Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis.

Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.

Association between postoperative radiotherapy for young-onset nonsmall cell lung cancer and risk of second primary malignancies: comparative study.

BACKGROUND: The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young­onset NSCLC in early stage. METHODS: The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. RESULTS: Among the 30 308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55). CONCLUSION: PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

Detoxification and Activating Blood Circulation Decoction Promotes Reendothelialization of Damaged Blood Vessels via VEGF Signaling Pathway Activation by miRNA-126.

The occurrence of in-stent restenosis (ISR) poses a significant challenge for percutaneous coronary intervention (PCI). Thus, the promotion of vascular reendothelialization is essential to inhibit endothelial proliferation. In this study, we clarified the mechanism by which Detoxification and Activating Blood Circulation Decoction (DABCD) promotes vascular reendothelialization to avoid ISR by miRNA-126-mediated modulation of the vascular endothelial growth factor (VEGF) signaling pathway. A rat model of post-PCI restenosis was established by balloon injury. The injured aortic segment was collected 14 and 28 d after model establishment. Our findings indicate that on the 14th and 28th days following balloon injury, DABCD reduced intimal hyperplasia and inflammation and promoted vascular reendothelialization. Additionally, DABCD markedly increased nitric oxide (NO) expression and significantly decreased ET-1 production in rat serum. DABCD also increased the mRNA level of endothelial nitric oxide synthase (eNOS) and the protein expression of VEGF, p-Akt, and p-extracellular signal-regulated kinase (ERK)1/2 in vascular tissue. Unexpectedly, the expression of miR-126a-5p mRNA was significantly lower in the aortic tissue of balloon-injured rats than in the aortic tissue of control rats, and higher miR-126a-5p levels were observed in the DABCD groups. The results of this study indicated that the vascular reendothelialization effect of DABCD on arterial intimal injury is associated with the inhibition of neointimal formation and the enhancement of vascular endothelial activity. More specifically, the effects of DABCD were mediated, at least in part, through miR-126-mediated VEGF signaling pathway activation.

[Corrigendum] MicroRNA­222­3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with an unfavorable prognosis of patients with renal cell carcinoma.

Following the publication of the above article, an interested reader drew to the attention of the Editorial Office that, in Fig. 3A on p. 530, two pairs of data panels were overlapping, such that certain of the panels appeared to have been derived from the same original sources where the results from differently performed experiments were intended to have been portrayed. The authors have examined their original data, and realize that errors associated with data handling/labelling during the preparation of the representative images in Fig. 3A had occurred. The revised version of Fig. 3, showing the correct data for the 'NC/ACHN/Invasion and Migration' data panels, the 'Inhibitor NC/786­O' panel and the 'Inhibitor NC/ACHN/Invasion' panel, is shown on the next page. The authors can confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for giving them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 525­534, 2019; DOI: 10.3892/ijmm.2018.3931].

Physiological and transcriptomic responses of seawater halobios to micro/nano-scale polystyrene-cadmium exposure in a marine food web.

Micro/nano-plastics (MPs/NPs) represent an emerging contaminant, posing a significant threat to oceanic halobios. While the adverse effects of joint pollutants on marine organisms are well-documented, the potential biological impacts on the food chain transmission resulting from combinations of MPs/NPs and heavy metals (HMs) remain largely unexplored. This study exposed the microbial loop to combined contaminants (MPs/NPs + HMs) for 48h, bacteria and contaminants are washed away before feeding to the traditional food chain, employing microscopic observation, biochemical detection, and transcriptome analysis to elucidate the toxicological mechanisms of the top predator. The findings revealed that MPs/NPs combined with Cd2+ could traverse both the microbial loop and classical food chain. Acute exposure significantly affected the carbon biomass of the top predator Tigriopus japonicus (75.8% lower). Elevated antioxidant enzyme activity led to lipid peroxidation, manifesting in increased malondialdehyde levels. Transcriptome sequencing showed substantial differential gene expression levels in T. japonicus under various treatments. The upregulation of genes associated with apoptosis and inflammatory responses, highlighting the impact of co-exposure on oxidative damage and necroptosis within cells. Notably, NPs-Cd exhibited stronger toxicity than MPs-Cd. NPs-Cd led to a greater decrease in the biomass of top predators, accompanied by lower activities of GSH, SOD, CAT, and GSH-PX, resulting in increased production of lipid peroxidation product MDA and higher oxidative stress levels. This investigation provides novel insights into the potential threats of MPs/NPs combined with Cd2+ on the microbial loop across traditional food chain, contributing to a more comprehensive assessment of the ecological risks associated with micro/nano-plastics and heavy metals.

Machine Learning-Based Integration Develops a Macrophage-Related Index for Predicting Prognosis and Immunotherapy Response in Lung Adenocarcinoma.

BACKGROUND: Macrophages play a critical role in tumor immune microenvironment (TIME) formation and cancer progression in lung adenocarcinoma (LUAD). However, few studies have comprehensively and systematically described the characteristics of macrophages in LUAD. METHODS: This study identified macrophage-related markers with single-cell RNA sequencing data from the GSE189487 dataset. An integrative machine learning-based procedure based on 10 algorithms was developed to construct a macrophage-related index (MRI) in The Cancer Genome Atlas (TCGA), GSE30219, GSE31210, and GSE72094 datasets. Several algorithms were used to evaluate the associations of MRI with TIME and immunotherapy-related biomarkers. The role of MRI in predicting the immunotherapy response was evaluated with the GSE91061 dataset. RESULTS: The optimal MRI constructed by the combination of the Lasso algorithm and plsRCox was an independent risk factor in LUAD and showed a stable and powerful performance in predicting the overall survival rate of patients with LUAD. Those with low MRI scores had a higher TIME score, a higher level of immune cells, a higher immunophenoscore, and a lower Tumor Immune Dysfunction and Exclusion (TIDE) score, indicating a better response to immunotherapy. The IC50 value of common drugs for chemotherapy and target therapy with low MRI scores was higher compared to high MRI scores. Moreover, the survival prediction nomogram, developed from MRI, had good potential for clinical application in predicting the 1-, 3-, and 5-year overall survival rate of LUAD. CONCLUSION: Our study constructed for the first time a consensus MRI for LUAD with 10 machine learning algorithms. The MRI could be helpful for risk stratification, prognosis, and selection of treatment approach in LUAD.

Modified McKeown vs. traditional McKeown minimally invasive esophagectomy in improving short-term efficacy and the quality of life of esophageal cancers: a retrospective comparative cohort study.

Background: Traditional McKeown minimally invasive esophagectomy (MIE-McKeown) with resection of the thoracic and abdominal branches of vagus nerve, the azygos vein and the bronchial artery, is notorious for high complications incidence and sharply decreased quality of life (QoL) postoperatively in esophageal cancer (EC). Recently, reports of preservation of azygos vein arch or the vagus nerve have shown the advantages of decreasing postoperative complication incidence. However, the modified MIE-McKeown with preservation of azygos vein arch, vagus nerve and the bronchial artery has never been investigated in EC. In the present study, we aimed to compare the short-term efficacy and postoperative QoL between modified MIE-McKeown and traditional MIE-McKeown. Methods: A total of 218 eligible patients with esophageal squamous cell carcinoma (ESCC) who met our inclusion criteria between October 2018 and January 2022 in our center were retrospectively enrolled and divided into modified MIE-McKeown group (N=48) and the control group with traditional MIE-McKeown (N=170) according to their surgical procedure. We compared the perioperative parameters (e.g., operation time and postoperative complications) between the two groups. The core quality of life questionnaire (QLQ-C30) (version 3.0) and the EC-specific QoL assessment form (QLQ-OES18) were used to evaluate the QoL in the 2 groups at 1 and 3 months after operation. Results: There were no significant differences in baseline characteristics between modified MIE-McKeown group and the control group. Compared with the control group, the modified MIE-McKeown group had significantly lower postoperative drainage volume (551.46±249.45 vs. 812.96±405.82; P<0.001) and a lower incidence of thoracic stomach syndrome (TSS; P=0.001). The bleeding loss in the modified MIE-McKeown group was lower than that in the control group (56.88±20.44 vs. 83.18±97.93; P=0.066), but not significantly. There were no significant differences observed in postoperative complications and other perioperative parameters between the two groups. The results of QLQ-C30 and QLQ-OES18 questionnaire revealed that the modified MIE-McKeown group was associated with better physical function, better global health status and milder symptoms of gastroesophageal reflux and cough. Conclusions: The modified MIE-McKeown is a safe and efficient procedure and has the potential to improve postoperative health status of patients with EC.

Nickel-cobalt layered double hydroxide nanosheets anchored to the inner wall of wood carbon tracheids by nitrogen-doped atoms for high-performance supercapacitors.

In this paper, a novel type of electrode material for high-performance hybrid supercapacitors is designed. The electrode mainly uses nitrogen-doped atoms to anchor the nickel-cobalt layered double hydroxide on the inner wall of wood-derived carbon tracheids from Chinese fir wood scraps. The specific capacity of the composite single electrode is 14.26 mAh cm-2 at 10 mA cm-2. The hybrid supercapacitor with a composite electrode cathode and nitrogen-doped wood-derived monolithic carbon materials as the anode has a high specific capacitance of 4.74F cm-2 at 5 mA cm-2, and the capacitance retention rate is 93.15% after 8000 charge-discharge cycles. The highest energy density and power density reach 1.48 mWh cm-2 and 22.40 mW cm-2, respectively. After doping with nitrogen, the combination with the nickel-cobalt layered double hydroxide is more uniform and stable, and the capacitance and cycling stability are significantly improved.

Prevalence of Atrial Fibrillation and Associated Mortality Among Hospitalized Patients With COVID-19: A Systematic Review and Meta-Analysis.

Background: Epidemiological studies have shown that atrial fibrillation (AF) is a potential cardiovascular complication of coronavirus disease 2019 (COVID-19). We aimed to perform a systematic review and meta-analysis to clarify the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19. Methods: PubMed, Embase, the Cochrane Library, and MedRxiv up to February 27, 2021, were searched to identify studies that reported the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19. The study was registered with PROSPERO (CRD42021238423). Results: Nineteen eligible studies were included with a total of 21,653 hospitalized patients. The pooled prevalence of AF was 11% in patients with COVID-19. Older (≥60 years of age) patients with COVID-19 had a nearly 2.5-fold higher prevalence of AF than younger (<60 years of age) patients with COVID-19 (13 vs. 5%). Europeans had the highest prevalence of AF (15%), followed by Americans (11%), Asians (6%), and Africans (2%). The prevalence of AF in patients with severe COVID-19 was 6-fold higher than in patients with non-severe COVID-19 (19 vs. 3%). Furthermore, AF (OR: 2.98, 95% CI: 1.91 to 4.66) and new-onset AF (OR: 2.32, 95% CI: 1.60 to 3.37) were significantly associated with an increased risk of all-cause mortality among patients with COVID-19. Conclusion: AF is quite common among hospitalized patients with COVID-19, particularly among older (≥60 years of age) patients with COVID-19 and patients with severe COVID-19. Moreover, AF and new-onset AF were independently associated with an increased risk of all-cause mortality among hospitalized patients with COVID-19.

m6A-Related lncRNA to Develop Prognostic Signature and Predict the Immune Landscape in Bladder Cancer.

Abnormal m6A methylation plays a significant role in cancer progression. Increasingly, researchers have focused on developing lncRNA signatures to evaluate the prognosis of cancer patients. The specific function of m6A-related lncRNAs in the prognosis of bladder cancer patients and the immune microenvironment of bladder cancer remains elusive. Herein, we performed a comprehensive analysis of m6A-related lncRNA prognostic values and their association with the immune microenvironment in bladder cancer using the TCGA dataset. A total of 9 m6A-related lncRNAs were dramatically correlated with overall survival outcomes in bladder cancer. Two molecular subtypes (cluster 1 and cluster 2) were identified by consensus clustering for 9 m6A-related prognostic lncRNAs. Cluster 1 was significantly correlated with poor prognosis, advanced clinical stage, higher PD-L1 expression, a higher ESTIMATEScore and immuneScore, and distinct immune cell infiltration. GSEA revealed the enrichment of apoptosis and the JAK-STAT signaling pathway in cluster 2. A prognostic risk score was constructed using 9 m6A-related prognostic lncRNAs, which functioned as an independent prognostic factor for bladder cancer. Moreover, bladder cancer patients in the low-risk score group had a higher pN stage, pT stage, and clinical stage and a lower tumor grade and immuneScore. The risk score was correlated with the infiltration levels of certain immune cells, including B cells, plasma cells, follicular helper T cells, regulatory T cells, resting NK cells, neutrophils, M0 macrophages, M1 macrophages, and M2 macrophages. Collectively, our study elucidated the important role of m6A-related lncRNAs in the prognosis of bladder cancer patients and in the bladder cancer immune microenvironment. The results suggest that the components of the m6A-related prognostic lncRNA signature might serve as a crucial mediator of the immune microenvironment in bladder cancer, representing promising therapeutic targets for improving immunotherapeutic efficacy.

Identification of the pyroptosis­related prognostic gene signature and the associated regulation axis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains the most common deadly disease and has a poor prognosis. Pyroptosis could regulate tumour cell proliferation, invasion, and metastasis, thereby affecting the prognosis of cancer patients. However, the role of pyroptosis-related genes (PRGs) in LUAD remains unclear. In our study, comprehensive bioinformatics analysis was performed to construct a prognostic gene model and ceRNA network. The correlations between PRGs and tumour-immune infiltration, tumour mutation burden, and microsatellite instability were evaluated using Pearson's correlation analysis. A total of 23 PRGs were upregulated or downregulated in LUAD. The genetic mutation variation landscape of PRG in LUAD was also summarised. Functional enrichment analysis revealed that these 33 PRGs were mainly involved in pyroptosis, the NOD-like receptor signalling pathway, and the Toll-like receptor signalling pathway. Prognosis analysis indicated a poor survival rate in LUAD patients with low expression of NLRP7, NLRP1, NLRP2, and NOD1 and high CASP6 expression. A prognostic PRG model constructed using the above five prognostic genes could predict the overall survival of LUAD patients with medium-to-high accuracy. Significant correlation was observed between prognostic PRGs and immune-cell infiltration, tumour mutation burden, and microsatellite instability. A ceRNA network was constructed to identify a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis in LUAD. In conclusion, we performed a comprehensive bioinformatics analysis and identified a prognostic PRG signature containing five genes (NLRP7, NLRP1, NLRP2, NOD1, and CASP6) for LUAD patients. Our results also identified a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis, which may also play an important role in the progression of LUAD. Further study needs to be conducted to verify this result.

Teratogenic effects of environmentally relevant concentrations of phenanthrene on the early development of marine medaka (Oryzia melastigma).

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants in marine environments and have arouse great concern since they pose adverse effects to marine ecosystem. To determine the potential impacts of environmentally relevant PAHs on early life stages of marine fish, this study exposed embryos of marine medaka (Oryzias melastigma) to 0, 2, 10, 50, and 250 µg/L of phenanthrene (Phe), one of the most abundant PAHs. The results demonstrated that Phe exposure decreased hatching rates, delayed hatching time of embryos, and increased deformity rate of newly-hatched larvae. Exposure to 10 and 50 µg/L Phe decreased the survival rate of marine medaka larvae at 28 days post-fertilization (dpf), and no embryo successfully hatched in 250 µg/L Phe exposure group. Morphology results showed that 10, 50, and 250 µg/L Phe exposure significantly retarded the development of embryos, and 2, 10, and 50 µg/L caused yolk sac edema and pericardial edema in newly-hatched larvae, indicating that low concentrations of Phe could induce developmental cardiac toxicity. Furthermore, the changes in the expression of heart development-related genes were determined, and the results showed that Phe-induced cardiac malformation might be related with fgf8, bmp4, smyd1, ATPase and gata4 genes. Overall, environmentally relevant PAHs could disrupt heart morphogenesis and hatching process of marine medaka, which might have profound consequences for sustainability of fish population.

Tumor suppressor miR-33b-5p regulates cellular function and acts a prognostic biomarker in RCC.

BACKGROUND: Renal cell carcinoma (RCC) is a renal parenchyma neoplasm with a 30% recurrence rate even when treated properly. MicroRNAs are noncoding small RNAs that are involved in cellular communication and may participate in cancer development. This study aimed to explore the relationship between miR-33b-5p expression and RCC progression and prognosis. METHOD: RT-qPCR, CCK-8 assay, wound scratch assay, transwell assay and flow cytometry assay were used to evaluate the expression and function of miR-33b-5p in RCC. Additionally, RCC samples and survival data from The Cancer Genome Atlas were used to analyze the prognostic functions of miR-33b-5p. RESULTS: miR-33b-5p expression in RCC tissues and cell lines (786-O, ACHN) were found to be significantly downregulated, compared with normal tissues and cell lines (P<0.001). The miR-33b-5p mimic transfected cells showed a slower proliferation rate (P<0.01), while its invasion ability decreased by 38.16% (786-O, P<0.001) and 49.19% (ACHN, P<0.05), compared with the negative control (NC). The migration ability of both RCC lines were found to be as follows: miR-33b-5p inhibitor > NC or NC inhibitor > miR-33b-5p mimic. Additionally, TCGA and RCC samples reveal that low miR-33b-5p expression is related to poor survival outcomes (univariate analysis, P=0.029; multivariate analysis, P=0.024; Kaplan-Meier survival curves, P=0.014). Target genes prediction suggests that miR-33b-5p performs its tumor-suppressive effects and prognostic role through targeting TBX15, SLC12A5, and PTGFRN. CONCLUSIONS: miR-33b-5p may function as a tumor-suppressive regulator and prognostic biomarker in RCC.

Mining therapeutic and prognostic significance of STATs in renal cell carcinoma with bioinformatics analysis.

Renal cell carcinoma is one of the most common malignancies with high morbidity and mortality. STAT proteins play a significant role in cell biological behavior and immune response associated with cancer progression. In our study, the datasets analyzed for the expression and potential functions can be found in several bioinformatics analysis tools. We found that STAT1/2/4/6 were upregulated in RCC while STAT3/5B were downregulated. The expression of STAT2/4/5B were significantly associated with the pathological stage of RCC patients. RCC patients with high expression of STAT2/4 and low/medium expression of STAT5B had a poor overall survival. The function of STATs and the neighboring genes mainly enriched in JAK-STAT signaling pathway and NOD-like receptor signaling pathway. Several transcription factor, kinase, and miRNA targets were identified. Close correlations were obtained between immune cell infiltration and STATs in RCC. Our results have provided novel insights for the selection of immunotherapeutic targets and prognostic biomarkers.

Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent malignancies with high incidence and mortality. The circadian clock, which is also involved in the regulation of the immune system and tumor microenvironment, is an internal timing system that allows organisms to adjust biological processes and behaviors according to geophysical time. RESULT: A wide range of circadian clock genes are epigenetically altered in KIRC, and associated with the overall survival and disease-free survival of patients. SNV analysis revealed missense mutation and splice site to be the most common variant types of circadian clock genes in KIRC. Several circadian clock genes were involved in the regulation of some cancer-related hallmark pathways, including apoptosis and cell cycle pathway. Further, immune infiltrates analysis not only revealed that the expression of circadian clock genes is associated with immune cell infiltrates, but also that somatic copy-number alteration of circadian clock genes could inhibit the immune infiltrates. Moreover, enrichment analysis implied that the circadian clock genes could regulate transcription factor activity and circadian rhythm in KIRC. CONCLUSION: Our results demonstrate the potential of chrono-immunotherapy as a candidate option for the management of KIRC. METHOD: Multi-omics analysis was performed to comprehensively determine the roles of core circadian clock genes in KIRC.

JAK3 is a potential biomarker and associated with immune infiltration in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is one of the most common cancers globally, with an overall poor prognosis. The Janus kinase (JAK) family plays an essential role in cellular mechanisms such as proliferation, metastasis, invasion, and immunity. In our study, various web-portals were used to explore the expression and clinical significance of JAK3 in KIRC. JAK3 expression was significantly up-regulated in KIRC tissues. Patients with KIRC having high JAK3 levels displayed a substantially decreased disease-free survival rate and overall survival rate. Significant correlations were obtained between JAK3 expression and the abundance of immune cells and immune biomarker sets. Enrichment function analysis revealed that gene function significantly correlated with JAK3, which was primarily associated with the immune response, JAK-STAT signaling pathway, Ras signaling pathway via several cancer-related kinases, miRNAs, and transcription factors. Moreover, we also identified several kinase, miRNA or transcription factor targets of JAK3 in KIRC. The hub genes (JAK3, FCHO1, INSl3, DEF6, and GPR132) were associated with the activation or inhibition of several famous cancer related pathways. Our results demonstrated that JAK3 is a potential biomarker and associated with immune infiltration in KIRC.

Bioinformatic identification of renal cell carcinoma microenvironment-associated biomarkers with therapeutic and prognostic value.

Renal cell carcinoma (RCC) is the ninth most prevalent form of malignancy worldwide. The tumor microenvironment significantly affects gene expression in tumor tissues, which subsequently impacts the prognosis of RCC patients. Available datasets such as The Cancer Genome Atlas (TCGA) can be utilized to improve diagnostic methods and search for novel tumor therapeutic targets and prognostic biomarkers. The current study used the ESTIMATE algorithm to explore the immune and stromal components in RCC. Differentially expressed genes (DEGs) were identified by comparing the gene expression patterns in groups with high and low immune/stromal scores. Functional enrichment analysis was conducted and Kaplan-Meier survival curves were plotted to explore the functions of the DEGs in the tumorigenesis, progression, and prognosis of RCC. Our results revealed that immune and stromal scores are associated with specific clinicopathologic variables in RCC. These variables include gender, tumor grade, tumor stage, tumor size, distant metastasis and prognosis. A total of 48 upregulated and 47 downregulated genes were obtained. Functional enrichment analysis demonstrated a correlation between DEGs and the tumor microenvironment, tumor immune response and RCC tumorigenesis. Kaplan-Meier survival curves showed that 43 out of the 48 identified tumor microenvironment related genes are involved in the prognosis of RCC. Three genes, IL10, IGLL5 and POU2AF1, were selected as the hub genes, and their kinase targets were identified as MAPK1 and PPKCA. A positive correlation was obtained between the expression of IL/POU2AF1 and the abundance of six immune cells. Our study provides potential biomarkers for the therapy and prognosis of RCC.

miR-625-3p promotes migration and invasion and reduces apoptosis of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common malignancy, yet, the mechanisms underlying tumorigenesis remain unclear. Several miRNAs have been implicated in the development of RCC previously via regulation of target gene expression. As miR-625-3p has recently been identified to play a role in development of other malignancies and is reportedly upregulated in ccRCC, we sought to investigate the role of this miRNA in the progression of ccRCC. Analysis of 30 paired fresh ccRCC tissues and adjacent normal renal tissues revealed that the expression of miR-625-3p was increased in ccRCC tissues compared to normal tissues. Subsequently, in 136 formalin-fixed paraffin-embedded ccRCC tissues, the increased miR-625-3p expression was correlated with poor prognosis for ccRCC patients. The diagnostic value of miR-625-3p was identified in 50 ccRCC patients and 74 healthy controls by ROC curve. miR-625-3p was decreased in serum of ccRCC patients compared to healthy individuals. miR-625-3p could serve as a promising serum biomarker for yielding an area under the receiver operating characteristic curve of 0.792 with 70.3% sensitivity and 80.0% specificity in discriminating ccRCC from healthy individuals. Using in vitro functional assays, we found that overexpression of miR-625-3p promoted migration and invasion of ccRCC cells but reduced ccRCC cell apoptosis. Inhibition of miR-625-3p, on the other hand, exerted the opposite effects. Bioinformatic analyses indicated that predicted gene targets of miR-625-3p are correlated with lower overall survival of ccRCC patients. Together, these findings demonstrate that miR-625-3p promotes ccRCC migration and invasion and reduces apoptosis, providing a prognostic marker for survival and a potential diagnostic and therapeutic target against ccRCC.