LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma.
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ABSTRACT:
SUBMITTER: Zhu J
PROVIDER: S-EPMC9281593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Excision repair cross‑complementation group 6 like (ERCC6L) has been reported to be upregulated in a variety of malignant tumors and plays a critical oncogenic role. However, the role and molecular mechanism of ERCC6L in lung adenocarcinoma (LUAD) remain unclear, and were therefore investigated in the present study. Clinical data of patients with LUAD were obtained and bioinformatics analysis was performed to investigate the expression characteristics, prognostic value, and biological function of ERCC6L. In addition, cell function experiments were performed to detect the effect of ERCC6L silencing on the biological behavior of LUAD cells. The results revealed that ERCC6L expression was significantly higher in LUAD tissues vs. normal lung tissues and closely associated with nodal invasion, advanced clinical stage and survival in LUAD. Overexpression of ERCC6L was an independent prognostic biomarker of overall survival, progression‑free interval, and disease‑specific survival in patients with LUAD. DNA amplification and low methylation levels of ERCC6L suggested regulation at both the genetic and epigenetic levels. The most significant positive genes co‑expressed with ERCC6L were mainly enriched in the cell cycle signaling pathway. The major functions of ERCC6L in LUAD cells were positively correlated with the cell cycle, DNA damage, DNA repair, proliferation, invasion and epithelial‑mesenchymal transition (EMT). Knockdown of ERCC6L inhibited the proliferative, migratory and invasive abilities of A549 and PC9 cells. It also promoted cell apoptosis, and led to cell cycle arrest in the S phase. ERCC6L may regulate the EMT process through the Wnt/β‑catenin and Wnt/Notch 3 signaling pathways, thus regulating the tumorigenesis and progression of LUAD. The overexpression of ERCC6L may be a biological indicator for the diagnosis and prognosis of LUAD. ERCC6L may be a novel molecular target for the treatment of lung cancer.
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Project description:Despite the progress achieved in the treatment of breast cancer, there are still many unsolved clinical issues, being the diagnosis, prognosis, and treatment of papillary diseases, one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the lesion, while others support an only expectant follow-up. Previous results of our group suggested that procollagen 11 alpha 1 (pro-COL11A1) expression correlates with infiltrating phenotype in breast lesions. We analyzed the correlation between expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Immunohistochemistry of pro-COL11A1 was performed in 62 samples of intraductal papilloma. Ten out 11 cases relapsed as carcinoma presents positive staining for COL11A1, while just 17 out of 51 cases with benign behaviour present immunostaining. There were significant differences (P < 0.0001) when comparing patients with malignant recurrence versus nonmalignant relapse patients. These data suggest that pro-COL11A1 expression is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma and it can be used as indicative factor for prevention programs.
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Project description:Long non-coding RNA (lncRNA) LINC00665 was demonstrated to be upregulated in lung adenocarcinoma (LUAD) and target miR-181c-5p. ZIC2, which is upregulated in LUAD, serves as a putative target of miR-181c-5p. In this study, we aimed to reveal whether LINC00665 regulates miR-181c-5p/ZIC2 axis to promote LUAD progression. The results showed that LINC00665, HOXA1, ZIC2, and HOXA11 levels were increased in LUAD tissues, while miR-181c-5p level was decreased when compared to the adjacent normal tissues. High expression levels of LINC00665, ZIC2, HOXA1 and HOXA11, and low expression of miR-181c-5p were closely linked to poor prognosis of LUAD patients. Knockdown of LINC00665 induced obvious inhibitions in cell viability, clone formation, invasion and tumorigenesis in LUAD cells, whereas miR-181c-5p downregulation significantly neutralized these effects. In addition, downregulation of ZIC2 obviously reversed the enhancements of cell viability, clone formation, invasion and tumorigenesis induced by miR-181c-5p knockdown. In summary, the present study reveals that silencing of LINC00665 suppresses LUAD progression through targeting miR-181c-5p/ZIC2 axis.
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Project description:BackgroundTumor-infiltrating immune cells participate in the initiation and progression of prostate adenocarcinoma (PRAD). However, it is not fully known how immune infiltration affects the development of PRAD and its clinical presentation.MethodsHerein, we investigated the immune infiltration phenotypes in PRAD based on transcriptome profiles, methylation profiles, somatic mutation, and copy number variations. We also developed an immune prognostic model (IPM) to identify unfavorable prognosis. To verify this model, immunohistochemistry staining was performed on a cohort of PRAD samples. Moreover, we constructed a nomogram to assess the survival of PRAD incorporating immune infiltration and other clinical features.ResultsWe categorized PRAD patients into high and low-level clusters based on immune infiltration phenotypes. The patients in the high-level clusters had worse survival than their low-level counterparts. Gene set enrichment analysis indicated that both anti- and pro-tumor terms were enriched in high-level cluster. Moreover, we identified a positive correlation between anti- and pro-tumor immune cells in PRAD microenvironment. Notably, Somatic mutation analysis showed patients in high-level cluster had a higher somatic mutation burden of KMT2D, HSPA8, CHD7, and MAP1A. In addition, we developed an IPM with robust predictive ability. The model can distinguish high-risk PRAD patients with poor prognosis from low-risk PRAD patients in both training and another three independent validation datasets. Besides, we constructed a nomogram incorporating Gleason score, pathological T stage, and IPM for the prognosis prediction of PRAD patients, which displayed robust predictive ability and might contribute to clinical practice.ConclusionOur work illustrated the immune infiltration phenotypes strongly related to the poor prognosis of PRAD patients, and highlighted the potential of the IPM to identify unfavorable tumor features.
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Project description:Retinoblastoma (RB) is the most common pediatric intraocular malignancy and is a serious vision- and life-threatening disease. The biallelic mutation of the retinoblastoma gene RB1 is the initial event in the malignant transformation of RB, but the exact molecular mechanism is still unclear. E2F transcription factors can be activated by RB1 loss of function and lead to uncontrolled cell division. Among E2F family numbers, E2F1 has higher expression abundance than E2F2 and E2F3 in RB clinical samples. By integrating E2F1 ChIP-seq data, RNA-seq profiling from RB samples and RNA-seq profiling upon E2F1 knockdown, together with pathway analysis, literature searching and experimental validation, we identified Cyclin-dependent kinases regulatory subunit 2 (CKS2) as a novel regulator in regulating tumor-associated phenotypes in RB. CKS2 exhibited aberrantly higher expression in RB. Depletion of CKS2 in Y79 retinoblastoma cell line led to reduced cell proliferation, delayed DNA replication and decreased clonogenic growth. Downregulation of CKS2 also slowed tumor xenograft growth in nude mice. Importantly, reversed expression of CKS2 rescued cancer-associated phenotypes. Mechanistically, transcription factor E2F1 enhanced CKS2 expression through binding to its promoter and CKS2 regulated the cancer-associated PI3K-AKT pathway. This study discovered E2F1/CKS2/PTEN signaling axis regulates malignant phenotypes in pediatric retinoblastoma, and CKS2 may serve as a potential therapeutic target for this disease.
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Project description:GREB1L is a protein-coding gene that is an important paralog of GREB1. However, its effects in lung adenocarcinoma (LUAD) have not been determined. Thus, we evaluated the prognostic value of GREB1L in LUAD using bioinformatics approaches. In particular, we evaluated the relationship between GREB1L and LUAD using a wide range of databases and analysis tools, including TCGA, GEO, HPA, TIMER, cBioPortal, and MethSurv. Compared with its expression in normal lung tissues, GREB1L expression was significantly increased in LUAD tissues. A univariate Cox analysis showed that high GREB1L expression levels were correlated with a poor OS in LUAD. Additionally, GREB1L expression was independently associated with OS through a multivariate Cox analysis. GSEA analysis revealed enrichment in cell cycle, immune regulation, and methylation. Moreover, high GREB1L expression was associated with poor survival. We also found that the methylation and genetic alteration level was associated with prognosis in patients with LUAD. Finally, an analysis of immune infiltration showed that GREB1L is correlated with immune cell infiltration, PD-1, and PD-L1. In summary, these results indicate that GREB1L is a potential molecular marker for poor prognosis in LUAD and provide additional insight for the development of therapies and prognostic markers.
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Project description:Colon adenocarcinoma (COAD) is the most common pathologic type of colon cancer. Metastasis is responsible for the high mortality rate of patients with COAD. The gene, metastasis-associated in colon cancer 1 (MACC1), is a biomarker predictive of both metastatic and metastasis-free survival in patients with colon cancer and other solid tumors. However, the underlying mechanism by which MACC1 affect COAD progression and metastasis remains unknown. In this study, we analyzed the expression level and prognostic value of MACC1, as well as their correlation, in patients with various types of cancer included in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. High MACC1 expression was found to be significantly associated with poor prognosis in patients with COAD. Analysis of the potential upstream miRNA of MACC1 showed that miR-642a-5p was downregulated in COAD and was negatively correlated with MACC1 expression. Analysis of the upstream regulators of miR-642a-5p showed that the long non-coding RNA (lncRNA) ZFAS1was the most likely upstream regulator of miR-642a-5p. In addition, the expression of MACC1 correlated positively with tumor immune cell infiltration, as well as with the levels of biomarkers of five kinds of immune cells. In summary, these findings suggest that MACC1 contributes to COAD progression and immune cell infiltration via the ZFAS1/miR-642a-5p/MACC1 axis.
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Project description:BackgroundThymocyte selection-associated high mobility group box (TOX) plays a crucial role on the development of innate immunity and tumor microenvironment. This study aims to explore the prognostic potential of TOX and comprehensively analyze the correlations between TOX, immune infiltration, and T cells function in diverse cancers particularly lung adenocarcinoma (LUAD).MethodsTIMER was used to analyze TOX expression in different cancers. Potential prognostic value of TOX was evaluated by the PrognoScan, Kaplan-Meier Plotter, and GEPIA2. The relationships between TOX, immune infiltration, and related gene marker sets were analyzed by TIMER and GEPIA2. Single-cell RNA-seq for T cells in LUAD was analyzed to further investigate the correlations between TOX expression and different T cells populations.ResultsTOX downregulates in most of the cancer types and correlates with poor prognosis in LUAD. TOX shows significant impacts on survival of LUAD with early stage, ever-smoking, or low-TMB status. Increased TOX expression positively correlates with high immune infiltration levels in most of the immune cells and functional T cells including exhausted T cells. Moreover, multiple key genes of exhausted T cells comprising PD-1, TIM-3, TIGHT, and CXCL13 have remarkable interaction with TOX. Specifically, TOX is observed with high enrichment in exhausted CD4+ and CD8+ T cells populations in single-cell RNA-seq analysis for LUAD.ConclusionTOX is a prognosis-related biomarker for multiple cancer types especially LUAD. Increased TOX expression significantly increase immune infiltration levels in most of the immune cells comprising CD8+ T cells, CD4+ T cells, mast cells, and functional T cells. Moreover, we verified that TOX highly correlates with exhausted T cells and is probable a critical regulator promoted T cells exhaustion in LUAD. Detection of TOX expression could help to predict prognosis and regulating TOX expression in exhausted T cells may offer a novel strategy in maximizing immunotherapy efficacy for LUAD.
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Project description:The amino propeptide of collagen α1(XI) (NPP) has been shown to bind glycosaminoglycans and to form a dimer. While these are independent biochemical events, it is likely that dimerization facilitates the interaction with glycosaminoglycans or alternatively, that glycosaminoglycan interaction facilitates the formation of an NPP:NPP dimer. The computer program MODELLER was used to generate a homology model of the collagen α1(XI) NPP monomer using the crystal structure of the closely related noncollagenous-4 (NC4) domain of collagen α1(IX) (PDB:2UUR) as the template. Additionally, a dimer model of collagen α1(XI) NPP domain was created based upon the thrombospondin dimer template (PDB:1Z78). The structure of the dimer created in MODELLER was validated by comparison to a dimer model generated by docking two monomers of PDB:2UUR using ClusPro. Calculations of relative binding energy for the interaction between each collagen α1(XI) NPP model and glycosaminoglycans as ligands was performed using AutoDock4. Computational results support a higher affinity between heparan sulfate and a dimer compared to a monomer. These findings are supported by affinity chromatography experiments in which distinct monomer and dimer peaks were observed. Sequential point mutation studies of the putative binding site (147-KKKITK-152) indicated the importance of the basic lysine residue for binding to heparan sulfate. Two orders of magnitude change in binding affinity was predicted when comparing wild type to the mutation K152A. Experimental data supports the predicted change in affinity.
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Project description:The family with sequence similarity 83, member D (FAM83D) gene is upregulated in hepatocellular carcinoma and ovarian cancer, and its overexpression has been reported to positively correlate with tumor progression. However, the clinical significance and biological function of FAM83D in lung adenocarcinoma has not been investigated. We determined the expression profile and clinical significance of FAM83D using The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) analysis. Considerable upregulation of FAM83D was observed in LUAD tissues compared with adjacent normal tissues, and its overexpression was significantly associated with more advanced clinicopathological characteristics. Importantly, multivariate Cox regression analysis indicated that a high level of FAM83D expression was an independent risk factor for worse overall survival in LUAD patients (HR = 1.692, P = 0.006). Inhibition of FAM83D suppressed the proliferation of LUAD cells via G1 phase arrest by downregulating cyclin D1 (CCND1) and cyclin E1 (CCNE1). The oncogenic role of FAM83D was also confirmed in vivo. In conclusion, our study demonstrated that FAM83D might exert its oncogenic activity in LUAD by regulating cell cycle, and that it could serve as a novel biomarker and a potential therapeutic target for LUAD.
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