YBX1 Promotes Esophageal Squamous Cell Carcinoma Progression via m5C­Dependent SMOX mRNA Stabilization.

The modification and recognition of 5-methylcytosine (m5C) are involved in the initiation and progression of various tumor types. However, the precise role and potential mechanism of Y-box-binding protein 1 (YBX1) in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, it is found that YBX1 is frequently upregulated in ESCC compared with matched nontumor tissues. Gain- and loss-of-function assays show that YBX1 promoted the proliferation and metastasis of ESCC cells both in vitro and in vivo. Functional studies revealed that NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a critical RNA methyltransferase that facilitates YBX1-mediated ESCC progression. Mechanistically, integrated analysis based on RNA immunoprecipitation sequencing (RIP-seq) and m5C methylated RNA immunoprecipitation and sequencing (MeRIP-seq) assays identified spermine oxidase (SMOX) as a target gene containing an m5C site in its coding sequence (CDS) region, which coincided well with the binding site of YBX1. Overexpression of SMOX-WT but not SMOX-Mut partially restored the proliferation and invasion ability of ESCC cells curbed by YBX1 knockdown. Moreover, YBX1 activated the mTORC1 signaling pathway by stabilizing SMOX mRNA. The study reveals that YBX1 promotes ESCC development by stabilizing SMOX mRNA in an m5C-dependent manner, thus providing a valuable therapeutic target for ESCC.

Wnt/ß-catenin-driven EMT regulation in human cancers.

Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/ß-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3ß that destructs ß-catenin, while ligand-receptor interaction impairs GSK-3ß function to increase ß-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/ß-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance ß-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/ß-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/ß-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

The pan-cancer landscape of glutamate and glutamine metabolism: A comprehensive bioinformatic analysis across 32 solid cancer types.

Glutamine metabolism is a hallmark of cancer metabolism, which matters in the progression of the tumor. This synthetic study conducted a large-scale systematic analysis at the pan-cancer level on the glutamate and glutamine metabolism (GGM) across 32 solid tumors from the TCGA database. The glutamine metabolism activity was quantified through a scoring system. This study revealed that the GGM score in tumor tissues was up-regulated in 13 cancer types (BCLA, BRCA, COAD, KICH, KIRP, LUAD, LUSC, PAAD, PRAD, READ, STAD, THYM, UCEC) and down-regulated in 4 cancer types (CHOL, GBM, LIHC, THCA), exhibiting tissue specificity. The mRNA expression levels of glutamine metabolism-related genes were relatively high, and GLUL exhibited the highest expression level. The expression levels were up-regulated with copy number amplification. ALDH18A1, PYCR1, and PYCR2 show a significant upregulation in protein levels in cancer tissues compared to normal tissues, making them potential pan-cancer therapeutic targets. For the TME related to glutamine metabolism, the GGM score exhibited significant immune and stromal environment inhibitory effects in all involved tumors. Up-regulated GGM score indicated the widespread promotion of drug resistance at the pan-cancer level. GGM score and glutamine metabolism-related genes signature tended to be risk factors for the overall survival of cancer patients.

The role of N6-methyladenosine methylation in PAHs-induced cancers.

Polycyclic aromatic hydrocarbons (PAHs), which are a wide range of environmental toxicants, may act on humans through inhalation, ingestion, and skin contact, resulting in a range of toxic reactions. Epidemiological studies showed that long-term exposure to PAHs in the occupational and living environment results in a substantial rise in the incidence rate of many cancers in the population, so the prevention and treatment of these diseases have become a major worldwide public health problem. N6-methyladenosine (m6A) modification greatly affects the metabolism of RNA and is implicated in the etiopathogenesis of many kinds of diseases. In addition, m6A-binding proteins have an important role in disease development. The abnormal expression of these can cause the malignant proliferation, migration, invasion, and metastasis of cancers. Furthermore, a growing number of studies revealed that environmental toxicants are one of the cancer risk factors and are related to m6A modifications. Exposure to environmental toxicants can alter the methylation level of m6A and the expression of the m6A-binding protein, thus promoting the occurrence and development of cancers through diverse mechanisms. m6A may serve as a biomarker for early environmental exposure. Through the study of m6A, we can find the health injury early, thus providing a new sight for preventing and curing environmental health-related diseases.

Lipid metabolism as a target for cancer drug resistance: progress and prospects.

Cancer is the world's leading cause of human death today, and the treatment process of cancer is highly complex. Chemotherapy and targeted therapy are commonly used in cancer treatment, and the emergence of drug resistance is a significant problem in cancer treatment. Therefore, the mechanism of drug resistance during cancer treatment has become a hot issue in current research. A series of studies have found that lipid metabolism is closely related to cancer drug resistance. This paper details the changes of lipid metabolism in drug resistance and how lipid metabolism affects drug resistance. More importantly, most studies have reported that combination therapy may lead to changes in lipid-related metabolic pathways, which may reverse the development of cancer drug resistance and enhance or rescue the sensitivity to therapeutic drugs. This paper summarizes the progress of drug design targeting lipid metabolism in improving drug resistance, and providing new ideas and strategies for future tumor treatment. Therefore, this paper reviews the issues of combining medications with lipid metabolism and drug resistance.

NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer.

NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.

Norepinephrine inhibits CD8+ T-cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma.

BACKGROUND: Mental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies. METHODS: In this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine's (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/ß-catenin signalling pathway plays a crucial role in this progression. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

The Role of Alternative Splicing Factors hnRNP G and Fox-2 in the Progression and Prognosis of Esophageal Cancer.

Aim: Alternative splicing (AS) has been widely demonstrated in the occurrence and progression of many cancers. Nevertheless, the involvement of cancer-associated splicing factors in the development of esophageal carcinoma (ESCA) remains to be explored. Method: RNA-Seq data and the corresponding clinical information of the ESCA cohort were downloaded from The Cancer Genome Atlas database. Bioinformatics methods were used to further analyzed the differently expressed AS (DEAS) events and their splicing network. Kaplan-Meier, Cox regression, and unsupervised cluster analyses were used to assess the association between AS events and clinical characteristics of ESCA patients. The splicing factors screened out were verified in vitro at the cellular level. Results: A total of 50,342 AS events were identified, of which 3,988 were DEAS events and 46 of these were associated with overall survival (OS) of ESCA patients, with a 5-year OS rate of 0.941. By constructing a network of AS events with survival-related splicing factors, the AS factors related to prognosis can be further identified. In vitro experiments and database analysis confirmed that the high expression of hnRNP G in ESCA is related to the high invasion ability of ESCA cells and the poor prognosis of ESCA patients. In contrast, the low expression of fox-2 in esophageal cancer is related to a better prognosis. Conclusion: ESCA-associated AS factors hnRNP G and Fox-2 are of great value in deciphering the underlying mechanisms of AS in ESCA and providing clues for therapeutic goals for further validation.

Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

Transcriptome sequencing and metabolome analysis reveal the mechanism of Shuanghua Baihe Tablet in the treatment of oral mucositis.

Oral mucositis (OM) caused by cancer therapy is the most common adverse reaction in the radiotherapy of head and neck tumors. In severe cases, it can lead to the interruption of treatment, which affects the control of the disease and the quality of life. Shuanghua Baihe Tablet (SBT) is a traditional Chinese medicine (TCM) formula, which is administerd to treat OM in China. It has been clinically effective for more than 30 years, but the underlying mechanism is not completely understood. With the development of multiple omics, it is possible to explore the mechanism of Chinese herbal compound prescriptions. Based on transcriptomics and metabolomics, we explored the underlying mechanism of SBT in the treatment of OM. An OM model of rats was established by 5-FU induction, and SBT was orally administered at dosages of 0.75 and 3 g·kg-1·d-1. In order to search for SBT targets and related metabolites, the dysregulated genes and metabolites were detected by transcriptomics and metabolomics. Immune related indicators such as interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Treg cell disorders was analyzed by flow cytometry. Our results showed that SBT significantly alleviated the symptoms of OM rats and the inflammatory infiltration of ulcer tissues. After SBT administration, inflammatory related metabolic pathways including linoleic acid metabolism, valine, leucine and isoleucine biosynthesis were significantly altered. Furthermore, the production of proinflammatory factors like IL-17 and TNF-α, were also dramatically reduced after SBT administration. Besides, the infiltration degree of Treg cells in the spleen of OM modeling rats was significantly improved by SBT administration, thus maintaining the immune balance of the body. The current study demonstrates that SBT regulates inoleic acid metabolism, glycerophospholipid metabolism and amino acid metabolism, and inhibits IL-17/TNF signal transduction to restore Treg and Th17 cell homeostasis in OM rats, thereby alleviating chemotherapy-induced OM.

Precise medication for tumor patients in the context of mental stress.

Cancer is the leading cause of disease-related death worldwide due to its late diagnosis and poor outcomes. Precision medicine plays an important role in the treatment of tumors. As found for many types of tumors, mental stress plays a vital role in the promotion and progression of tumors. In this paper, we briefly introduce the manifestation and effects of mental symptoms in tumor patients. We next specifically discuss the multiple roles of precision medicine in the tumor therapy. Finally, we also highlight the precision medicine strategy for psychiatric symptoms in tumor patients, which promises to enhance the efficacy of tumor therapy.

Comprehensive Analysis of the Prognostic Value and Immune Infiltrates of the Three-m5C Signature in Colon Carcinoma.

BACKGROUND: The 5-methylcytosine (m5C) is one of the important forms of RNA post modification, and its regulatory mechanism in tumors has received increasing attention. However, its potential role in colorectal cancer remains unclear. MATERIALS AND METHODS: Here, we systematically investigated the genetic variation and prognostic value of the 14 m5c RNA methylation regulators in colon cancer. The prognostic risk score was constructed using three m5C regulators, which was verified in the GSE17536 (N=177), GSE41258 (N=248) and GSE38832 (N=122) datasets. RESULTS: The risk score developed from the three-m5C signature represents an independent prognostic factor, which can accurately predict the prognosis of patients with colon cancer in multiple datasets. The cytokine-cytokine receptor interaction and chemokine signaling pathway were significantly enriched in the low-risk score group. Further analysis showed that the three-m5C signature was related to tumor immune microenvironment (TIME), affecting the abundance of tumor-infiltrating immune cells. Especially, patients with low risk score had higher immune score than those with high risk score. In addition, gene set enrichment analysis (GSEA) confirmed that all three regulatory factors are associated with the MAPK/p38 signaling pathway. CONCLUSION: In conclusion, our study illustrates that the three-m5C signature may be involved in the regulation of colon cancer immune microenvironment in synergy with the MAPK signaling pathway. Therefore, further studying the three-m5C signature regulatory mechanisms might provide promising targets for improving the responsiveness of colon cancer to immunotherapy.

Molecular mechanism study of HGF/c-MET pathway activation and immune regulation for a tumor diagnosis model.

BACKGROUND: Hepatocyte growth factor (HGF) binds to the c-mesenchymal-epithelial transition (C-MET) receptor and activates downstream signaling pathways, playing an essential role in the development of various cancers. Given the role of this signaling pathway, the primary therapeutic direction focuses on identifying and designing HGF inhibitors, antagonists and other molecules to block the binding of HGF to C-MET, thereby limiting the abnormal state of other downstream genes. METHODS: This study focuses on the analysis of immune-related genes and corresponding immune functions that are significantly associated with the HGF/c-MET pathway using transcriptome data from 11 solid tumors. RESULTS: We systematically analyzed 11 different cancers, including expression correlation, immune infiltration, tumor diagnosis and survival prognosis from HGF/c-MET pathway and immune regulation, two biological mechanisms having received extensive attention in cancer analysis. CONCLUSION: We found that the HGF/c-MET pathway affected the tumor microenvironment mainly by interfering with expression levels of other genes. Immune infiltration is another critical factor involved in changes to the tumor microenvironment. The downstream immune-related genes activated by the HGF/c-MET pathway regulate immune-related pathways, which in turn affect the degree of infiltration of immune cells. Immune infiltration is significantly associated with cancer development and prognosis.

Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma.

The nuclear receptor-binding SET domain (NSD) protein family encoding histone lysine methyltransferases is involved in cancer progression. However, the role of NSDs in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we examined the expression of NSDs in cisplatin-resistant and parental ESCC cells and revealed the upregulation of NSD2 in cisplatin-resistant cells. Ectopic expression of NSD2 increased cisplatin resistance and attenuated cisplatin-induced apoptosis. Colony formation assay indicated that NSD2 overexpression enhanced long-term survival of ESCC cells after treatment with cisplatin. In contrast, knockdown of NSD2 inhibited ESCC cell proliferation and sensitized ESCC cells to cisplatin. Depletion of NSD2 augmented the cytotoxic effect of cisplatin on EC109 xenograft tumors. NSD2 stimulated long non-coding RNA MACC1-AS1 in ESCC cells. Knockdown of MACC1-AS1 impaired NSD2-induced cisplatin resistance. Moreover, MACC1-AS1 overexpression promoted ESCC cell proliferation and cisplatin resistance. Clinically, MACC1-AS1 was upregulated in ESCC relative to adjacent noncancerous tissues. High MACC1-AS1 levels were significantly associated with reduced overall survival of ESCC patients. There was a positive correlation between MACC1-AS1 and NSD2 expression in ESCC specimens. Taken together, MACC1-AS1 induced by NSD2 mediates resistance to cisplatin in ESCC and may represent a novel target to improve cisplatin-based chemotherapy.

Involvement of long non-coding RNAs in the progression of esophageal cancer.

Esophageal cancer (EC) is one of the most common malignant tumors of the digestive system with high incidence and mortality rate worldwide. Therefore, exploring the pathogenesis of EC and searching for new targeted therapies are the current research hotspot for EC treatment. Long non-coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides, but without protein-coding function. In recent years, lncRNAs have gradually become the focuses in the field of non-coding RNA. Some lncRNAs have been proved to be closely related to the pathogenesis of EC. Many lncRNAs are abnormally expressed in EC and participate in many biological processes including cell proliferation, apoptosis, and metastasis by inhibiting or promoting target gene expression. LncRNAs can also regulate the progression of EC through epithelial-mesenchymal transformation (EMT), which is closely related to the occurrence, development, and prognosis of EC. In this article, we review and discuss the involvement of lncRNAs in the progression of EC.

Identification of candidate genes encoding tumor-specific neoantigens in early- and late-stage colon adenocarcinoma.

Colon adenocarcinoma (COAD) is one of the most common gastrointestinal malignant tumors and is characterized by a high mortality rate. Here, we integrated whole-exome and RNA sequencing data from The Cancer Genome Atlas and investigated the mutational spectra of COAD-overexpressed genes to define clinically relevant diagnostic/prognostic signatures and to unmask functional relationships with both tumor-infiltrating immune cells and regulatory miRNAs. We identified 24 recurrently mutated genes (frequency > 5%) encoding putative COAD-specific neoantigens. Five of them (NEB, DNAH2, ABCA12, CENPF and CELSR1) had not been previously reported as COAD biomarkers. Through machine learning-based feature selection, four early-stage-related (COL11A1, TG, SOX9, and DNAH2) and four late-stage-related (COL11A1, SOX9, TG and BRCA2) candidate neoantigen-encoding genes were selected as diagnostic signatures. They respectively showed 100% and 97% accuracy in predicting early- and late-stage patients, and an 8-gene signature had excellent prognostic performance predicting disease-free survival (DFS) in COAD patients. We also found significant correlations between the 24 candidate neoantigen genes and the abundance and/or activation status of 22 tumor-infiltrating immune cell types and 56 regulatory miRNAs. Our novel neoantigen-based signatures may improve diagnostic and prognostic accuracy and help design targeted immunotherapies for COAD treatment.

Over-Expression and Prognostic Significance of FN1, Correlating With Immune Infiltrates in Thyroid Cancer.

BACKGROUND: Thyroid cancer (THCA) is a malignancy affecting the endocrine system, which currently has no effective treatment due to a limited number of suitable drugs and prognostic markers. METHODS: Three Gene Expression Omnibus (GEO) datasets were selected to identify differentially expressed genes (DEGs) between THCA and normal thyroid samples using GEO2R tools of National Center for Biotechnology Information. We identified hub gene FN1 using functional enrichment and protein-protein interaction network analyses. Subsequently, we evaluated the importance of gene expression on clinical prognosis using The Cancer Genome Atlas (TCGA) database and GEO datasets. MEXPRESS was used to investigate the correlation between gene expression and DNA methylation; the correlations between FN1 and cancer immune infiltrates were investigated using CIBERSORT. In addition, we assessed the effect of silencing FN1 expression, using an in vitro cellular model of THCA. Immunohistochemical(IHC) was used to elevate the correlation between CD276 and FN1. RESULTS: FN1 expression was highly correlated with progression-free survival and moderately to strongly correlated with the infiltration levels of M2 macrophages and resting memory CD4+ T cells, as well as with CD276 expression. We suggest promoter hypermethylation as the mechanism underlying the observed changes in FN1 expression, as 20 CpG sites in 507 THCA cases in TCGA database showed a negative correlation with FN1 expression. In addition, silencing FN1 expression suppressed clonogenicity, motility, invasiveness, and the expression of CD276 in vitro. The correlation between FN1 and CD276 was further confirmed by immunohistochemical. CONCLUSION: Our findings show that FN1 expression levels correlate with prognosis and immune infiltration levels in THCA, suggesting that FN1 expression be used as an immunity-related biomarker and therapeutic target in THCA.

Over-Expression and Prognostic Significance of FATP5, as a New Biomarker, in Colorectal Carcinoma.

Background: Fatty acid transporters (FATPs) family play an important role in the uptake and metabolism regulation of long-chain fatty acids, which influence the occurrence and developing of multiple tumors. Fatty acid transporter 5(FATP5), a member of FATPs family, participates in fatty acid transport and lipid metabolism and is related to tumor development, whose mechanism in colorectal cancer (CRC) remains unclear. Methods: In this study, we comprehensively utilized a range of relevant bioinformatic tools along with multiple databases to analyze the expression of FATPs family and investigate the biological function and prognostic value of FATP5 in CRC. Besides, cell proliferation and cell cycle distribution analysis, western blotting and immunohistochemistry (IHC) further validated the conclusion of bioinformatics analysis. Results: FATP5 is the only member of FATPs family which was overexpressed in CRC. In the survival analysis based on the GSE39582 databases, the low expression of FATP5 predicts poor prognosis in CRC. Similar results were also observed in GSE17536, GSE28814 and TCGA colon cohorts. The potential function of DNA methylation regulated the abnormal expression of FATP5 in CRC. In addition, enrichment analysis indicated that FATP5 also participates in the regulation of cell cycle. Furthermore, Gene Set Enrichment Analysis (GSEA) showed a strong negative correlation between FATP5 and cell growth, implying that it may participate in regulating cancer cell proliferation by the regulation of cell cycle G2/M transition. At last, we identified that FATP5 was overexpressed in colorectal carcinoma tissues through immunohistochemistry staining, and played an important role in cell cycle by cell proliferation and cell cycle distribution analysis. Conclusion: This study suggested that FATP5 was overexpression in colorectal carcinoma and predicted favorable prognosis, indicating it as a novel appealing prognostic marker for CRC.