Lung cancer has high morbidity and mortality worldwide with non-small cell lung cancer (NSCLC) accounting for 85% of the cases. Therapies for lung cancer have relatively poor outcomes and further ...improvements are required. Circular RNAs have been reported to participate in the occurrence and progression of cancer. Information on the functions and mechanism of circRNAs in lung cancer is limited and needs more exploration.
We detected expression of genes and proteins by qPCR and western blot. Function of circSATB2 was investigated using RNA interference and overexpression assays. Location of circSATB2 was assessed by fluorescence in situ hybridization (FISH). Interaction of circSATB2, miR-326 and FSCN1 was confirmed by dual-luciferase reporter assay.
Data from the investigation showed that circSATB2 was highly expressed in NSCLC cells and tissues. circSATB2 positively regulated fascin homolog 1, actin-bundling protein 1 (FSCN1) expression via miR-326 in lung cancer cells. Furthermore, circSATB2 can be transferred by exosomes and promote the proliferation, migration and invasion of NSCLC cells, as well as induce abnormal proliferation in normal human bronchial epithelial cells. Also, circSATB2 was highly expressed in serumal exosomes from lung cancer patients with high sensitivity and specificity for clinical detection and was related to lung cancer metastasis.
circSATB2 participated in the progression of NSCLC and was differentially expressed in lung cancer tissue and serumal exosomes. circSATB2 may be potential biomarker for the diagnosis of NSCLC.
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, despite improvements in the clinical trial and diagnosis, HCC still remains high mortality due to the 70% recurrence ...and lung metastasis after surgical resection. Exosomes are small membrane vesicles, which are shuttled from donor cells to recipient cells, contributing to the recruitment and reprogramming of constituents via an autocrine or paracrine fashion. HCC derived exosomes could redirect metastasis of tumor cells which lack the capacity to metastasize to a specific organ via generating pre-metastatic niche. These findings emphasize a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. We herein summarize recent findings that implicate oncogenes and non-canonical signaling of HCC exosomes, as well as the impact of exosomal bioactive molecules in high recurrence induced by organ-specific metastasis. The aim of review is to illustrate the underlying mechanism of exosomes in tumor metastasis, immune evasion, and the potential application of prognostic biomarker in HCC process.
•The cargo of tumor derived exosomes induce epithelial mesenchymal transition (EMT) progression.•Exosomes promote specific-organ metastasis and immunomodulatory effects via generating a premetastatic niche formation.•Tumor derived exosomes have potent immunomodulatory effects to foster the tumor escape from immunosurveillance in host.•The exosomal RNAs in patients with HCC can be the appropriate markers for early diagnosis.
Circular RNAs are widely expressed in eukaryotic cells and associated with cancer. However, limited studies to date have focused on the potential role of circRNAs in progression of lung cancer. Data ...from the current investigation showed that circRNA 100146 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and the chemically induced malignant transformed bronchial cell line, 16HBE-T, as well as 40 paired tissue samples of NSCLC. Suppression of circRNA 100146 inhibited the proliferation and invasion of cells and promoted apoptosis. Furthermore, circRNA 100146 could interact with splicing factors and bind miR-361-3p and miR-615-5p to regulate multiple downstream mRNAs. Our collective findings support a role of circRNA 100146 in the development of NSCLC and further demonstrate endogenous competition among circRNA 100146, SF3B3 and miRNAs, providing novel insights into the mechanisms underlying non-small cell lung cancer.
Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor ...suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess.
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•PM2.5 induces inflammatory response by NLRP3 inflammasome activation.•CircBbs9 contributes to the pulmonary inflammation and thus further aggravates COPD caused by PM2.5.•CircBbs9 interacts with ...miR-30e-5p to facilitate the inflammation via activating NLRP3 inflammasome.
Fine particulate matter (PM2.5) is one of the most important components of environmental pollutants, and is associated with pulmonary injury. However, the biological mechanisms of pulmonary damage caused by PM2.5 are poorly defined, especially the molecular pathways related to inflammation. Following system exposure to PM2.5 for 3 months in normal mice and in chronic obstructive pulmonary disease (COPD) model mice, it was found that PM2.5 exposure increased the expression of IL-1β and IL-18 in lung tissues via NLRP3 activation, and these effects were more intense in COPD model mice. Circular RNA (circRNA) sequencing showed that the expression profiles of circRNAs were changed after PM2.5 exposure, and the positive roles of circBbs9 in inflammation induced by PM2.5 were verified. The circBbs9 knockdown alleviated PM2.5-induced inflammation via NLRP3 inflammasome inactivation, as well as IL-1β and IL-18 inhibition in RAW264.7 cells, while overexpression of circBbs9 had the opposite effect. Bioinformatics and luciferase reporter assays showed that circBbs9 bound to microRNA-30e-5p (miR-30e-5p) and co-regulated the expression of Adar, a downstream target gene of miR-30e-5p. Taken together, these results revealed that PM2.5 induced pulmonary inflammation through NLRP3 inflammasome activation regulated by the circBbs9-miR-30e-5p-Adar pathway. Our findings provide a new target, circBbs9, for the assessment of lung inflammation and COPD exacerbation induced by PM2.5 exposure.
Lead is a metal that has toxic effects on the developing nervous system. However, the mechanisms underlying lead-induced neurotoxicity are not well understood. Non-coding RNAs (ncRNAs) play an ...important role in epigenetic regulation, but few studies have examined the function of ncRNAs in lead-induced neurotoxicity. We addressed this in the present study by evaluating the functions of a long non-coding RNA (named
lncRpa
) and a circular RNA (named
circRar1
) in a mouse model of lead-induced neurotoxicity. High-throughput RNA sequencing showed that both
lncRpa
and
circRar1
promoted neuronal apoptosis. We also found that
lncRpa
and
circRar1
induced the upregulation of apoptosis-associated factors caspase8 and p38 at the mRNA and protein levels via modulation of their common target microRNA
miR
-
671
. This is the first report of a regulatory interaction among a lncRNA, circRNA, and miRNA mediating neuronal apoptosis in response to lead toxicity.
•CircRNA interact with protein to regulate the PM2.5-induced inflammatory responses.•Circ_406961 inhibit PM2.5-induced BEAS-2B cells inflammatory responses.•ILF2 affect inflammatory response via ...STAT3/JNK signal pathway.
Fine particulate matter (PM2.5) has been verified to augmented the incidence of pneumonia, asthma, pulmonary fibrosis, and other pulmonary diseases. Airway inflammation is the pathological basis of the respiratory system, and understanding the molecular mechanisms responsible for airway inflammation may thus support the diagnosis and treatment of respiratory diseases. In our study, human bronchial epithelial cells (BEAS-2B) were exposed to various concentrations of PM2.5 for 48 h. PM2.5 entered the cells, resulting in increased production of interleukin 6 (IL-6) and interleukin 8 (IL-8) and decreased the expression of circular RNA 406961 (circ_406961). Further, PM2.5 with a concentration of 75 μg/mL was applied to mechanism study. Functional experiments further confirmed that circ_406961 inhibited PM2.5-induced BEAS-2B cell inflammation. RNA pull-down and mass spectrometry showed that circ_406961 interacted with interleukin enhancer-binding factor 2 (ILF2), which could regulate phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase 8 (MAPK8, JNK). Our studies showed that circ_406961 inhibited activation of STAT3/JNK pathways via interacting with ILF2 protein, thereby inhibiting the PM2.5-induced inflammatory reaction.
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A surge of platinum(IV) compounds are utilized or investigated in cancer treatment but their therapeutic outcomes have been greatly compromised by remaining adverse effects and ...limited antitumor performance, attributable to nonspecific distribution and insufficient activation in tumor site. Herein, we designed a series of disulfide bond introduced Pt(IV)-lipid prodrugs with different branch length, all of which are able to self-stabilize into nanomedicine and be activated by high intracellular glutathione (GSH) level. The impact of precise modification of these prodrugs on their assembly stability, pharmacokinetics and cytotoxicity was probed to establish a connection between chemical structure and antiproliferation efficiency. With optimal assembly manner and delivery efficacy, the longest axial branched Pt(IV) prodrug CSS18 exhibited the most impressive therapeutic outcome, providing a potential path to more efficient nanocarriers for chemotherapeutic agents by chemical modulation and, giving insights into the rational design of reduction responsive platinum delivery system.
Lung cancer is the most common form of cancer throughout the world. The specific targeting of long noncoding RNAs (lncRNAs) by resveratrol opened a new avenue for cancer chemoprevention. In this ...study, we found that 21 lncRNAs were upregulated and 19 lncRNAs were downregulated in lung cancer A549 cells with 25μmol/L resveratrol treatment determined by microarray analysis. AK001796, the lncRNA with the most clearly altered expression, was overexpressed in lung cancer tissues and cell lines, but its expression was downregulated in resveratrol-treated lung cancer cells. By monitoring cell proliferation and growth in vitro and tumor growth in vivo, we observed a significant reduction in cell viability in lung cancer cells and a slow growth in the tumorigenesis following AK001796 knockdown. We also found that AK001796 knockdown caused a cell-cycle arrest, with significant increases in the percentage of cells in G0/G1 in lung cancer cells. By using cell cycle pathway-specific PCR arrays, we detected changes in a number of cell cycle-related genes related to lncRNA AK001796 knockdown. We further investigated whether AK001796 participated in the anticancer effect of resveratrol and the results showed that reduced lncRNA AK001796 level potentially impaired the inhibitory effect of resveratrol on cell proliferation. To our knowledge, this is the first study to report the changes in an lncRNA expression profile induced by resveratrol in lung cancer.
•LncRNA AK001796 played an oncogenic role in lung carcinogenesis.•LncRNA AK001796 was downregulated in resveratrol-treated lung cancer cells.•LncRNA AK001796 was involved in the inhibition of cell growth by resveratrol.
•BaP induces DNA damage response (DDR) in bronchial epithelial cells.•BaP upregulates circ_0057504 through suppressing DNMT3A-mediated DNA methylation.•Circ_0057504 promotes BaP-induced DDR via ...modulating NONO-SFPQ complex formation.
Benzoapyrene (BaP) is a class I carcinogen and hazardous environmental pollutant with genetic toxicity. Understanding the molecular mechanisms underlying genetic deterioration and epigenetic alterations induced by environmental contaminants may contribute to the early detection and prevention of cancer. However, the role and regulatory mechanisms of circular RNAs (circRNAs) in the BaP-induced DNA damage response (DDR) have not been elucidated. In this study, human bronchial epithelial cell lines (16HBE and BEAS-2B) were exposed to various concentrations of BaP, and BALB/c mice were treated with BaP intranasally. BaP exposure was found to induce DNA damage and upregulate circular RNA hsa_circ_0057504 (circ_0057504) expression in vitro and in vivo. In addition, BaP upregulated TMEM194B mRNA and circ_0057504 expression through inhibition of DNA methyltransferase 3 alpha (DNMT3A) expression in vitro. Modulation (overexpression or knockdown) of circ_0057504 expression levels using a lentiviral system in human bronchial epithelial cells revealed that circ_0057504 promoted BaP-induced DNA damage. RNA pull-down and western blot assays showed that circ_0057504 interacted with non-POU domain-containing octamer-binding (NONO) and splicing factor proline and glutamine rich (SFPQ) proteins and regulated formation of the NONO-SFPQ protein complex. Thus, our findings indicate that circ_0057504 acts as a novel regulator of DNA damage in human bronchial epithelial cells exposed to BaP. The current study reveals novel insights into the role of circRNAs in the regulation of genetic damage, and describes the effect and regulatory mechanisms of circ_0057504 on BaP genotoxicity.
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