Ionizing radiation induces neurotoxicity in Xenopus laevis embryos through neuroactive ligand-receptor interaction pathway.

Ionizing radiation (IR) poses a significant threat to both the natural environment and biological health. Exposure to specific doses of ionizing radiation early in an organism's development can lead to developmental toxicity, particularly neurotoxicity. Through experimentation with Xenopus laevis (X. laevis), we examined the effects of radiation on early developmental stage. Our findings revealed that radiation led to developmental abnormalities and mortality in X. laevis embryos in a dose-dependent manner, disrupting redox homeostasis and inducing cell apoptosis. Additionally, radiation caused neurotoxic effects, resulting in abnormal behavior and neuron damage in the embryos. Further investigation into the underlying mechanisms of radiation-induced neurotoxicity indicated the potential involvement of the neuroactive ligand-receptor interaction pathway, which was supported by RNA-Seq analysis. Validation of gene expression associated with this pathway and analysis of neurotransmitter levels confirmed our hypothesis. In addition, we further validated the important role of this signaling pathway in radiation-induced neurotoxicity through edaravone rescue experiments. This research establishes a valuable model for radiation damage studying and provides some insight into radiation-induced neurotoxicity mechanisms.

PET imaging of new target CDK19 in prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) is a superior method to predict patients' risk of cancer progression and response to specific therapies. However, its performance is limited for neuroendocrine prostate cancer (NEPC) and PSMA-low prostate cancer cells, resulting in diagnostic blind spots. Hence, identifying novel specific targets is our aim for diagnosing those prostate cancers with low PSMA expression. METHODS: The Cancer Genome Atlas (TCGA) database and our cohorts from men with biopsy-proven high-risk metastatic prostate cancer were used to identify CDK19 and PSMA expression. PDX lines neP-09 and P-16 primary cells were used for cellular uptake and imaging mass cytometry in vitro. To evaluate in vivo CDK19-specific uptake of gallium(Ga)-68-IRM-015-DOTA, xenograft mice models and blocking assays were used. PET/CT imaging data were obtained to estimate the absorbed dose in organs. RESULTS: Our study group had reported the overexpression of a novel tissue-specific gene CDK19 in high-risk metastatic prostate cancer and CDK19 expression correlated with metastatic status and tumor staging, independently with PSMA and PSA levels. Following up on this new candidate for use in diagnostics, small molecules targeting CDK19 labeled with Ga-68 (68Ga-IRM-015-DOTA) were used for PET in this study. We found that the 68Ga-IRM-015-DOTA was specificity for prostate cancer cells, but the other cancer cells also took up little 68Ga-IRM-015-DOTA. Importantly, mouse imaging data showed that the NEPC and CRPC xenografts exhibited similar signal strength with 68Ga-IRM-015-DOTA, but 68Ga-PSMA-11 only stained the CRPC xenografts. Furthermore, target specificity was elucidated by a blocking experiment on a CDK19-bearing tumor xenograft. These data concluded that 68Ga-CDK19 PET/CT was an effective technology to detect lesions with or without PSMA in vitro, in vivo, and in the PDX model. CONCLUSION: Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that 68Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.

Amelioration of gamma irradiation-induced salivary gland damage in mice using melatonin.

Salivary gland damage caused by ionizing radiation (IR) severely affects the patient quality of life and influences the efficacy of radiotherapy. Most current treatment modalities are palliative, so effective prevention of damage caused by IR is essential. Melatonin (MLT) is an antioxidant that has been reported to prevent IR-induced damage in a range of systems, including the hematopoietic system and gastrointestinal tract. In this study, we explored the effects of MLT on whole-neck irradiation (WNI)-induced salivary gland damage in mice. The results revealed that by protecting the channel protein AQP-5, MLT not only alleviates salivary gland dysfunction and maintains salivary flow rate, but also protects salivary gland structure and inhibits the WNI-induced reduction in mucin production and degree of fibrosis. Compared with WNI-treated mice, in those receiving MLT, we observed a modulation of oxidative stress in salivary glands via its effects on 8-OHdG and SOD2, as well as an inhibition of DNA damage and apoptosis. With respect to its radioprotective mechanism, we found that MLT may alleviate WNI-induced xerostomia partly by regulating RPL18A. In vitro, we demonstrated that MLT has radioprotective effects on salivary gland stem cells (SGSCs). In conclusion, our data this study indicate that MLT can effectively alleviate radiation-induced damage in salivary glands, thereby providing a new candidate for the prevention of WNI-induced xerostomia.

The exciting encounter between lncRNAs and radiosensitivity in IR-induced DNA damage events.

Radiation therapy is a commonly used tool in cancer management due to its ability to destroy malignant tumors. Mechanically, the efficacy of radiotherapy mainly depends on the inherent radiosensitivity of cancer cells and surrounding normal tissues, which mostly accounts for molecular dynamics associated with radiation-induced DNA damage. However, the relationship between radiosensitivity and DNA damage mechanism deserves to be further probed. As the well-established RNA regulators or effectors, long noncoding RNAs (lncRNAs) dominate vital roles in modulating ionizing radiation response by targeting crucial molecular pathways, including DNA damage repair. Recently, emerging evidence has constantly confirmed that overexpression or inhibition of lncRNAs can greatly influence the sensitivity of radiotherapy for many kinds of cancers, by driving a diverse array of DNA damage-associated signaling cascades. In conclusion, this review critically summarizes the recent progress in the molecular mechanism of IR-responsive lncRNAs in the context of radiation-induced DNA damage. The different response of lncRNAs when IR exposure. IR exposure can trigger the changes in expression pattern and subcellular localization of lncRNAs that influences the different radiology processes.

MiR-145 modulates the radiosensitivity of non-small cell lung cancer cells by suppression of TMOD3.

Radioresistance is a major problem encountered in the treatment of non-small cell lung cancer (NSCLC). Aberrant microRNA (miRNA) expression contributes to multiple cancer-associated signaling pathways and profoundly influences effects of radiotherapy (RT) in cancers. MicroRNA-145-5p (miR-145) is recognized as a tumor suppresser in NSCLC. However, the roles of miR-145 during radiotherapy of NSCLC are largely unknown. The present study aimed to investigate the function and underlying mechanism of miR-145 in modulation of radiosensitivity in NSCLC. We generated radioresistant H460 and A549 subclones, named H460R and A549R, respectively, and found that irradiation (IR) could suppress the expression levels of miR-145 in radioresistant NSCLC cells. Furthermore, overexpression of miR-145 could sensitize radioresistant NSCLC cells to IR, whereas knockdown of miR-145 in NSCLC cells acted the converse manner. Mechanically, miR-145 was able to directly target 3'UTR of tropomodulin 3 (TMOD3) mRNA and decrease the expression of TMOD3 at the levels of mRNA and protein. Additionally, we confirmed that miR-145 could enhance the radiosensitivity of radioresistant NSCLC cells by targeting TMOD3 in vitro and in vivo, and could be used as a target in clinical treatment of NSCLC. Collectively, restoration of miR-145 expression increases the radiosensitivity of radioresistant NSCLC cells by suppression of TMOD3, and miR-145 can act as a new radiosensitizer for NSCLC therapy.

FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway.

Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4-DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4-DRI is inclined to kill TGF-ß-induced myofibroblast in vitro. The inhibited effect of FOXO4-DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM-induced PF. Above all, FOXO4-DRI ameliorates BLM-induced PF in mouse and may be served as a viable therapeutic option for PF.

Caloric restriction alleviates radiation injuries in a sex-dependent fashion.

Safe and effective regimens are still needed given the risk of radiation toxicity from iatrogenic irradiation. The gut microbiota plays an important role in radiation damage. Diet has emerged as a key determinant of the intestinal microbiome signature and function. In this report, we investigated whether a 30% caloric restriction (CR) diet may ameliorate radiation enteritis and hematopoietic toxicity. Experimental mice were either fed ad libitum (AL) or subjected to CR preconditioning for 10 days and then exposed to total body irradiation (TBI) or total abdominal irradiation (TAI). Gross examinations showed that short-term CR pretreatment restored hematogenic organs and improved the intestinal architecture in both male and female mice. Intriguingly, CR preconditioning mitigated radiation-induced systemic and enteric inflammation in female mice, while gut barrier function improved in irradiated males. 16S rRNA high-throughput sequencing showed that the frequency of pro-inflammatory microbes, including Helicobacter and Desulfovibrionaceae, was reduced in female mice after 10 days of CR preconditioning, while an enrichment of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibaculum, Clostridiales, and Lactobacillus, was observed in males. Using fecal microbiota transplantation (FMT) or antibiotic administration to alter the gut microbiota counteracted the short-term CR-elicited radiation tolerance of both male and female mice, further indicating that the radioprotection of a 30% CR diet depends on altering the gut microbiota. Together, our findings provide new insights into CR in clinical applications and indicate that a short-term CR diet prior to radiation modulates sex-specific gut microbiota configurations, protecting male and female mice against the side effects caused by radiation challenge.

Social Hierarchy Dictates Intestinal Radiation Injury in a Gut Microbiota-Dependent Manner.

Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application.

Gut metabolite Urolithin A mitigates ionizing radiation-induced intestinal damage.

Ionizing radiation (IR)-induced intestinal damage is the major and common injury of patients receiving radiotherapy. Urolithin A (UroA) is a metabolite of the intestinal flora of ellagitannin, a compound found in fruits and nuts such as pomegranates, strawberries and walnuts. UroA shows the immunomodulatory and anti-inflammatory capacity in various metabolic diseases. To evaluate the radioprotective effects, UroA(0.4, 2 and 10 mg/kg) were intraperitoneally injected to C57BL/6 male mice 48, 24, 1 h prior to and 24 h after 9.0Gy TBI. The results showed that UroA markedly upregulated the survival of irradiated mice, especially at concentration of 2 mg/kg. UroA improved the intestine morphology architecture and the regeneration ability of enterocytes in irradiated mice. Then, UroA significantly decreased the apoptosis of enterocytes induced by radiation. Additionally, 16S rRNA sequencing analysis showed the effect of UroA is associated with the recovery of the IR-induced intestinal microbacteria profile changes in mice. Therefore, our results determinated UroA could be developed as a potential candidate for radiomitigators in radiotherapy and accidental nuclear exposure. And the beneficial functions of UroA might be associated with the inhibition of p53-mediated apoptosis and remodelling of the gut microbes.

Knockout of zebrafish colony-stimulating factor 1 receptor by CRISPR/Cas9 affects metabolism and locomotion capacity.

Colony-stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor and a key regulator of proliferation, differentiation, migration, and colonization in macrophage lineage cells. CSF1R was found to be involved in the pathogenesis of immune disorders, hematopoietic diseases, tissue damage, tumor growth and metastasis, and so on. Hence, understanding the role of CSF1R is important. CSF1R is highly conserved among vertebrates. In zebrafish, it is encoded by the colony-stimulating factor 1 receptor a (csf1ra) gene. In this study, a csf1ra-/- zebrafish mutant line was generated using clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. csf1ra-/- larvae lacked the yellow cast on their heads and over their flanks, while adult mutants had poorly formed stripes. RNA-sequence analysis revealed that genes related to bile acid secretion, fat digestion and absorption, and pancreatic secretion were differentially expressed in csf1ra-/- mutants, which led to fatty changes in the liver. In addition, genes related to locomotion were also significantly changed, with the more active movement observed in csf1ra-/- larvae. Our study demonstrated that csf1ra participates in the metabolic process and behavior. This study provides new insights into csf1ra function during zebrafish development.

Exosomes are involved in total body irradiation-induced intestinal injury in mice.

Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg-1·d-1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.

The Effects of Melatonin Administration on Intestinal Injury Caused by Abdominal Irradiation from Mice.

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.

Gut Microbiota-Derived l-Histidine/Imidazole Propionate Axis Fights against the Radiation-Induced Cardiopulmonary Injury.

Radiation-induced cardiopulmonary injuries are the most common and intractable side effects that are entwined with radiotherapy for thorax cancers. However, the therapeutic options for such complications have yielded disappointing results in clinical applications. Here, we reported that gut microbiota-derived l-Histidine and its secondary metabolite imidazole propionate (ImP) fought against radiation-induced cardiopulmonary injury in an entiric flora-dependent manner in mouse models. Local chest irradiation decreased the level of l-Histidine in fecal pellets, which was increased following fecal microbiota transplantation. l-Histidine replenishment via an oral route retarded the pathological process of lung and heart tissues and improved lung respiratory and heart systolic function following radiation exposure. l-Histidine preserved the gut bacterial taxonomic proportions shifted by total chest irradiation but failed to perform radioprotection in gut microbiota-deleted mice. ImP, the downstream metabolite of l-Histidine, accumulated in peripheral blood and lung tissues following l-Histidine replenishment and protected against radiation-induced lung and heart toxicity. Orally gavaged ImP could not enter into the circulatory system in mice through an antibiotic cocktail treatment. Importantly, ImP inhibited pyroptosis to nudge lung cell proliferation after radiation challenge. Together, our findings pave a novel method of protection against cardiopulmonary complications intertwined with radiotherapy in pre-clinical settings and underpin the idea that gut microbiota-produced l-Histidine and ImP are promising radioprotective agents.

Hyaluronic Acid-Modified Au-Ag Alloy Nanoparticles for Radiation/Nanozyme/Ag+ Multimodal Synergistically Enhanced Cancer Therapy.

Gold nanoparticles (AuNPs) have been widely documented as tumor radiosensitizers via enhanced energy deposition of ionizing radiation. However, the sensitization efficiency of AuNPs is still far from satisfactory owing to the irradiation on nontarget tissues and the tumor radio-resistance. To address these issues, we report herein the rational design and development of hyaluronic acid-modified Au-Ag alloy nanoparticles (Au-Ag@HA NPs) with effective tumor radiosensitization by receptor mediated tumor targeting as well as microenvironment-activated hydroxyl radicals (•OH) generation. In our work, Au-Ag@HA NPs were synthesized by the coreduction of HAuCl4 and AgNO3 in the presence of trisodium citrate, followed by surface modification of HA to the Au-Ag alloy NPs. HA modification affords the alloy NPs with specific targeting to 4T1 breast cancer cells overexpressing CD44 receptor, while the introduction of Ag atom imparts the alloy NPs with superior multienzyme-like activities to the monometallic AuNPs for efficient tumor catalytic therapy. More importantly, the ionizing radiation and peroxidase-like activity of Au-Ag@HA NPs boost the production of •OH and the release of toxic Ag+ in the tumor sites, thereby leading to effective tumor therapeutic outcome. This work provides a promising treatment paradigm for radiation/nanozyme/Ag+ combined therapy against cancer and will advance the design and development of multifunctional nanoplatforms for synergetically enhanced tumor therapy.

CLPTM1L induces estrogen receptor ß signaling-mediated radioresistance in non-small cell lung cancer cells.

INTRODUCTION: Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor ß (ERß) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERß in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERß-mediated transcriptional activation and radioresistance of NSCLC cells. METHODS: Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERß and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. RESULTS: CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERß, and CLPTM1L upregulated ERß-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERß by directly interacting with ERß through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERß silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. CONCLUSIONS: The present results indicate that CLPTM1L acts as a critical coactivator of ERß to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy. Video Abstract.

Enhanced radiotherapy using photothermal therapy based on dual-sensitizer of gold nanoparticles with acid-induced aggregation.

The damaged DNA strands caused by radiotherapy (RT) can repair by themselves. A gold nanoparticles (GNPs) system with acid-induced aggregation was developed into a dual sensitizer owing to its high radioactive rays attenuation ability and enhanced photothermal heating efficiency after GNPs aggregation to achieve a combination therapy of RT and photothermal therapy (PTT). In this combination therapy, the formed GNP aggregates firstly showed a higher sensitize enhancement ratio (SER) value (1.52). Importantly, the self-repair of damaged DNA strands was inhibited by mild PTT through down-regulating the expression of DNA repair protein, thus resulting in a much higher SER value (1.68). Anti-tumor studies further demonstrated that this combination therapy exhibited ideal anti-tumor efficacy. Furthermore, the imaging signals of GNPs in computed tomography and photoacoustic were significantly improved following the GNPs aggregation. Therefore, a dual sensitizer with multimodal imaging was successfully developed and can be further applied as a new anti-tumor therapy.

MiR-365 enhances the radiosensitivity of non-small cell lung cancer cells through targeting CDC25A.

Radioresistance is a major challenge in lung cancer radiotherapy (RT), and consequently, new radiosensitizers are urgently needed. MicroRNAs (miRNAs) have been demonstrated to participate in many important cellular processes including radiosensitization. MiR-365 is dysregulated in non-small cell lung cancer (NSCLC) and is able to restrain the development of NSCLC. However, the relationship between miR-365 and radiosensitivities of NSCLC cells remains largely unknown. Here we reveal that overexpression of miR-365 is able to enhance the radiosensitivity of NSCLC cells through targeting CDC25A. We found that the expression level of miR-365 was positively correlated with the radiosensitivity of NSCLC cell lines. Furthermore, our results showed that overexpression of miR-365 could sensitize A549 cells to the irradiation. However, knockdown of miR-365 in H460 cells could act the converse manner. Mechanically, miR-365 was able to directly target 3'UTR of cell division cycle 25A (CDC25A) mRNA and reduce the expression of CDC25A at the levels of mRNA and protein. And we confirmed that miR-365 could increase the radiosensitivity of NSCLC cells by targeting CDC25A using in vitro and in vivo assays. Taken together, restoration of miR-365 expression enhances the radiosensitivity of NSCLC cells by suppressing CDC25A, and miR-365 could be used as a radiosensitizer for NSCLC therapy.

Cordycepin sensitizes breast cancer cells toward irradiation through elevating ROS production involving Nrf2.

Radiation therapy toward malignancies is often ineffective owing to radioresistance of cancer cells. On the basis of anti-tumor properties of cordycepin, we examined the effects of cordycepin on sensitizing breast cancer cells toward radiotherapy. Cordycepin administration promoted G2/M arrest and apoptosis of MCF-7 and MDA-MB-231 cells resulting in restraining the proliferation of the cells in vitro and in vivo following irradiation. Mechanistic investigations showed that the breast cancer cells cultured with cordycepin harbored higher levels of intracellular reactive oxygen species (ROS) and incremental numbers of γ-H2AX foci after irradiation exposure. Importantly, cordycepin treatment down-regulated the expression levels of Nuclear factor erythroid 2-related factor (Nrf2) and a series of downstream genes, such as heme oxygenase-1 (HO-1), to enhance ROS in breast cancer cells exposed to irradiation. Together, our observations demonstrate that cordycepin treatment sensitizes breast carcinoma cells toward irradiation via Nrf2/HO-1/ROS axis. Thus, our findings provide novel insights into the function and the underlying mechanism of cordycepin in radiotherapy, and suggest that cordycepin might be employed as a radiosensitizer during radiotherapy toward breast cancer in a pre-clinical setting.

Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC.

Irradiation exposure positive correlates with tumor formation, such as breast cancer and lung cancer. However, whether low dose irradiation induces hepatocarcinogenesis and the underlying mechanism remain poorly defined. In the present study, we reported that low dose irradiation facilitated the proliferation of hepatocyte through up-regulating HULC in vitro and in vivo. Low dose irradiation exposure elevated HULC expression level in hepatocyte. Deletion of heightened HULC erased the cells growth accelerated following low dose irradiation exposure. CDKN1, the neighbor gene of HULC, was down-regulated by overexpression of HULC following low dose irradiation exposure via complementary base pairing, resulting in promoting cell cycle process. Thus, our findings provide new insights into the mechanism of low dose irradiation-induced hepatocarcinogenesis through HULC/CDKN1 signaling, and shed light on the potential risk of low dose irradiation for the development of hepatocellular carcinoma in pre-clinical settings.

The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways.

Mammalian hepatitis B X-interacting protein (HBXIP) is an 18-kDa protein that regulates a large number of transcription factors such as TF-IID, E2F1, SP1, STAT3, c-Myc, and LXR by serving as an oncogenic transcription coactivator and plays an important role in the development of breast cancer. We previously showed that HBXIP as an oncoprotein could enhance the promoter activity of MDM2 through coactivating p53, promoting the MDM2 transcription in breast cancer. In this study we investigated the molecular mechanisms underlying the modulation of MDM2/p53 interaction by HBXIP in human breast cancer MCF-7 cells in vitro and in vivo. We showed that HBXIP could up-regulate MDM2 through inducing DNA methylation of miR-18b, thus suppressing the miR-18b expression, leading to the attenuation of p53 in breast cancer cells. In addition, HBXIP could promote the phosphorylation of MDM2 by increasing the level of pAKT and bind to pMDM2, subsequently enhancing the interaction between MDM2 and p53 for the down-regulation of p53 in breast cancer cells. In MCF-7 breast cancer xenograft nude mice, we also observed that overexpression of HBXIP promoted breast cancer growth through the miR-18b/MDM2 and pAKT/MDM2 pathways. In conclusion, oncoprotein HBXIP suppresses miR-18b to elevate MDM2 and activates pAKT to phosphorylate MDM2 for enhancing the interaction between MDM2 and p53, leading to p53 degradation in promotion of breast cancer growth. Our findings shed light on a novel mechanism of p53 down-regulation during the development of breast cancer.