factor 5A (EIF5A), and integrin subunit beta 4 (ITGB4), were potential prognostic biomarkers for patients with LUAD. In conclusion, this finding provides possible mechanisms underlying the abnormal upregulation of AL139385.1 as well as a comprehensive view of the AL139385.1-mediated competing endogenous RNAs (ceRNA) network in LUAD, thereby highlighting its potential role in diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Growing evidence has demonstrated that UBE2C plays a critical role in cancer progression, but there is no study focusing on the prognosis, upstream regulation mechanism, and immunological roles of UBE2C across diverse tumor types. In this study, we found that UBE2C was elevated in this human pan-cancer analysis, and high expression of UBE2C was correlated with poor prognosis. In addition, UBE2C expression was markedly associated with tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and diverse drug sensitivities. Finally, we showed that the METTL3/SNHG1/miRNA-140-3p axis could potentially regulate UBE2C expression. N(6)-Methyladenosine (m6A) modifications improved the stability of methylated SNHG1 transcripts by decreasing the rate of RNA degradation, which lead to upregulation of SNHG1 in non-small cell lung cancer (NSCLC). In vitro functional experiments showed that SNHG1, as a competing endogenous RNA, sponges miR-140-3p to increase UBE2C expression in NSCLC cell lines. Our study elucidates the clinical importance and regulatory mechanism of the METTL3/SNHG1/miRNA-140-3p/UBE2C axis in NSCLC and provides a prognostic indicator, as well as a promising therapeutic target for patients with NSCLC. [ABSTRACT FROM AUTHOR]

LncRNA-AC02278.4 (ENSG00000248538) is a long non-coding RNA (lncRNA) found to be highly expressed in multiple human cancers including lung adenocarcinoma (LUAD). However, the underlying biological function and potential mechanisms of AC02278.4 driving the progression of LUAD remain unclear. In this study, we investigated the role of AC02278.4 in LUAD and found that AC02278.4 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of lncRNAAC02278.4 was correlated with advanced clinical parameters. Receiver operating characteristic (ROC) curve analysis revealed the significant diagnostic ability of AC02278.4 [area under the ROC curve (AUC) = 0.882]. In addition, gene set enrichment analysis (GSEA) enrichment showed that AC02278.4 expression was correlated with immune response-related signaling pathways. Finally, we determined that AC02278.4 regulated cell proliferation and migration of LUAD in vitro. Our clinical sample results also confirmed that AC02278.4 was highly expressed in LUAD and correlated with adverse clinical outcomes. In conclusion, our data demonstrated that AC02278.4 was correlated with progression and immune infiltration and could serve as a prognostic biomarker for LUAD. [ABSTRACT FROM AUTHOR]