Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

Benzidine induces epithelial-mesenchymal transition in human uroepithelial cells through ERK1/2 pathway.

Prolonged benzidine exposure is a known cause of urothelial carcinoma (UC). Benzidine-induced epithelial-to-mesenchymal transition (EMT) is critically involved in cell malignant transformation. The role of ERK1/2 in regulating benzidine-triggered EMT has not been investigated. This study was to investigate the regulatory role of ERK1/2 in benzidine-induced EMT. By using wound healing and transwell chamber migration assays, we found that benzidine could increase SV-HUC-1 cells invasion activity, western blotting and Immunofluorescence showed that the expression levels of Snail, ß-catenin, Vimentin, and MMP-2 were significantly increased, while, the expression levels of E-cadherin, ZO-1 were decreased. To further demonstrate the mechanism in this process, we found that the phosphorylation of ERK1/2, p38, JNK and AP-1 proteins were significantly enhanced compared to the control group (*P < 0.05). Afterward, treated with MAPK pathways inhibitors, only ERK inhibitor（U0126）could reduce the expression of EMT markers in SV-HUC-1 cells, but not p38 and JNK inhibitor（SB203580, SP600125）, which indicated that benzidine induces the epithelial-mesenchymal transition in human uroepithelial cells through ERK1/2 pathway. Taken together, findings from this study could provide into the molecular mechanisms by which benzidine exerts its bladder-cancer-promoting effect as well as its target intervention.

The effect of phytochemicals in N-methyl-N-nitro-N-nitroguanidine promoting the occurrence and development of gastric cancer.

Gastric cancer is a common malignant tumor of the digestive tract, with a low early diagnosis rate. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the main risk factors for gastric cancer. Phytochemicals are healthy active substances derived from vegetables, fruits, nuts, tea, herbal medicines and other plants. Taking phytochemicals is a very promising strategy for the prevention and treatment of gastric cancer. Many studies have proved that phytochemicals have protective effects on MNNG induced gastric cancer via inhibiting cell proliferation, enhancing immunity, suppressing cell invasion and migration, inducing apoptosis and autophagy, blocking angiogenesis, inhibiting Helicobacter pylori infection as well as regulating metabolism and microbiota. The intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer have attracted more and more attention. In order to better study and explore the role, advantages and challenges of phytochemicals in MNNG induced gastric cancer, we summarized the intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer. This review may help to further promote the research and clinical application of phytochemicals in MNNG induced gastric cancer, and provide some new insights.

Non-coding RNAs' function in cancer development, diagnosis and therapy.

While previous research on cancer biology has focused on genes that code for proteins, in recent years it has been discovered that non-coding RNAs (ncRNAs)play key regulatory roles in cell biological functions. NcRNAs account for more than 95% of human transcripts and are an important entry point for the study of the mechanism of cancer development. An increasing number of studies have demonstrated that ncRNAs can act as tumor suppressor genes or oncogenes to regulate tumor development at the epigenetic level, transcriptional level, as well as post-transcriptional level. Because of the importance of ncRNAs in cancer, most clinical trials have focused on ncRNAs to explore whether ncRNAs can be used as new biomarkers or therapies. In this review, we focus on recent studies of ncRNAs including microRNAs (miRNAs), long ncRNAs (lncRNAs), circle RNAs (circRNAs), PIWI interacting RNAs (piRNAs), and tRNA in different types of cancer and explore the application of these ncRNAs in the development of cancer and the identification of relevant therapeutic targets and tumor biomarkers. Graphical abstract drawn by Fidraw.

Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670.

As one of the most common malignant cancers in the world, gastric cancer is caused by mang factors among which tobacco smoke is an important risk factor. Gastric cancer stem cells (GCSCs) and the derived exosomes play a key role in the occurrence and development of gastric cancer, and exosomal circRNA is considered as a new regulatory factor in the development of gastric cancer. However, it is unclear whether tobacco smoke can affect exosomes and their transport circRNAs to promote the development of gastric cancer. Herein, we provided a new insight into tobacco smoke promoting the progression of gastric cancer. In the present study, we demonstrated that tobacco smoke-induced exosomes promoted the spheroidizing ability, stemness genes expression, and epithelial-mesenchymal transition (EMT) process of GCSCs. We further found that hsa-circRNA-000670 (circ670) was up-regulated in tissues of gastric cancer patients with smoking history, tobacco smoke-induced GCSCs, and their exosomes. Functional assays have shown that circ670 knockdown inhibited the stemness and EMT process of GCSCs, whereas circ670 overexpression appeared to have an opposite effect. Our findings indicated that exosomal circ670 promotes the development of tobacco smoke-induced gastric cancer, which may provide insight into the mechanism of tobacco smoke promoting the progression of gastric cancer.

Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer.

Circular RNAs (circRNAs) are non-coding single-stranded covalently closed circular RNA, mainly produced by reverse splicing of exons of precursor mRNAs (pre-mRNAs). The characteristics of high abundance, strong specificity, and good stability of circRNAs have been discovered. A large number of studies have reported its various functions and mechanisms in biological events, such as the occurrence and development of cancer. In this review, we focus on the classification, characterization, biogenesis, functions of circRNAs, and the latest advances in cancer research. The development of circRNAs as biomarkers in cancer diagnosis and treatment also provides new ideas for studying circRNAs research.

Role of ferroptosis and ferroptosis-related non-coding RNAs in the occurrence and development of gastric cancer.

Gastric cancer (GC) is a malignant cancer of the digestive tract and is a life-threatening disease worldwide. Ferroptosis is a newly discovered form of regulated cell death, which involves the accumulation of iron-dependent lipid peroxides. It has been found that ferroptosis plays an important regulatory role in the occurrence, development, drug resistance, and prognosis of GC. Non-coding RNAs (ncRNAs) play a critical role in the occurrence and progression of a variety of diseases including GC. In recent years, the role of ferroptosis and ferroptosis-related ncRNAs (miRNA, lncRNA, and circRNA) in the occurrence, development, drug resistance, and prognosis of GC has attracted more and more attention. Herein, we briefly summarize the roles and functions of ferroptosis and ferroptosis-related ncRNAs in GC tumorigenesis, development, and prognosis. We also prospected the future research direction and challenges of ferroptosis and ferroptosis-related ncRNAs in GC.

Tobacco Smoke Plays an Important Role in Initiation and Development of Lung Cancer by Promoting the Characteristics of Cancer Stem Cells.

Lung cancer is one of the most common causes of cancer-related deaths worldwide. Tobacco smoke is the single greatest risk factor of lung cancer. Although enormous progress in understanding the molecular mechanisms by which tobacco smoke leading to lung cancer has been made, the molecular pathogenesis remains largely unclear. Cancer stem cells have been implicated in cancer initiation, development, and drug resistance. In this review, we reviewed the relationship between tobacco smoke and lung cancer, the key role of cancer stem cells in lung cancer and other tumors. More importantly, we elucidate the mechanism of tobacco smoke promoting lung cancer from the perspective of the characteristics of cancer stem cells induced by tobacco smoke.

Simulation of the distribution of main atmospheric pollutants and the influence of land use on them in central urban area of Nanchang City, China.

With the rapid urbanization and industrialization in China, atmospheric pollution becomes increasingly urgent. It is of great importance to examine the distribution of atmospheric pollutants and the influence of land use for sake of reducing pollution. We simulated and analyzed the temporal and spatial distribution characteristics of the six main atmospheric pollutants in the central urban area of Nanchang City, i.e. PM2.5, PM10, SO2, NO2, CO and O3 based on land-use regression models (LUR). Four types of area, i.e. residential, commercial, educational and industrial area, were defined according to dominated land use type. Fifteen samples from each type were collected. The concentration of six air pollutants of fifteen sample areas for each type and each season were averaged to reduce the influence of meteorological factors. By means of double factor varian-ce analysis and multiple comparisons, we analyzed the effects of land use (expressed by sample area) on those atmospheric pollutants. The results showed that the concentrations of all the six atmospheric pollutants were well simulated by LUR model, with an average absolute error were 11.9%, 13.4%, 12.5%, 12.0%, 12.7% and 13.5% respectively. The concentration of six atmospheric pollutants showed obvious temporal and spatial distribution characteristics, with O3 presenting the highest in summer, then spring, autumn, and winter in order, and the remaining five pollutants peaked in winter, then spring, autumn and summer in order. The concentrations of PM2.5, PM10, SO2, NO2 and CO showed a decreasing trend from urban center to suburb, while the concentration of O3 was the opposite. The concentrations of varied seasons or land use sample areas were all significantly different, indicating that both meteorology and land use had significant effects on air pollution. The effects of land use on main atmospheric pollutants varied, with stronger effects on PM2.5, NO2 and O3 than on CO.

[Influence of land intensive use level on main atmospheric pollutants in the central urban area of Nanchang City, China.] / 南昌市中心城区土地集约利用水平对主要大气污染物的影响.

At present, urbanization has gradually changed from denotative expansion to connotative development in China. It is urgently needed for intensive use of land resources and the construction of "compact city". However, intensive land use means less land resources to carry more urban elements, therefore people will become more and more sensitive to environmental pollution, especially atmospheric pollution. It is of great significance to study the influence of intensive land use on atmospheric pollution. Taking the central urban area of Nanchang City as a case, this study simulated the concentration of the six main atmospheric pollutants i.e. PM2.5, PM10, SO2, NO2, CO and O3 by ordinary kriging interpolation firstly. Then, sixteen intensive land use variables, including the volume ratio, building density, population density, were analyzed with the partial least squares regression and path analysis in order to reveal the effects of intensive land use level on the atmospheric pollutants. The results showed that the correlations between intensive land use level and PM2.5, PM10 were the strongest, followed by O3 and NO2, and the weakest correlation was between intensive land use level and SO2, CO. The sequence of the correlation between intensive land use variables and the six main atmospheric pollutants in different sample areas was residential area> education area > business area > industrial area. The more intensive the land use was, it had greater impacts on the atmospheric pollutants. The greatest effect was on PM2.5 and PM10, followed by O3, and the least effect was on NO2. The direct, indirect, and integrated influences of intensive land use on atmospheric pollutants were generally equal. Overall, the direct influence of the intensive land use level was greater than the indirect one, among which the influence of the intensive land use level of the residential area was the strongest, followed by the business area, and the education area least. This study provided a new perspective on studying the influence of intensive land use on atmospheric environment, which would provide some reference to solve the atmospheric problems in compacted city.

MAPK/AP-1 pathway regulates benzidine-induced cell proliferation through the control of cell cycle in human normal bladder epithelial cells.

Bladder cancer is the most common malignancy of the urinary tract. Long-term exposure to benzidine is one of the major causes of bladder cancer. However, the mechanism of benzidine-induced bladder cancer is not yet sufficiently characterized. Dysregulated cell proliferation serves a critical role in cancer initiation and development; whether benzidine promotes cell proliferation, and the role of MAPKs in this process, have not previously been investigated. The present study aimed to investigate the benzidine-induced modulation of intracellular mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) signaling cascades on cell proliferation in SV-40 immortalized human uroepithelial cells (SV-HUC-1). It was identified that benzidine exposure enhanced the proliferation of SV-HUC-1 cells, promoted the transition of cells from G1 to S phase and altered the expression level of cell cycle-associated genes at the mRNA and protein levels. Furthermore, exposure of the SV-HUC-1 cells to benzidine was associated with the activation of MAPKs, including extracellular regulated protein kinases 1 and 2, p38 and Jun N-terminal kinase. The downstream target of MAPKs, AP-1 monomers, was also activated. Benzidine-induced proliferation was reversed by MAPK-specific inhibitors. Thus, the present study demonstrated that benzidine enhances the proliferation of bladder cells via activating the MAPK/AP-1 pathway, which may provide novel insights into the molecular mechanisms of benzidine-initiated bladder tumorigenesis, as well as cancer prevention.

Cigarette smoke extract induces the proliferation of normal human urothelial cells through the NF-κB pathway.

Bladder cancer is a common genitourinary malignant disease worldwide. Convincing evidence shows that cigarette smoke (CS) is a crucial risk factor for bladder cancer, yet the role of the NF-κB signaling pathway in the development of CS-associated bladder cancer has not been fully elucidated. In the present study, we found that exposure to cigarette smoke extract (CSE) induced proliferation and triggered the transition of normal human urothelial cells from G1 to S phase. Moreover, CSE exposure enhanced the expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) and decreased the expression of p21 in SV-HUC-1 cells. Furthermore, the levels of nuclear NF-κB p65/p50 were significantly elevated by CSE. Pre-treatment with the NF-κB inhibitor (PDTC) reversed CSE-triggered cell proliferation. Taken together, our study revealed that CSE induced proliferation of normal human urothelial cells through the NF-κB pathway, and these data enhance our understanding of the CSE-related carcinogenesis of bladder cancer.

Curcumin reverses benzidine-induced cell proliferation by suppressing ERK1/2 pathway in human bladder cancer T24 cells.

Bladder cancer is one of the leading causes of cancer-related death in the world. Prolonged exposure to benzidine is a known cause of bladder cancer. Curcumin has been clinically used in chemoprevention and treatment of cancer. However, it remains unknown whether mitogen-activated protein kinase (MAPK) pathways are involved in curcumin-mediated protection from benzidine-associated promotive effects on bladder cancer. In our study, we found that benzidine increased the proliferation of human bladder cancer T24 cells, triggered transition of the cells from G1 to S phase, elevated the expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) and decreased p21 expression. Meanwhile, exposure of T24 cells to benzidine resulted in activation of extracellular regulated protein kinases 1 and 2 (ERK1/2) pathway as well as activator protein 1 (AP-1) proteins. Treatment with ERK1/2 inhibitor U0126 or curcumin effectively abrogated benzidine-triggered cell proliferation and ERK1/2/AP-1 activation. These results suggested for the first time that curcumin in low concentrations played a protective role in benzidine-induced ERK1/2/AP-1 activation and proliferation of bladder cancer cells, therefore providing new insights into the pathogenesis and chemoprevention of benzidine-associated bladder cancer.