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Although kidney is a target organ of arsenic cytotoxicity, the underlying mechanisms of arsenic-induced nephrotoxicity remain poorly understood. As tetramethylpyrazine (TMP) has recently been found to be a renal protectant in multiple kidney injuries, we hypothesize that TMP could suppress arsenic nephrotoxicity. In this study, human renal proximal tubular epithelial cell line HK-2 was used to elucidate the precise mechanisms of arsenic nephrotoxicity as well as the protective mechanism of TMP in these cells. Sodium arsenite exposure dramatically increased cellular reactive oxygen species (ROS) production, decreased levels of cellular glutathione (GSH), decreased cytochrome c oxidase activity and mitochondrial membrane potential, which indicated mitochondrial dysfunction. On the other hand, sodium arsenite activated pro-inflammatory signals, including β-catenin, nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor alpha and cyclooxygenase-2 (COX-2). Small molecule inhibitors of NF-κB and p38 MAPK blocked arsenic-induced COX-2 expression, suggesting arsenic-induced COX-2 up-regulation was NF-κB- and p38 MAPK-dependent. Finally, sodium arsenite induced autophagy in HK-2 cells at early phase (6 h) and the subsequent apoptosis at 24 h. Treatment by TMP or by the antioxidant N -acetylcysteine decreased arsenic-induced ROS production, enhanced GSH levels, prevented mitochondria dysfunction and suppressed the activation of pro-inflammatory signals and the development of autophagy and apoptosis. Our results suggested that TMP may be used as a new potential therapeutic agent to prevent arsenic-induced nephrotoxicity by suppressing these pathological processes.

Long noncoding RNAs (lncRNAs) in eukaryotic transcripts have long been believed to regulate various aspects of cellular processes, including carcinogenesis. Herein, it is found that lncRNA AFAP1‐AS1 encodes a conserved 90‐amino acid peptide located on mitochondria, named lncRNA AFAP1‐AS1 translated mitochondrial‐localized peptide (ATMLP), and it is not the lncRNA but the peptide that promotes the malignancy of nonsmall cell lung cancer (NSCLC). As the tumor progresses, the serum level of ATMLP increases. NSCLC patients with high levels of ATMLP display poorer prognosis. Translation of ATMLP is controlled by m6A methylation at the 1313 adenine locus of AFAP1‐AS1. Mechanistically, ATMLP binds to the 4‐nitrophenylphosphatase domain and non‐neuronal SNAP25‐like protein homolog 1 (NIPSNAP1) and inhibits its transport from the inner to the outer mitochondrial membrane, which antagonizes the NIPSNAP1‐mediated regulation of cell autolysosome formation. The findings uncover a complex regulatory mechanism of NSCLC malignancy orchestrated by a peptide encoded by a lncRNA. A comprehensive judgment of the application prospects of ATMLP as an early diagnostic biomarker for NSCLC is also made. Noncoding RNA is widely considered without coding capability, and the traditional gene annotation process filters out proteins that are less than 100 amino acids in length. This makes us lose many proteins encoded by micro‐open reading frames in long noncoding RNA. These findings break the traditional understanding and successfully identify the AFAP1‐AS1 translated mitochondrial‐localized peptide, which can be used as early diagnostic biomarker for NSCLC.

Lung cancer has been the most common cancer worldwide for several decades. The outcomes of patients with locally advanced lung cancer remain dismal, and only a minority of patients survive more than 5 years. However, tumor therapeutic resistance mechanisms are poorly studied. Identification of therapeutic resistance pathways in lung cancer in order to increase the sensitivity of lung tumor cells to therapeutic agents is a crucial but challenging need. To identify novel genes that modulate the response to platinum-based therapy, we performed a genome-wide high-throughput ribonucleic acid interference (RNAi) screen via transfection of human lung cancer (PC9) cells with a viral short hairpin RNA (shRNA) library. We further validated a potential target via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic survival assays on PC9 and A549 lung tumor cells transfected with small interfering RNAs (siRNAs) to successfully downregulate protein expression and then treated with increasing doses of cisplatin or X-ray radiation. We determined protein expression by immunohistochemistry (IHC) after chemoradiotherapy and analyzed gene expression-based survival outcomes in two cohorts of human non-small-cell lung cancer (NSCLC) patients. The screen identified several targets involved in epithelial-to-mesenchymal transition (EMT), including Smurf1, Smurf2, YAP1, and CEBPZ, and glycolytic pathway proteins, including PFKFB3. Furthermore, we found that the small molecule proteasome inhibitor bortezomib significantly downregulated Smurf2 in lung cancer cells. The addition of bortezomib in combination with cisplatin and radiation therapy in PC9 and A549 cells led to an increase in deoxyribonucleic acid (DNA) double-strand breaks with increased numbers of γ-H2AX-positive cells and upregulation of apoptosis. Finally, we found that Smurf2 protein expression was upregulated in situ after treatment with cisplatin and radiation therapy in a relevant cohort of patients with stage III NSCLC. Additionally, Smurf2 gene expression was the strongest predictor of survival in patients with squamous NSCLC after chemotherapy or chemoradiotherapy. We successfully identified and validated Smurf2 as both a common modulator of resistance and an actionable target in lung cancer. These results suggest the urgent need to investigate clinical Smurf2 inhibition via bortezomib in combination with cisplatin and radiation for patients with locally advanced NSCLC.

Background Photon radiation has been shown to stimulate the secretion of radioresistant factors from tumor cells, ultimately promoting tumor angiogenesis and metastasis. On the other hand, heavy-ion radiotherapy has been demonstrated to control tumor angiogenesis and metastasis levels. The molecular mechanisms responsible for the different angiogenic responses to photon and heavy-ion irradiation are not fully understood. This study aims to explore the irradiation-responsive genes related to tumor angiogenesis and reveal the regulatory effect. Methods In order to clarify the potential regulatory mechanisms of tumor angiogenesis after X-ray or carbon ion (C-ion) irradiation, we performed RNA-sequencing (RNA-seq), as well as bioinformatics, public database analysis, Western blotting, immunohistochemistry, and immunofluorescence. Results In this study, we identified the long intergenic noncoding RNA PRDM10 divergent transcript (PRDM10-DT), which was responsive to X-rays but not carbon ions. Mechanistically, PRDM10-DT triggers tumor angiogenesis by upregulating the TGF-β1/VEGF signaling pathway through its competitive binding to miR-663a. Additionally, the transcription factor SP1 facilitated the transcription of PRDM10-DT by binding to its promoter region. It’s notable that the DNA-binding activity of SP1 was enhanced by reactive oxygen species (ROS). The knockdown of either PRDM10-DT or SP1 effectively inhibited NSCLC angiogenesis and metastasis. Conclusion These results illustrate the proangiogenic function of the PRDM10-DT/miR-663a/TGF-β1 axis and reveal the regulatory role of ROS and SP1 in the upstream response to radiation, with differential ROS production mediating the differential angiogenesis levels after X-ray and C-ion irradiation. Our findings suggest the potential of PRDM10-DT as a nucleic acid biomarker after radiotherapy and that targeting this gene could be a therapeutic strategy to counteract angiogenesis in NSCLC radiotherapy.

Objective: Phytoestrogens display an array of pharmacologic properties, and in recent years investigation of their potential as anticancer agents has increased dramatically. In this article we review the published literature related to phytoestrogens and breast cancer as well as suggest the possible mechanisms that may underlie the relationship between phytoestrogens and breast cancer. Data sources: Electronic searches on phytoestrogens and breast cancer were performed on MEDLINE and EMBASE in June 2007. No date restriction was placed on the electronic search. Data extraction: We focused on experimental data from published studies that examined the characteristics of phytoestrogens using in vivo or in vitro models. We also include human intervention studies in this review. Data synthesis: We evaluated evidence regarding the possible mechanisms of phytoestrogen action. Discussions of these mechanisms were organized into those activities related to the estrogen receptor, cell growth and proliferation, tumor development, signaling pathways, and estrogen-metabolizing enzymes. Conclusions: We suggest that despite numerous investigations, the mechanisms of phytoestrogen action in breast cancer have yet to be elucidated. It remains uncertain whether these plant compounds are chemoprotective or whether they may produce adverse outcomes related to breast carcinogenesis.

Adult neurons, which are terminally differentiated cells, demonstrate substantial radioresistance. In contrast, human neural stem cells (NSC), which have a significant proliferative capacity, are highly sensitive to ionizing radiation. Cranial irradiation that is widely used for treatment of brain tumors may induce death of NSC and further cause substantial cognitive deficits such as impairing learning and memory. The main goal of our study was to determine a mechanism of NSC radiosensitivity. We observed a constitutive high-level expression of TRAIL-R2 in human NSC. On the other hand, ionizing radiation through generation of reactive oxygen species targeted cell signaling pathways and dramatically changed the pattern of gene expression, including upregulation of TRAIL. A significant increase of endogenous expression and secretion of TRAIL could induce autocrine/paracrine stimulation of the TRAIL-R2-mediated signaling cascade with activation of caspase-3-driven apoptosis. Furthermore, paracrine stimulation could initiate bystander response of non-targeted NSC that is driven by death ligands produced by directly irradiated NSC. Experiments with media transfer from directly irradiated NSC to non-targeted (bystander) NSC confirmed a role of secreted TRAIL for induction of a death signaling cascade in non-targeted NSC. Subsequently, TRAIL production through elimination of bystander TRAIL-R-positive NSC might substantially restrict a final yield of differentiating young neurons. Radiation-induced TRAIL-mediated apoptosis could be partially suppressed by anti-TRAIL antibody added to the cell media. Interestingly, direct gamma-irradiation of SK-N-SH human neuroblastoma cells using clinical doses (2–5 Gy) resulted in low levels of apoptosis in cancer cells that was accompanied however by induction of a strong bystander response in non-targeted NSC. Numerous protective mechanisms were involved in the maintenance of radioresistance of neuroblastoma cells, including constitutive PI3K-AKT over-activation and endogenous synthesis of TGFβ1. Specific blockage of these survival pathways was accompanied by a dramatic increase in radiosensitivity of neuroblastoma cells. Intercellular communication between cancer cells and NSC could potentially be involved in amplification of cancer pathology in the brain.

Radiation-induced lung injury (RILI), especially radiation pneumonitis (RP), is a common clinical complication associated with thoracic radiotherapy for malignant tumors. However, the specific contributions of each cell subtype to this process are unknown. Here, we provide the single-cell pathology landscape of the RP in a mouse model by unbiased single-cell RNA-seq (scRNA-seq). We found a decline of type 2 alveolar cells in the RP lung tissue, with an expansion of macrophages, especially the Fabp4low and Spp1high subgroup, while Fabp4high macrophages were almost depleted. We observed an elevated expression of multiple mitochondrial genes in the RP group, indicating a type 2 alveolar cell (AT2) response to oxidative stress. We also calculated the enrichment of a cGAS-STING signaling pathway, which may be involved in regulating inflammatory responses and cancer progression in AT2 cells of PR mice. We delineate markers and transcriptional states, identify a type 2 alveolar cell, and uncover fundamental determinants of lung fibrosis and inflammatory response in RP lung tissue of mice.

Mechanotransduction sensing of tissue architecture and cellular microenvironment is a fundamental regulator of cell fate, including cancer. Meanwhile, long noncoding RNAs (lncRNAs) play multifunctions during cancer development and treatment. However, the link between lncRNAs and cellular mechanotransduction in the context of cancer progression has not yet been elucidated. In this study, using atomic force microscopy (AFM), we find that ionizing radiation reduces tumor stiffness. Ionizing radiation-induced lncRNA CRYBG3 can blunt YAP/TAZ activity through interference with mechanotransduction, resulting in the inhibition of cell proliferation, invasion, and metastasis of lung cancer cells. In vivo, we found that loss of lncRNA CRYBG3 could power the tumor initiation and metastasis ability, but this was abolished by concomitant deplete TAZ. At the molecular level, lncRNA CRYBG3 that in turn dysregulates F-actin organization, activates the LATS1/2 kinase, all in all resulting in YAP/TAZ nuclear exclusion. Our research proposes that lncRNA CRYBG3 is a mediator of radiotherapy through its control of cancer-tissue mechanotransduction and wiring YAP/TAZ activity to control tumor growth and metastasis.

Understanding the mechanisms underlying the bystander effects of low doses/low fluences of low- or high-linear energy transfer (LET) radiation is relevant to radiotherapy and radiation protection. Here, we investigated the role of gap-junction intercellular communication (GJIC) in the propagation of stressful effects in confluent normal human fibroblast cultures wherein only 0.036–0.144% of cells in the population were traversed by primary radiation tracks. Confluent cells were exposed to graded doses from monochromatic 5.35 keV X ray (LET ∼6 keV/μm), 18.3 MeV/u carbon ion (LET ∼103 keV/μm), 13 MeV/u neon ion (LET ∼380 keV/μm) or 11.5 MeV/u argon ion (LET ∼1,260 keV/μm) microbeams in the presence or absence of 18-α-glycyrrhetinic acid (AGA), an inhibitor of GJIC. After 4 h incubation at 37°C, the cells were subcultured and assayed for micronucleus (MN) formation. Micronuclei were induced in a greater fraction of cells than expected based on the fraction of cells targeted by primary radiation, and the effect occurred in a dose-dependent manner with any of the radiation sources. Interestingly, MN formation for the heavy-ion microbeam irradiation in the absence of AGA was higher than in its presence at high mean absorbed doses. In contrast, there were no significant differences in cell cultures exposed to X-ray microbeam irradiation in presence or absence of AGA. This showed that the inhibition of GJIC depressed the enhancement of MN formation in bystander cells from cultures exposed to high-LET radiation but not low-LET radiation. Bystander cells recipient of growth medium harvested from 5.35 keV X-irradiated cultures experienced stress manifested in the form of excess micronucleus formation. Together, the results support the involvement of both junctional communication and secreted factor(s) in the propagation of radiation-induced stress to bystander cells. They highlight the important role of radiation quality and dose in the observed effects.