Erratum: Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/ß-catenin signaling: Erratum.

[This corrects the article DOI: 10.7150/thno.30726.].

The potential therapeutic value and application prospect of engineered exosomes in human diseases.

Exosomes are tiny vesicles produced by a wide range of cells that contain complex RNA and protein. In the diagnosis, treatment, and prevention of illness, they offer great potential. In vitro engineering technique modifies exosomes to produce designed exosomes that include nucleic acids, proteins, and medicines, and are targeted to particular tissues or cells. Their applications range from tumor imaging and gene therapy to vaccine production and regenerative medicine to targeted medication delivery. Many disciplines have promising futures for using this technology. In this review, we'll look at the potential therapeutic usefulness and use of engineered exosomes in a variety of human illnesses with various systemic manifestations.

GTPBP4: A New Therapeutic Target Gene Promotes Tumor Progression in Non-Small Cell Lung Cancer via EMT.

Lung cancer has a complex etiology involving multiple regulatory systems. Uncertainty about the biology and evolution of lung cancer has made it difficult to improve its poor prognosis. To create efficient therapeutic targets and optimal molecular screening tools for lung cancer, the most important task seems to be to understand how it develops and progresses. The expression and regulation of GTPBP4 in non-small cell lung cancer (NSCLC) are not well understood. Using methods such as knocking down GTPBP4 in lung cancer cells and establishing a mouse lung cancer model, we found that the expression of GTPBP4 was upregulated in human lung adenocarcinoma cells and tissues, and that knocking down the expression of the GTPBP4 gene in A549 and Calu-1 lung adenocarcinoma cells can inhibit the proliferation of lung adenocarcinoma cells and reduce their invasion ability. The results of the mouse lung cancer model showed that the lung weight and the number of lung surface nodules decreased significantly in the LLC-GTPBP4 KO group. The mechanism by which GTPBP4 regulation affects the progression of lung adenocarcinoma may be related to the regulation of EMT. From this study, new research ideas emerge to explore GTPBP4 as a biomarker and therapeutic target for early diagnosis and treatment of lung cancer.

Immune cell-lipoprotein imbalance as a marker for early diagnosis of non-small cell lung cancer metastasis.

The underlying molecular mechanisms and evolutionary patterns of lung cancer metastasis remain unclear, resulting in a lack of effective indicators for early diagnosis of metastasis. We retrospectively analyzed 117 patients with primary non-small cell lung cancer (NSCLC) admitted to Tongji Hospital of Tongji University in 2021, of which 93 patients with tumor metastasis were set as the metastasis group. 24 patients without metastasis were set as the non-metastasis group. The differences of each index in the two groups of patients and the expression levels in different TNM stages were compared. This study intends to evaluate the diagnostic value and net clinical benefit of common blood-related indicators Neutrophil/lymphocyte (NLR), lymphocyte/monocyte (LMR), High density lipoprotein/neutrophil (HNR), High density lipoprotein/monocyte (HMR) and combined assays in NSCLC metastasis for the early diagnosis of patients with NSCLC metastasis. It was found that the level of NLR was higher in metastatic NSCLC than non-metastatic, but the level of LMR, HNR and HMR was lower. The levels of NLR, LMR, HNR and HMR in patients with different TNM stages showed that NLR levels increased with TNM stage, while LMR, HNR and HMR levels decreased. The threshold probability range of the 4 combined tests was greater and the overall clinical benefit rate was higher compared to the individual tests. Our findings suggest that NLR, LMR, HNR and HMR have better diagnostic value for NSCLC metastasis. This study provides a clinical basis for investigating the mechanisms by which immune cells and lipid metabolism-related proteins remodel the microenvironment prior to NSCLC metastasis.

The Function and Molecular Mechanism of Commensal Microbiome in Promoting Malignant Progression of Lung Cancer.

The human commensal microbiome existing in an internal environment is relatively consistent with that of the host. The presence of bacterial dysbiosis, on the other hand, promptly results in the termination of this symbiotic association. The altered microbial structure in the lung may be responsible for the development of lung cancer by controlling the host's inflammatory response and influencing a variety of immunological pathways. More and more studies have pointed to the fact that the commensal microbiota plays a vital role in both the development of tumors and the body's response to lung cancer treatment. Microbiome dysbiosis, genotoxicity, virulence effect, and epigenetic dysregulations are some of the potential mechanisms that may lie behind the process of tumorigenesis that is mediated by microbiome. Other potential mechanisms include regulating host immune activity through a variety of pathogenic factors, dysregulating host metabolism as a result of microbiome alterations, and microbiome dysbiosis. In this historical overview, we go through some of the more recent mechanistic discoveries into the biological processes that are involved in lung cancer that are caused by bacteria. Without a question, obtaining a greater knowledge of the dynamic link between the lung microbiome and lung cancer has the potential to inspire the development of innovative early detection and customized treatment methods for lung cancer.

Immune Infiltration of Ulcerative Colitis and Detection of the m6A Subtype.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by persistent colon inflammation. N6-methyladenosine (m6A) methylation is one of the most prevalent RNA modifications with key roles in both normal and illness, but m6A methylation in ulcerative colitis is unknown. This research investigated m6A methylation in UC. We examined the expression of known m6A RNA methylation regulators in UC using the Gene Expression Omnibus database (GEO database). First, we used m6A regulators to examine m6A change in UC samples. These two patient groups were created by clustering three m6A gene expression datasets. These genes were then utilized to build an m6A gene network using WGCNA and PPI. These networks were built using differentially expressed genes. The 12 m6A regulators were found to be dispersed throughout the chromosome. The study's data were then connected, revealing positive or negative relationships between genes or signaling pathways. Then, PCA of the 12 m6A-regulated genes indicated that the two patient groups could be discriminated in both PC1 and PC2 dimensions. The ssGSEA algorithm found that immune invading cells could be easily distinguished across diverse patient groups. Both groups had varied levels of popular cytokines. The differential gene analysis of the two samples yielded 517 genes like FTO and RFX7. It found 9 hub genes among 121 genes in the blue module, compared their expression in two groups of samples, and found that the differences in expression of these 9 genes were highly significant. The identification of 9 possible m6A methylation-dependent gene regulatory networks suggests that m6A methylation is involved in UC pathogenesis. Nine candidate genes have been identified as possible markers for assessing UC severity and developing innovative UC targeted therapeutic approaches.

NCOA4: An Immunomodulation-Related Prognostic Biomarker in Colon Adenocarcinoma and Pan-Cancer.

Treatment of cancer in humans requires a thorough understanding of the multiple pathways by which it develops. Recent studies suggest that nuclear receptor coactivator 4 (NCOA4) may be a predictive biomarker for renal cancer. In the present work, TCGA, GEPIA, and several bioinformatics approaches were used to analyze the NCOA4 expression patterns, prognostic relevance, and association between NCOA4 and clinicopathological features and immune cell infiltration. We investigated NCOA4 expression in malignancies. Low NCOA4 expression was associated with poor overall survival in individuals with malignancies such as cholangiocarcinoma, colon adenocarcinoma, and clear cell renal carcinoma. We also analyzed NCOA4 DNA methylation in normal and primary tumor tissues and investigated possible functional pathways underlying NCOA4-mediated oncogenesis. In conclusion, downregulation of NCOA4 is associated with poor prognosis, and NCOA4 may be a predictive biomarker for COAD.

Tumor Microenvironment: Lactic Acid Promotes Tumor Development.

Lactic acid is a "metabolic waste" product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells' effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.

PLAC8 Overexpression Promotes Lung Cancer Cell Growth via Wnt/ß-Catenin Signaling.

The PLAC8 expression in lung cancer tissues and in vitro grown lung cancer cells, as well as the involvement of the Wnt/ß-Catenin signaling pathway, was investigated in this process. PLAC8 protein expression in human lung cancer tissues and lung tumor cells of different strains was discovered using immunohistochemistry staining and Western blot, respectively. Animal models of PLAC8 overexpression and knockdown were created using lentivirus. The development in tumor tissue was seen both in vitro and vivo. The Wnt/ß-Catenin signaling pathway played an important part in this process, as shown by the dual luciferase reporter gene system. PLAC8 expression was elevated in lung cancer tissues and plasma and decreased in plasma after lung tumor resection. PLAC8 upregulation promotes cell proliferation in vivo and in vitro, while PLAC8 downregulation inhibits cell viability and proliferation. The results of the dual luciferase reporter gene system suggest that PLAC8 can significantly activate the Wnt/ß-Catenin signaling pathway in cells and can conduct signaling through it. A potential treatment targeting the prognosis of lung cancer patients may be PLAC8 overexpression, which promotes the lung cancer cell proliferation through controlling the Wnt/ß-Catenin signaling pathway.

Neuropeptide Y in the amygdala contributes to neuropathic pain-like behaviors in rats via the neuropeptide Y receptor type 2/mitogen-activated protein kinase axis.

Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems, which has been implicated in nociceptive signaling in neuropathic pain. However, downstream mechanistic actions remain uncharacterized. In this study, we sought to investigate the mechanism of NPY and its receptor NPY2R in the amygdala in rats with neuropathic pain-like behaviors induced by chronic constriction injury (CCI) of the sciatic nerve. The expression of NPY and NPY2R was found to be aberrantly up-regulated in neuropathic pain-related microarray dataset. Further, NPY was found to act on NPY2R in the basolateral amygdala (BLA). As reflected by the decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) as well as the increase of NPY expression in the amygdala of rats with neuropathic pain-like behaviors, NPY was closely related to the effect of amygdala nerve activity in neuropathic pain. Subsequently, mechanistic investigations indicated that NPY2R activated the MAPK signaling pathway in the amygdala. NPY2R-induced decrease of MWT and TWL were also restored in the presence of MAPK signaling pathway antagonist. Moreover, it was revealed that NPY2R overexpression promoted the viability while inhibiting the apoptosis of microglia. Taken together, NPY in the amygdala interacts with NPY2R to activate the MAPK signaling pathway, thereby promoting the occurrence of neuropathic pain.

Corrigendum: Immune cell-lipoprotein imbalance as a marker for early diagnosis of non-small cell lung cancer metastasis.

[This corrects the article DOI: 10.3389/fonc.2022.942964.].

Proteomics-Based Identification of Candidate Exosomal Glycoprotein Biomarkers and Their Value for Diagnosing Colorectal Cancer.

Early diagnosis and treatment of colorectal cancer (CRC) significantly improves the survival rate and quality of life. Here we screened for differences in glycoproteins associated with tumor-derived exosomes and validated their clinical value to serve as liquid biopsy biomarkers to diagnosed early CRC. Exosomes were extracted from paracancerous tissues, cancer tissues, and plasma. LC-MS/MS proteomic and glycoproteomics analyses were performed using an LTQ-Orbitrap Elite mass spectrometer. The differences in glycoproteins associated with exosomes of paracancerous tissues and cancer tissue were determined, and their levels in plasma exosomes were determined. Statistical analysis was performed to evaluate the diagnostic efficacy of exosome-associated glycoproteins for CRC. We found that the levels of fibrinogen beta chain (FGB) and beta-2-glycoprotein 1 (ß2-GP1) in the exosome of CRC tissue were significantly higher compared with those of paracancerous tissues exosome. The areas under the receiver operating characteristic (ROC) curves of plasma exosomal FGB and ß2-GP1 as biomarkers for CRC were 0.871 (95% CI = 0.786-0.914) and 0.834 (95% CI = 0.734-0.901), respectively, compared with those of the concentrations of carcinoembryonic antigen concentration [0.723 (95% CI = 0.679-0.853)] and carbohydrate antigen19-9 concentration [0.614 (95% CI = 0.543-0.715)]. Comprehensive proteomics analyses of plasma exosomal biomarkers in CRC identified biomarkers with significant diagnostic efficacy for early CRC, which can be measured using relatively non-invasive techniques.

Retinoic Acid-Induced Gene G(RIG-G) as a Novel Monitoring Biomarker in Leukemia and Its Clinical Applications.

Retinoic acid inducible gene G (RIG-G) is an inducible gene produced during the treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA). However, it is unclear the expression level of RIG-G gene in the peripheral blood of healthy subjects and patients with acute promyelocytic leukemia (APL or AML-M3). In the present study, we established the TaqMan-MGB fluorescent probe qPCR (real-time polymerase chain reaction) method for the first time to detect the expression of RIG-G gene in APL. Twenty APL patients were selected, and their RIG-G expression levels were quantified to assess the correlation between the expression of peripheral blood and bone marrow samples. U test was used to analyze the expression level of RIG-G in the peripheral blood of 40 normal specimens and 20 APL patients to observe the prognostic monitoring effect of RIG-G gene in the ATRA treatment process. ROC (receiver operating characteristic curve) was used to analyze and test the diagnostic efficiency of RIG-G gene for APL patients. There is a strong positive correlation between the expression of RIG-G in peripheral blood and bone marrow of APL patients. The expression level of RIG-G in peripheral blood of APL patients is significantly lower than that in healthy controls (p < 0.001). The changes in the expression level of RIG-G in peripheral blood changed indicates the remission and recurrence of APL patients after ATRA treatment, and the ROC curve shows that it has a better diagnostic power for APL. In summary, the TaqMan-MGB real-time PCR method we have established has successfully run. The detection of RIG-G gene expression in peripheral blood can effectively monitor the disease changes of APL patients and avoid harmful bone marrow puncture injury.

Association of laboratory parameters and genetic polymorphisms with ischemic stroke in Chinese Han population.

Numerous genetic polymorphisms and clinical laboratory parameters are associated with ischemic stroke (IS). However, the results of such studies have frequently been inconsistent. The aim of the present study was to evaluate associations between clinical laboratory parameters with genetic polymorphisms that influence the risk of IS in a Chinese Han population. Clinical laboratory parameters were measured by an automatic biochemical analyzer. Genotype and allele frequencies of the polymorphisms angiotensin-converting enzyme (ACE) D/I, methylene tetrahydrofolate reductase (MTHFR) C677T and ß-fibrinogen (ß-Fg) A/G, 455/148T/C were characterized by restriction fragment length polymorphism-PCR. Furthermore, the gene polymorphisms plasminogen activator inhibitor (PAI)-1-4G/5G and apolipoprotein E (ApoE) ε2,3,4 were characterized by allele-specific PCR. The associations of genotype and allele frequencies of the six risk genes in different groups with clinical laboratory parameters were analyzed by chi-square tests. The distribution maps of the polymorphisms of the six genes and clinical laboratory parameters were compared between a control group of 336 healthy individuals and 762 patients with IS. Certain laboratory parameters were associated with ACE I/D, ß-Fg-455 A/G and PAI-1 4G/5G. The D allele of ACE I/D was associated with high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C). Furthermore, high levels of fasting blood glucose, triglyceride and LDL-C were risk factors for IS. There were significant differences in the genotype frequencies of ACE I/D, ß-Fg-455 A/G and ß-Fg-148 T/C between the IS and the control group. In conclusion, clinical laboratory parameters were associated with the risk of polymorphisms of IS-related genes. The present results support the determination of a range of control values of clinical laboratory parameters for common genotypes in patients with diabetes and hyperlipidemia as a strategy for the early prevention of IS.

Correction to: Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils.

An amendment to this paper has been published and can be accessed via the original article.

PLAC8 inhibits oral squamous cell carcinogenesis and epithelial-mesenchymal transition via the Wnt/ß-catenin and PI3K/Akt/GSK3ß signaling pathways.

Placenta-specific 8 (PLAC8) is closely associated with the proliferation, apoptosis and autophagy of several tumor cells. However, the expression and function of PLAC8 in oral squamous cell carcinoma (OSCC) remain unknown. Therefore, the present study investigated the function and mechanism of PLAC8 in OSCC. Reverse transcription-quantitative PCR and western blot analyses were performed to quantify the expression of PLAC8 in OSCC cell lines. The function of PLAC8 in OSCC was investigated via transfection, the Transwell and Cell Counting Kit-8 assays, immunofluorescence staining and western blotting. The results demonstrated that PLAC8 exspression was downregulated in OSCC cell lines. PLAC8 inhibited the cell proliferation in OSCC. In addition, PLAC8 restrained invasion and epithelial-mesenchymal transition of OSCC cells. Furthermore, ß-catenin helped to repress PLAC8 expression by regulating the Wnt/ß-catenin and PI3K/Akt/GSK3ß signaling pathways in OSCC cells. Collectively, the results of the present study suggest that PLAC8 acts as a tumor suppressor in OSCC by downregulating ß-catenin.

A nomogram from the SEER database for predicting the prognosis of patients with non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to establish and validate a nomogram to predict the prognosis in patients with non-small cell lung cancer (NSCLC) from multiple perspectives. RESULTS: A total of 98,640 eligible patients were randomly divided into a training set (n = 69,048) and a validation set (n = 29,592). The baseline characteristics of the two sets were similar. We used clinical data from patients in the training set for univariate and multivariate Cox regression analyses. Twelve independent risk factors were incorporated for constructed a prognostic nomogram. And the nomogram with a concordance index of 0.777 (95 % CI, 0.775 to 0.779) for overall survival. The calibration curve results showed that the actual survival rate was consistent with the predicted survival rate. The area under curve of the receiver operating characteristic curves demonstrated that the nomogram has a high prediction of the overall survival rate in patients with NSCLC. CONCLUSION: We have developed a nomogram with high prediction accuracy and discrimination ability, which can help clinicians making personalized survival predictions for NSCLC patients.

Novel evidence for retinoic acid-induced G (Rig-G) as a tumor suppressor by activating p53 signaling pathway in lung cancer.

Lung cancer is one of most common malignancies worldwide. We have previously identified retinoic acid-induced gene G (Rig-G) as a tumor suppressor in not only acute promyelocytic leukemia, but also in other solid tumors. However, the clinical significance of Rig-G and the underlying mechanism(s) for its biological function in lung cancer remain largely unexplored. Herein, we first compared the expression of Rig-G between lung cancer (n = 138) and normal tissues (n = 23), from public-available data sets and our patient cohort. We further analyzed the correlation of Rig-G expression with key clinico-pathological features and survival outcomes in a multi-site clinical cohort of 300 lung cancer patients. Functional studies for Rig-G were performed in cell lines, and an animal model to support clinical findings. We found that Rig-G was frequently downregulated in lung cancer tissues and cell lines, and correlated with poor prognosis in lung cancer patients. Overexpression of Rig-G led to significantly reduced cell growth and suppressed migration in A549 and NCI-H1944 cells, accompanied by reduced epithelial-mesenchymal transition. Likewise, restoration of Rig-G in Lewis lung carcinoma cells permitted development of fewer cancer metastases versus controls in an animal model. Gene expression profiling results identified p53 pathway as a key downstream target of Rig-G, and p53 inhibition by pifithrin-α caused abrogation of tumor-suppressive effects of Rig-G in lung cancer. In conclusion, we, for the first time, have identified Rig-G as a novel and important tumor suppressor, which may serve as a potential therapeutic target for restoring p53 expression in lung cancer patients.

Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-ß1 axis.

BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear. METHODS: CRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils. RESULTS: Our study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-ß1 (TGF-ß1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-ß1 axis. CONCLUSION: Our study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.