CD44 Is Associated with Poor Prognosis of ccRCC and Facilitates ccRCC Cell Migration and Invasion through HAS1/MMP9.

BACKGROUND: In many solid tumors, CD44 has been identified as a cancer stem cell marker as well as an important molecular in cancer progression and metastasis, making it attractive for potential therapeutic applications. However, our knowledge of the biological function and mechanism of CD44 in clear cell renal cell carcinoma (ccRCC) is limited. METHODS: In this study, the expression, prognostic values and functional enrichment analysis of CD44 in ccRCC were analyzed using public databases. Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemical (IHC) assays were taken to detect CD44 expression in ccRCC tissues. The effects of CD44 on the proliferation, migration and invasion of ccRCC cells were investigated by gain-of-function and loss-of-function experiments. Subcutaneous models further confirmed the role of CD44 in tumor growth. The relationship between CD44, HAS1 and MMP9 was investigated to uncover the regulatory mechanism of CD44 in ccRCC. RESULTS: CD44 was significantly upregulated in ccRCC and associated with poor overall survival (OS). Based on the functional enrichment analysis and PPI network, we found that CD44 had associations with ECM interaction and focal adhesion pathway. Clinical ccRCC sample validation revealed that CD44 mRNA and protein expression were significantly increased in ccRCC tissues, and strong CD44 staining was observed in four metastatic ccRCC cases. In vitro experiments showed that CD44 overexpression promoted cell proliferation, migration and invasion. In vivo experiments also demonstrated that CD44 overexpression accelerated tumor formation in mice. Finally, we found that CD44 regulates the expression of HAS1 in ccRCC, which is essential for the secretion of MMP9 and cell migratory ability. CONCLUSION: The upregulation of CD44 mRNA and protein expressions in ccRCC is indicative of unfavorable clinical prognoses. The CD44/HAS1/MMP9 axis is believed to exert a significant influence on the regulation of ECM degradation and ccRCC metastasis.

ATAD2 promotes glycolysis and tumor progression in clear cell renal cell carcinoma by regulating the transcriptional activity of c-Myc.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urogenital tract. Given that ccRCC is often resistant to radiotherapy and traditional chemotherapy, the clinical treatment of patients with ccRCC remains a challenge. The present study found that ATAD2 was significantly upregulated in ccRCC tissues. In vitro and in vivo experiments showed that the inhibition of ATAD2 expression mitigated the aggressive phenotype of ccRCC. ATAD2 was also associated with glycolysis in ccRCC. Interestingly, we found that ATAD2 could physically interact with c-Myc and promote the expression of its downstream target gene, thereby enhancing the Warburg effect of ccRCC. Overall, our study emphasizes the role of ATAD2 in ccRCC. The targeted expression or functional regulation of ATAD2 could be a promising method to reduce the proliferation and progression of ccRCC.

L1CAM deployed perivascular tumor niche promotes vessel wall invasion of tumor thrombus and metastasis of renal cell carcinoma.

The survival of tumor cells in the bloodstream, and vasculature adhesion at metastatic sites are crucial for tumor metastasis. Perivascular invasion aids tumor cell self-renewal, survival, and formation of metastases by facilitating readily available oxygen, nutrients, and endothelial-derived paracrine factors. Renal cell carcinoma (RCC) is among the most prevalent tumors of the urinary system, and the formation of venous tumor thrombus (VTT) is a characteristic feature of RCC. We observed high expression of L1CAM in the VTT with vessel wall invasion. L1CAM promotes the adhesion, migration, and invasion ability of RCC and enhances metastasis by interacting with ITGA5, which elicits activation of signaling downstream of integrin α5ß1. L1CAM promotes ADAM17 transcription to facilitate transmembrane ectodomain cleavage and release of soluble L1CAM. In response to soluble L1CAM, vascular endothelial cells release several cytokines and chemokines. Endothelial-derived CXCL5 and its receptor CXCR2 promote the migration and intravasation of RCC toward endothelial cells suggesting that crosstalk between endothelial cells and tumor cells has a direct guiding role in driving the metastatic spread of RCC. LICAM plays a crucial role in the invasive ability of RCC, and regulation of L1CAM expression may contribute therapeutically to preventing RCC progression.

TPM2 attenuates progression of prostate cancer by blocking PDLIM7-mediated nuclear translocation of YAP1.

BACKGROUND: Prostate cancer (PCa) is a common malignant tumor of the genitourinary system. Clinical intervention in advanced PCa remains challenging. Tropomyosins 2 (TPM2) are actin-binding proteins and have been found as a biomarker candidate for certain cancers. However, no studies have explored the role of TPM2 in PCa and its regulatory mechanism. METHODS: TPM2 expression was assessed in Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) PCa patient dataset. The effect of TPM2 on PCa progression was assessed in vitro and in vivo by quantifying proliferation, migration, invasion and tumor growth assays, and the mechanism of TPM2 in PCa progression was gradually revealed by Western blotting, immunoprecipitation, and immunofluorescence staining arrays. RESULTS: TPM2 was found to be severely downregulated in tumor tissues of PCa patients compared with tumor-adjacent normal tissues. In vitro experiments revealed that TPM2 overexpression inhibited PCa cell proliferation, invasion and androgen-independent proliferation. Moreover, TPM2 overexpression inhibited the growth of subcutaneous xenograft tumors in vivo. Mechanistically, this effect was noted to be dependent on PDZ-binding motif of TPM2. TPM2 competed with YAP1 for binding to PDLIM7 through the PDZ-binding motif. The binding of TPM2 to PDLIM7 subsequently inhibited the nuclear transport function of PDLIM7 for YAP1. YAP1 sequestered in the cytoplasm phosphorylated at S127, resulting in its inactivation or degradation which in turn inhibited the expression of YAP1 downstream target genes. CONCLUSIONS: This study investigated the role of TPM2, PDLIM7, and YAP1 in PCa progression and castration resistance. TPM2 attenuates progression of PCa by blocking PDLIM7-mediated nuclear translocation of YAP1. Accordingly, targeting the expression or functional modulation of TPM2, PDLIM7, or YAP1 has the potential to be an effective therapeutic approach to reduce PCa proliferation and prevent the progression of castration-resistant prostate cancer (CRPC).

SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma.

Radioresistance is a principal culprit for the failure of radiotherapy in hepatocellular carcinoma (HCC). Insights on the regulation genes of radioresistance and underlying mechanisms in HCC are awaiting for profound investigation. In this study, the suppressor of cytokine signaling 2 (SOCS2) were screened out by RNA-seq and bioinformatics analyses as a potential prognosis predictor of HCC radiotherapy and then were determined to promote radiosensitivity in HCC both in vivo or in vitro. Meanwhile, the measurements of ferroptosis negative regulatory proteins of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), intracellular lipid peroxidation and Fe2+ concentration suggested that a high level of ferroptosis contributed to the radiosensitization of HCC. Moreover, SOCS2 and SLC7A11 were expressed oppositely in HCC clinical tissues and tumour xenografts with different radiosensitivities. Mechanistically, the N-terminal domain of SLC7A11 was specifically recognized by the SH2-structural domain of SOCS2. While the L162 and C166 of SOCS2-BOX region could bind elongin B/C compound to co-form a SOCS2/elongin B/C complex to recruit ubiquitin molecules. Herein, SOCS2 served as a bridge to transfer the attached ubiquitin to SLC7A11 and promoted K48-linked polyubiquitination degradation of SLC7A11, which ultimately led to the onset of ferroptosis and radiosensitization of HCC. In conclusion, it was demonstrated for the first time that high-expressed SOCS2 was one of the biomarkers predicting radiosensitivity of HCC by advancing the ubiquitination degradation of SLC7A11 and promoting ferroptosis, which indicates that targeting SOCS2 may enhance the efficiency of HCC radiotherapy and improve the prognosis of patients.

Comparative analysis of surgical and oncologic outcomes of robotic, laparoscopic and open radical nephrectomy with venous thrombectomy: a propensity-matched cohort study.

OBJECTIVE: To provide insight into the surgical and oncological outcomes of robotic, laparoscopic and open radical nephrectomy with venous thrombectomy (RALRN-VT, LRN-VT, ORN-VT) in patients with renal tumor and venous thrombus. MATERIALS AND METHODS: A propensity-matched retrospective cohort study containing 324 patients with renal tumor and venous thrombus from January 2014 to August 2021 was analyzed. We compared surgical outcomes and we used the Kalan-Meier method to assess the overall survival (OS), tumor-specific survival (TSS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). The Pearson chi-square test and Fisher exact test, Wilcoxon rank sum test, Cox proportional hazards regression model and log-rank test were used. RESULTS: After matching, baseline characteristics were comparable in the RALRN-VT, LRN-VT and ORN-VT group. The RALRN-VT group had the least operative time (median 134 min vs 289 min vs 330 min, P < 0.001), the least blood loss (median 250 ml vs 500 ml vs 1000 ml, P < 0.001) and the fewest packed red blood cells transfusion (median 400 ml vs 800 ml vs 1200 ml, P < 0.001). The ORN-VT group had the highest complication rate (18.2 vs 22.7 vs 43.2%, P = 0.005), the highest Clavien grade (P = 0.001) and the longest postoperative hospital stay (median 7d vs 8d vs 10d, P < 0.001). No significant difference in OS, TSS and MFS between the minimally invasive procedures (MIP, including RALRN-VT and LRN-VT) group and ORN-VT group was found. The hazard ratio of LRFS for the MIP group was 0.20 (95% CI 0.06-0.70, P = 0.01) compared with ORN-VT group. CONCLUSIONS: RALRN-VT can result in the best surgical outcomes compared with LRN-VT and ORN-VT. The MIP group had a better LRFS compared with ORN-VT group.

Irradiation combined with PD-L1-/- and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation.

Radiotherapy combined with immune checkpoint blockade has gradually revealed the superiority in the antitumor therapy; however, the contribution of host PD-L1 remains elusive. In this study, we found that the activation of CD8+ T cells was strikingly increased in both irradiated PD-L1-expressing primary tumor and distant non-irradiated syngeneic tumor in PD-L1-deficient mouse host, and thus enhanced radiation-induced antitumor abscopal effect (ATAE) by activating cGAS-STING pathway. Notably, the autophagy inhibitors distinctively promoted dsDNA aggregation in the cytoplasm and increased the release of cGAS-STING-regulated IFN-ß from irradiated cells, which further activated bystander CD8+ T cells to release IFN-γ and contributed to ATAE. These findings revealed a signaling cascade loop that the cytokines released from irradiated tumor recruit CD8+ T cells that in turn act on the tumor cells with amplified immune responses in PD-L1-deficient host, indicating a potential sandwich therapy strategy of RT combined with PD-L1 blockage and autophagy inhibition.

Identification of KIF23 as a Prognostic Biomarker Associated With Progression of Clear Cell Renal Cell Carcinoma.

About 3% of adult cancers are caused by renal cell carcinoma (RCC) and its pathogenesis remains elusive. Among RCC, clear cell renal cell carcinoma (ccRCC) is the predominant histological subtype. Resistance to conventional treatments leaves few treatment options for advanced ccRCC. Although the transcriptome profile of primary ccRCC has been comprehensively summarized, the transcriptome profile of metastatic ccRCC is still lacking. In this study we identified a list of metastasis-related genes and constructing a metastasis-associated prognostic gene signature. By analyzing data from GSE85258 and GSE105288 datasets, 74 genes were identified as metastasis-related genes. To construct prognostic features, we downloaded the expression data of ccRCC from the Cancer Genome Atlas (TCGA). Metastasis-associated genes were initially selected through the LASSO Cox regression analysis and 12 metastasis-related were included to construct prognostic model. Transcriptome profile, patient prognosis, and immune cell infiltration characteristics differed between low- and high-risk groups after grouping according to median risk score. Through explored the functions of differentially expressed genes (DEGs) between the two groups. Kinesin family member 23 (KIF23) was identified as a prognostic marker in ccRCC patients. Furthermore, inhibition of KIF23 expression reduced the proliferation, migration and invasion of ccRCC cells. We further demonstrated that KIF23 promote nuclear translocation of ß-catenin in ccRCC cells, which provides novel insight into the functions and molecular machinery of KIF23 in ccRCC.

Experimental and Theoretical Study of the Time-Effect-Based Instability Characteristics of the Gas Drainage Borehole Sealing Section in a Soft Coal Seam.

The instability and sealing difficulty confronted by gas drainage boreholes in a soft coal seam weakens the drainage efficiency. To address this problem, the instability characteristics of the sealing section of boreholes are investigated. On the basis of the findings of the mechanical properties of the borehole around the sealing section and in view of the physical and mechanical properties of the soft coal seam, a theoretical analysis was performed. A system consisting of the YYL200 electronic persistent creep test system and the DNS-200 electronic universal tester was used to observe the borehole under different filling conditions. The samples were subjected to a graded loading test, and the Kelvin-Voigt model was selected for parameter inversion and law analysis of the test results. The results show that the collapse of the broken area and the stress concentration and instability of the sealing section after the sealing of the soft coal seam are directly attributable to the instability of the soft coal seam and the sealing difficulty. The mechanical properties of the grouting sealing material are directly related to the loading of the hole-containing sample and dead load displacement. The maximal overall displacement of the sample in group B is close to 1.4 mm. The instantaneous deformation capacity and deformation space reflected by the generalized Kelvin model parameters E 1, E 2, and η are closely related to the mechanical properties of the filling material. The highly stress- and deformation-resistant sealing material can ensure the relative time-effect-based stability within the stress concentration area of the sealing section.

The temporal trend of disease burden attributable to metabolic risk factors in China, 1990-2019: An analysis of the Global Burden of Disease study.

Background and aims: The disease burden attributable to metabolic risk factors is rapidly increasing in China, especially in older people. The objective of this study was to (i) estimate the pattern and trend of six metabolic risk factors and attributable causes in China from 1990 to 2019, (ii) ascertain its association with societal development, and (iii) compare the disease burden among the Group of 20 (G20) countries. Methods: The main outcome measures were disability-adjusted life-years (DALYs) and mortality (deaths) attributable to high fasting plasma glucose (HFPG), high systolic blood pressure (HSBP), high low-density lipoprotein (HLDL) cholesterol, high body-mass index (HBMI), kidney dysfunction (KDF), and low bone mineral density (LBMD). The average annual percent change (AAPC) between 1990 and 2019 was analyzed using Joinpoint regression. Results: For all six metabolic risk factors, the rate of DALYs and death increased with age, accelerating for individuals older than 60 and 70 for DALYs and death, respectively. The AAPC value in rate of DALYs and death were higher in male patients than in female patients across 20 age groups. A double-peak pattern was observed for AAPC in the rate of DALYs and death, peaking at age 20-49 and at age 70-95 plus. The age-standardized rate of DALYs increased for HBMI and LBMD, decreased for HFPG, HSBP, KDF, and remained stable for HLDL from 1990 to 2019. In terms of age-standardized rate of DALYs, there was an increasing trend of neoplasms and neurological disorders attributable to HFPG; diabetes and kidney diseases, neurological disorders, sense organ diseases, musculoskeletal disorders, neoplasms, cardiovascular diseases, digestive diseases to HBMI; unintentional injuries to LBMD; and musculoskeletal disorders to KDF. Among 19 countries of Group 20, in 2019, the age-standardized rate of DALYs and death were ranked fourth to sixth for HFPG, HSBP, and HLDL, but ranked 10th to 15th for LBMD, KDF, and HBMI, despite the number of DALYs and death ranked first to second for six metabolic risk factors. Conclusions: Population aging continuously accelerates the metabolic risk factor driven disease burden in China. Comprehensive and tight control of metabolic risk factors before 20 and 70 may help to mitigate the increasing disease burden and achieve healthy aging, respectively.

Fractionated Irradiation of Right Thorax Induces Abscopal Damage on Bone Marrow Cells via TNF-α and SAA.

Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1-6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.

LACTB2 renders radioresistance by activating PINK1/Parkin-dependent mitophagy in nasopharyngeal carcinoma.

Radiotherapy is a standard and conventional treatment strategy for nasopharyngeal carcinoma (NPC); however, radioresistance remains refractory to clinical outcomes. Understanding the molecular mechanism of radioresistance is crucial for advancing the efficacy of radiotherapy and improving the prognosis of NPC. In this study, ß-lactamase-like-protein 2 (LACTB2) was identified as a potential biomarker for radioresistance using tandem mass tag proteomic analysis of NPC cells, gene chip analysis of NPC tissues, and differential gene analysis between NPC and normal nasopharyngeal tissues from the Gene Expression Omnibus database GSE68799. Meanwhile, LACTB2 levels were elevated in the serum of patients with NPC after radiotherapy. Inhibiting LACTB2 levels and mitophagy can sensitize NPC cells to ionizing radiation. In NPC cells, LACTB2 was augmented at the transcription and protein levels after radiation rather than nucleus-cytoplasm-mitochondria transposition to activate PTEN-induced kinase 1 (PINK1) and mitophagy. In addition, LACTB2 was first authenticated to co-locate with PINK1 by interacting with its N-terminal domain. Together, our findings indicate that overexpressed LACTB2 provoked PINK1-dependent mitophagy to promote radioresistance and thus might serve as a prognostic biomarker for NPC radiotherapy.

Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells.

Rationale: Radiotherapy has become a mainstay for tumor management, and more than 50% of patients with thoracic tumor need to be treated with radiotherapy. However, the potential adverse effects of thoracic radiotherapy on the reproductive system remain elusive. Methods: Western blot analysis, immunofluorescence assay and transmission electron microscopy (TEM) analysis were performed to investigate the integrity of blood-testis barrier (BTB) in male mice after hypofractionated irradiation (IR) on the right thorax. RNA sequencing, co-immunoprecipitation (IP), Duolink PLA and inhibitor experiments were carried out to demonstrate the molecular mechanisms of the BTB dynamics changes and the subsequent reproductive effect. Results: It was found that the hypofractionated IR on right thorax evoked ultrastructural destruction in distant testes, and thus caused radiation-induced abscopal reproductive effect (RIARE) in male mice. Mechanistically, thoracic IR induced significant nuclear translocation of Rac Family Small GTPase 1 (Rac1) in abscopal Sertoli cells, which closely correlated with the activation of TNF-α/p38 mitogen activated protein kinase (MAPK) pathway. Of note, YWHAZ, a critical polarity protein, was found to be co-localized with Rac1 in Sertoli cells, and this interaction was indispensable for thoracic IR-induced Rac1 nuclear translocation and subsequent degradation of BTB-associated proteins. Conclusions: Our findings imply for the first time that YWHAZ-mediated Rac1 nuclear translocation plays central roles in RIARE, and TNF-α/p38 MAPK/Rac1 axis can be employed as a therapeutic target against RIARE for young male patients receiving hypofractionated radiotherapy.

Radiation engenders converse migration and invasion in colorectal cancer cells through opposite modulation of ANXA2/AKT/GSK3ß pathway.

Radiation therapy is an effective non-surgical means to achieve local control for various solid tumors including colorectal cancer (CRC), but metastasis and recurrences after conventional radiotherapy remains a major obstacle in clinical practice, and the knowledge concerning the changes of metastatic potential after heavy ion radiation is still limited. This study investigated how radiation, including γ- and carbon ion radiation, would change the metastatic capacity of two CRC cell lines, HCT116 and DLD-1, and examined the underlying molecular mechanisms. We found that the migration and invasion was enhanced in DLD-1 cells but impaired in HCT116 cells in vitro and in vivo after radiation of γ-rays or carbons, and radiation induced epithelial mesenchymal transition (EMT) in DLD-1 cells but mesenchymal epithelial transition (MET) in HCT116 cells. The expression of snail, a key inducer of EMT, was significantly enhanced by inhibition of glycogen synthase kinase-3ß (GSK3ß) in both cell lines, suggesting the modulation of snail was alike in the two CRC cell lines. However, radiation inactivated GSK3ß through stimulating the phosphorylation of AKT and GSK3ß at Ser473 and Ser9 in DLD-1 cells respectively, but activated GSK3ß by decreasing the expression of pAKTSer473 and pGSK3ßSer9 or increasing the phosphorylation of GSK3ß at Tyr216 in HCT116 cells. Therefore, the above inverted motility changes was due to the opposite modulation of AKT/GSK3ß signaling pathway by radiation, which was further verified in other type of cancer cell lines including MCF-7, U251 and A549 cells. Moreover, it was found that annexin A2 (ANAX2) directly bound with GSK3ß and acted as a negative regulator of GSK3ß upon radiation. Knocking-down ANXA2 gene reversed the enhanced migration of the irradiated DLD-1 cells and strengthened radiation-impaired migration of HCT116 cells. Collectively, this study reveals that the change of cellular motility after radiation is independent of radiation type but is correlated with the inherent of cells.

Identification of a Two-m6A RNA Methylation Regulator Risk Signature as an Independent Prognostic Biomarker in Papillary Renal Cell Carcinoma by Bioinformatic Analysis.

N6-Methyladenosine (m6A), the most common form of mRNA modification, is dynamically regulated by the m6A RNA methylation regulators, which play an important role in regulating the gene expression and phenotype in both health and disease. However, the role of m6A in papillary renal cell carcinoma (pRCC) is unknown. The purpose of this work is to investigate the prognostic value of m6A RNA methylation regulators in pRCC; thus, we can build a risk score model based on m6A RNA methylation regulators as a risk signature for predicting the prognosis of pRCC. Here, we investigated the expression and corresponding clinical data by bioinformatic analysis based on 289 pRCC tissues and 32 normal kidney tissues obtained from TCGA database. As a result, we identified the landscape of m6A RNA methylation regulators in pRCC. We grouped all pRCC patients into two clusters by consensus clustering to m6A RNA methylation regulators, but we found that the clusters were not correlated to the prognosis and clinicopathological features of pRCC. Therefore, we additionally built a two-m6A RNA methylation regulator risk score model as a risk signature by the univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. The risk signature was constructed as follows: 0.031HNRNPC + 0.199KIAA1429. It revealed that the risk score was associated with the clinicopathological features such as pT status and pN status of pRCC. More importantly, the risk score was an independent prognostic marker for pRCC patients. Thus, m6A RNA methylation regulators contributed to the malignant progression of pRCC influencing its prognosis.

Do socioeconomic factors modify the effects of PM1 and SO2 on lung cancer incidence in China?

BACKGROUND: It remains uncertain whether socioeconomic factors modify the effect of air pollution on human health. Moreover, studies investigating socioeconomic modifying roles on the effect of PM1 are quite limited, especially in developing countries. OBJECTIVES: The present study aims to investigate socioeconomic modification effects on the associations of the incidence rate of male lung cancer with ambient PM1 and SO2 in China. METHODS: We conducted a nationwide analysis in 345 Chinese counties (districts) between 2014 and 2015. In terms of multivariable linear regression models, we examined the modification effects of urban-rural division, education level and proportion of construction workers in the stratified and combined datasets according to the tertile and binary divisions of the three factors. Moreover, we performed three sensitivity analyses to test the robustness of socioeconomic modification effects. RESULTS: We found a larger effect of PM1 on the incidence rate of male lung cancer in urban areas than in rural areas. The association between PM1 (or SO2) and the incidence rate of male lung cancer was stronger in counties with low education levels than in those with high education levels. The findings of the significant modification effects of urban-rural division and education level were robust in the three sensitivity analyses. No significant modification effect was observed for the proportion of construction workers. CONCLUSIONS: Male residents in urban areas have a high risk of lung cancer incidence associated with ambient PM1. Male residents with low education levels suffer from larger effects of PM1 and SO2 on the incidence rate of lung cancer. Area- and population-specific strategies should be developed to reduce the urban-rural and educational disparities in air pollution effects, which thereby alleviates air pollution-associated health disparities in China.

Proteomic analysis reveals distinctive protein expression patterns of thrombus in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of malignant tumor of the urinary system. The renal vein or vena cava thrombus can be found in a subset of ccRCC patients in whom it leads to worse prognosis. However, the protein expression profile and molecular features of ccRCC thrombus remain largely unclear. Here, a comparative proteomic analysis was performed using the 2D-LC-MS strategy for the thrombus-tumor-normal tissue triples of 15 ccRCC patients. Statistical analysis, GO enrichment analysis, protein-protein interaction network construction, and mRNA-based survival analysis were used to interpret the proteomic data. Three dysregulated proteins, GGT5 (gamma-glutamyl transferase 5), KRT7 (keratin 7) and CFHR1 (complement factor H related 1), were analyzed using western blot (WB) and immunohistochemistry (IHC) to validate the reliability of the proteomic analysis. The result of this analysis revealed 251 dysregulated proteins, which could be divided into 11 clusters depending on the changing trends, among the thrombus, tumor, and normal tissues. Several pathways and regulation networks were found to be associated with the thrombus, and some dysregulated proteins showed potential values for prognosis prediction. WB and IHC results were in accordance with the proteomic results, further validating the reliability of this study. In conclusion, our findings provide an overview of the thrombus at the molecular level as well as valuable information for further pathological studies or research on biomarkers and therapeutic targets.

Long non-coding RNA LINC01234 regulates proliferation, migration and invasion via HIF-2α pathways in clear cell renal cell carcinoma cells.

Long non-coding RNAs (lncRNAs) have been proved to have an important role in different malignancies including clear cell renal cell carcinoma (ccRCC). However, their role in disease progression is still not clear. The objective of the study was to identify lncRNA-based prognostic biomarkers and further to investigate the role of one lncRNA LINC01234 in progression of ccRCC cells. We found that six adverse prognostic lncRNA biomarkers including LINC01234 were identified in ccRCC patients by bioinformatic analysis using The Cancer Genome Atlas database. LINC01234 knockdown impaired cell proliferation, migration and invasion in vitro as compared to negative control. Furthermore, the epithelial-mesenchymal transition was inhibited after LINC01234 knockdown. Additionally, LINC01234 knockdown impaired hypoxia-inducible factor-2a (HIF-2α) pathways, including a suppression of the expression of HIF-2α, vascular endothelial growth factor A, epidermal growth factor receptor, c-Myc, Cyclin D1 and MET. Together, these datas showed that LINC01234 was likely to regulate the progression of ccRCC by HIF-2α pathways, and LINC01234 was both a promising prognostic biomarker and a potential therapeutic target for ccRCC.

Clinical significance of circulating tumor cells detection in renal cell carcinoma with thrombus: A STROBE-compliant study.

The aim of the study was to evaluate the potential role of circulating tumor cell (CTC) detection in the surgical assessment of renal cell carcinoma (RCC) patients with thrombi.Nine patients diagnosed with renal mass and thrombi were enrolled from June 2018 to January 2019. Blood samples were collected for CTC detection using SE-iFISH assay. CD45, DAPI, programmed death ligand 1, and fluorescence in situ hybridization with the centromere of chromosome 8 (CEP8) were immune-stained for analysis. Patient demographics, clinical features, pathological characteristics, and CTC detection results were extracted for analysis.Seven of 9 patients (77.8%) had 12 detectable CTCs, 5 of which were with CEP8-positive signal ≥5 and the others were CEP8-positive signal = 3. All 3 patients (100%) with IVC invasion had detectable CTCs, whereas CTCs were detected in 4 of 6 patients (66.7%) without IVC invasion. CEP8 analysis revealed that CTCs in IVC invasion patients were all of CEP8-positive signal ≥5 status, whereas only half of the CTCs in patients without IVC invasion were of CEP8-positive signal ≥5 pattern.In conclusion, both CTC subtype and total CTC number may serve as a marker for predicting inferior vena cava invasion in RCC patients.

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma.

Radiotherapy is a conventional and effective treatment method for nasopharyngeal carcinoma (NPC), although it can fail, mainly because radioresistance results in residual or recurrent tumors. However, the mechanisms and predictive markers of NPC radioresistance are still obscure. In this study, we identified Annexin A6 (ANXA6) as a candidate radioresistance marker by using Tandem Mass Tag quantitative proteomic analysis of NPC cells and gene chip analysis of NPC clinical samples with different radiosensitivities. It was observed that a high expression level of ANXA6 was positively correlated with radioresistance of NPC and that inhibition of ANXA6 by siRNA increased the radiosensitivity. The incidence of autophagy was enhanced in the established radioresistant NPC cells in comparison with their parent cells, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, ANXA6 siRNA (siANXA6) suppressed cellular autophagy by activating the PI3K/AKT/mTOR pathway, ultimately leading to radiosensitization. The combination of siANXA6 and CAL101 (an inhibitor of PI3K, p-AKT, and mTOR, concurrently) significantly reversed the above siANAX6-reduced autophagy. Suppression of PI3K/AKT/mTOR by CAL101 also increased the expression of ANXA6 in a negative feedback process. In conclusion, this study revealed for the first time that ANXA6 could promote autophagy by inhibiting the PI3K/AKT/mTOR pathway and that it thus contributes to radioresistance of NPC. The significance of this is that ANXA6 could be applied as a new predictive biomarker of NPC prognosis after radiotherapy.