Comprehensive Analysis of Immune Infiltrates of Ferroptosis-Related Long Noncoding RNA and Prediction of Colon Cancer Patient Prognoses
Wen-Zheng ChenYafei ChenLi LiuYukang WuPengcheng FuYi CaoJianbo XiongYi TuZhengrong LiYi LiuZhigang Jie
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Abstract:
Ferroptosis is a newly defined mode of programmed oxidative cell death. Knowledge of ferroptosis-related long noncoding (lnc) RNA in the tumor immune microenvironment of colon cancer is lacking. We systematically analyzed the correlations between ferroptosis-related lncRNAs and the tumor microenvironment, immune cell infiltration, and patient prognosis for 379 colon cancer samples in the Cancer Genome Atlas (TCGA). Using consensus clustering, we divided the 379 colon cancer patients into two subgroups (clusters 1 and 2) based on the differentially expressed ferroptosis-related lncRNAs. Cluster 1 was preferentially associated with longer overall survival, upregulated immune checkpoint inhibitor expressions, higher immunoscores, higher stromal scores, higher estimated scores, and distinct immune cell infiltration. Cancer- and metabolism-related pathways were enriched by gene set enrichment analyses. We constructed a prognostic signature of 15 ferroptosis-related lncRNAs (ZEB1-AS1, LINC01011, AC005261.3, LINC01063, LINC02381, ELFN1-AS1, AC009283.1, LINC02361, AC105219.1, AC002310.1, AL590483.1, MIR4435-2HG, NKILA, AC021054.1, and AL450326.1) and divided the patients into the high- and low-risk-score groups. The signature was validated using TCGA training and testing cohorts. The risk signature was an independent prognostic factor for predicting survival and excellently predicted the prognoses of patients with colon cancer. Moreover, the risk signature was related to immune characteristics. Chemosensitivity analyses showed that low-risk-score patients were more sensitive to sorafenib. In summary, our work revealed the important role of ferroptosis-related lncRNAs in the tumor microenvironment and immune cell infiltration and may help determine personalized prognoses and treatment for patients with colon cancer.Keywords:
Gene signature
Stromal-epithelial cell interaction is very important for the development of human benign prostatic hyperplasia (BPH). Growth factors and their receptors in the prostate are thought to mediate the cell communication and play some roles in the development of BPH. Among many growth factors, fibroblast growth factor (FGF) family members have received the most intensive study, and mRNAs for acidic FGF (aFGF), basic FGF (bFGF) and keratinocyte growth factor (KGF) have been identified in rat or human prostate. However, synthesis sites and roles of them in stromal-epithelial cell interaction remain to be undefined. In the present study, to define the mechanisms for the regulation of prostatic cell growth by stromal cells in human BPH, we established the method for isolation and culture of epithelial cells as well as stromal cells from human BPH tissue. Using these primary cultured prostatic cells, we evaluated the effects of stromal cell conditioned medium (SCM) and stromal cell extract (SCE) on the growth of stromal cells and epithelial cells by [3H]-thymidine incorporation assay. We also examined the expression of mRNAs for aFGF, bFGF, KGF, FGF receptor 1 (FGFR1) and FGFR2 in epithelial and stromal cells using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) analysis. As the results, both SCM and SCE stimulated the growth of stromal cells, and the growth promoting effects of them to stromal cells were completely suppressed by anti-bFGF neutralizing antibody, but not by anti-aFGF neutralizing antibody at all. SCM also stimulated the growth of epithelial cells. The growth promoting effect of it to epithelial cells was not completely suppressed by anti-bFGF neutralizing antibody, and not by anti-aFGF neutralizing antibody at all. Furthermore, RT-PCR analysis demonstrated the expression of mRNAs for bFGF, KGF and FGFR1 in stromal cells and that of FGFR2 in epithelial cells. These findings suggest that bFGF produced by stromal cells acts on stromal cells through FGFR1 by an autocrine mechanism, KGF produced by stromal cells acts on epithelial cells through FGFR2 by a paracrine manner in human BPH. These mechanisms for the regulation of cell growth by stromal cells were thought to contribute to the development of human BPH.
Keratinocyte growth factor
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To explore the biological effect of prostate peripheral zones (PZs) stromal cells on the proliferation of prostate cells by overexpression of LMO2 gene.Genes expressional distinction of different prostate stromal cells was screened by gene expression arrays. To validate the microarray data, real time-polymerase chain reaction (RT-PCR), Western blotting analysis were used to check the over expression of LMO2 in PZs cells.To compare the effect of stromal cells which overexpressed LMO2 gene on in vitro proliferation ability of BPH-1 and PC3 cell lines, cell proliferation was measured by CCK-8 and EdU assay. Cytokines chip was used to screen expression of cytokines in WPMY-1-LMO2 conditioned medium. The changes of BPH-1 and PC3 proliferation associated proteins were assessed by Western blotting.A total of 512 genes were identified as markedly differentially expressed in stromal cells originated from different zones. Among these genes, LMO2 gene was overexpression in peripheral zones stromal cells, and confirmed by RT-PCR and Western blotting. Expression level of LMO2 gene was significantly up-regulated in peripheral zones stromal cells compared with transitional zones stromal cells, increased by 3.36 folds on average (P<0.01). The proliferation of both PC3 and BPH-1 were found increased and STAT3 phosphorylation and CCND1 expression were increased after cultured in conditioned medium from stromal cells which stably expressed LMO2. Cytokines chip found increased FGF-9 and IL-11 expression in the medium supernatant reserved from LMO2-overexpressed stromal cell line.Distinct gene expression exists among prostate stromal cells originated from different zones. LMO2 overexpressed stromal cells can induce prostate epithelial cell growth via paracrine of FGF-9, IL-11 or other cytokines.
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Bladder cancer (BLCA) has become one of the most common malignant tumors in the genitourinary system. BLCA is one of the tumors considered suitable for immunotherapy because of the large proportion of immune cells in TME. Epithelial to mesenchymal transition (EMT) is closely related to tumor immunity through its crosstalk with immune cells. A recent study validated that EMT-related genes were mainly expressed by stromal cells and could influence immunotherapy responsiveness. Stromal EMT-related gene signature was also demonstrated to affect the prognosis of multiple tumors, including BLCA. To further explore the prognostic roles of stromal components, we performed a comprehensive analysis of LncRNAs closely associated with stromal EMT-related genes in the TCGA BLCA cohort. We identified a signature including five stromal EMT gene-related LncRNAs that showed significant prognostic value for BLCA patients. By the CIBERSORT and MCP-COUNTER algorithm, we found the signature was markedly correlated with infiltrated immune cells and stromal components of the tumor microenvironment, which may further influence patient’s responsiveness to immune checkpoint blockade therapy. Through immunohistochemical analysis, we confirmed the correlation of the signature with macrophages M2 and CAFs. Meanwhile, key genes related to these LncRNAs, including VIM, MMP2, were also differentially expressed in the stromal components concerning the signature. Our research confirmed the prognostic and immune-associated role of stromal EMT-related LncRNAs. Meantime, we further confirmed that EMT-related genes were mainly expressed in stromal components. Targeting these LncRNAs as well as their related stromal EMT genes may provide potential therapeutic targets for BLCA immunotherapy and precision medicine.
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Objective To detect the expression and role of PTTG mRNA in human colorectal cancer.Methods The expression of PTTG mRNA was evaluated in 12 normal colorectal tissues,20 colorectal adenoma tissues and 44 colorectal cancer tissues by RT-PCR.Results The expression of PTTG mRNA in colorectal cancer was significantly higher than that in colorectal adenoma and normal colorectal tissues.The PTTG mRNA expression in the Dukes C,D colorectal cancer was higher than that in the Dukes A,B cancer(P0.05).The expression in the colorectal cancer with lymph node metastasis was higher than that in the cancer without lymph node metastasis(P0.05).Conclusion The expression of PTTG mRNA increases in colorectal cancer,and is related with cell differentiation and metastasis.The abnormal expression of PTTG probably participates in genesis and development of colorectal cancers.
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Abstract Purpose There has been a resurgence of interest in the tumor stroma in recent years. Whether the relative abundance of various stromal cells can be used as a classification system for muscle-invasive bladder cancer (MIBC) remain elusive.Methods We applied single-cell RNA-sequence (scRNA-seq) data from two MIBCs to identify stromal cell (CD45 negative cells) clusters and the marker gene set of each cell cluster. The single sample gene set enrichment analysis method is used to estimate the relative abundance of the cell clusters in each MIBC sample from The Cancer Genome Atlas. Subsequently, k-means clustering was performed to cluster the MIBCs. Prognosis, oncogenic pathway enrichment score, epithelial-mesenchymal transition (EMT) score, gene mutation frequency, and tumor infiltrating lymphocytes (TILs) were compared among the stromal component-based types of MIBC.ResultsIn the scRNA-seq analysis, a total of nine cell clusters mainly composed of four types of cells were identified. Cell clusters 0, 1, 2, 3, 4, and 7 were considered as bladder epithelial cells, the cells in clusters 5 and 8 were mainly recognized as stem cells and fibroblasts, and the cell cluster 6 was recognized were endothelial cells. The 408 MIBC samples were classified into three types. Type 1 and 3, the “stromal-sufficient” type I and II with higher stromal cells, and Type 2, the “stromal-desert” type with lower stromal cells. The stromal-desert type had significantly better overall survival. As the tumor progresses, the stromal component of the stromal-desert type increases and change into the stromal-sufficient type. Increased stromal cells may come from EMT. The enrichment scores of multiple oncogenic pathways in stromal-sufficient types were significantly higher than those in stromal-desert type. More TILs were found in stromal-sufficient type, but their function may be inhibited by stromal cells. In addition, the three stromal types of MIBC may have specific gene mutation characteristics.Conclusions We proposed a novel stromal component-based classification system to divided into MIBC three phenotype. The three types of MIBC differ in various biological characteristics. The progress of MIBC may be summarized as the process of gradually increasing stromal components and constructing a microenvironment suitable for cancer cells.
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Prostatic carcinoma (PCa) derives from prostatic epithelial cells. However stromal microenvironment, associated with malignant epithelium, also plays a role in prostatic carcinogenesis. Alterations in prostatic stromal cells contribute to the loss of growth control in epithelial cells that lead to progression of PCa.To analyse the differences between Androgen Receptor (AR) expression in both epithelial and stromal cells in PCa and the surrounding benign prostatic hyperplasia (BPH) and to compare the results with tumour grade.Samples from 70 cases of radical prostatectomy specimens were used. The expression and intensity of the signal for AR was analysed in the epithelial and stromal cells of PCa and BPH, and the data was quantified using histological score (H-score).AR showed significantly lower expression in both epithelial and stromal cells of PCa compared to BPH. In PCa a significant positive correlation of AR expression was found between stromal and epithelial cells of PCa. AR expression showed a correlation between the stromal cells of PCa and tumour grade.AR expression is reduced in epithelial and stromal cells of PCa. Expression of AR in stromal cells of PCa significantly correlates with tumour grade.
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Bone marrow stromal cells have well documented effects on the production of B lymphocytes, but whether or not stromal cell signals are involved in the pre-B to B cell transition is unclear. The potential of two stromal cell lines, S10 and S17, in this process was examined. Initial experiments, using a short term liquid culture, indicated that S10 and S17 stroma efficiently supported the generation of clonable B cells (B lymphocyte CFU) from their immediate precursors in fresh bone marrow. The contribution of macrophages and other accessory cells in those experiments was minimized through use of a colony assay system that permits the direct effects of stromal cell signals on single B cell progenitors to be evaluated. The results indicated that soluble mediators from the S10 and S17 lines could support colony formation from fresh or cultured surface Ig- bone marrow cells. Colonies supported by S17 stroma appeared on day 15 and contained cells that expressed the B220 Ag; surface IgM expression was never observed. S10 supported colonies appeared on day 7 and routinely included surface IgM+ cells. Individual colonies were capable of undergoing additional growth when picked and replated directly onto the different stroma. Those colonies replated onto S10 stroma generated surface IgM expressing cells in up to 60% of experiments, but colonies transferred onto the S17 cell line included B cells only 10% of the time. These data demonstrate that stromal cells alone can provide the signals necessary for generating a surface IgM+ B cell from precursors but that not all stromal cell lines are equally efficient at doing so.
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The effects of in vitro irradiation on proliferation and hematopoietic supportive functions of stromal cells were studied. To assess the effects of radiation on stromal cells proliferation, marrow cells were exposed to a single dose of gamma radiation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that stromal cell proliferation was significantly suppressed after radiation in a dose-dependent manner. Stromal layers obtained from irradiated marrow cells failed to establish adherent layers after 6, 8, or 10 Gy of radiation. To assess the functions of stromal cells that survived radiation, stromal layers derived from irradiated marrow cells were cocultured with freshly isolated autologous hematopoietic cells and assayed for their capacity to support prolonged granulocyte-macrophage progenitors (CFU-GM) production. Stromal layers derived from 2-Gy-irradiated marrow cells resulted in similar CFU-GM production as control cells, while stromal layers derived from 4- to 10-Gy-irradiated marrow cells significantly decreased CFU-GM production. To study the influence of radiation on hematopoietic supportive capacity in established stromal layers, stromal layers generated from non-irradiated marrow cells were irradiated and cocultured with freshly isolated autologous hematopoietic cells. Established stromal layers irradiated up to 10 Gy sustained prolonged CFU-GM production, suggesting that hematopoietic stromal supportive functions remained intact at this dose of radiation. In conclusion, our results indicated that proliferation of stromal cells and bone-marrow stromal layer formation from stromal cells are sensitive to radiation in vitro, while established bone-marrow stromal layer originating from stromal cells is relatively resistant to radiation. Data generated may have implications in future bone-marrow transplantation research.
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