TDP-43 was Involved in Radiation-induced Neuronal Damage and May Not Through the BDNF/TrkB Pathway.

Cognitive dysfunction is the most common form of radiation-induced brain injury. TDP-43 is known to be associated with hippocampal degeneration and cognitive dysfunction, in this study we wanted to know if it also had an effect on radiation-induced hippocampus damage. At first, we found the expression of TDP-43 and p-TDP-43 was increased in the hippocampus of rats with radiation-induced cognitive dysfunction. Single-cell RNA-seq analysis of the rat hippocampus showed that TDP-43 was expressed in all cell types and was significantly upregulated in neuron cells after irradiation. Enrichment analysis of gene ontology (GO) functions and KEGG pathways showed that the differential expression genes in neuron after irradiation may be involved in synaptic plasticity. In vitro, the expression of TDP-43 was also increased in neuron cells after irradiation, while the expression of brain-derived neurotrophic factor (BDNF), TrkB, typical synaptic signature proteins (SYN, GAP43 and PSD95), ß-tubulin and dendritic spines were decreased. In the irradiated neurons, the ß-tubulin, dendritic and spines typical synaptic signature proteins had more severe damage in pcDNA3.1-TDP-43 plasmid transfections group, however, the damages were alleviated in the siRNA-TDP-43 plasmid transfections group. BDNF was highly expressed in the irradiated pcDNA3.1-TDP-43 plasmid transfections group, while its expression was decreased in the siRNA-TDP-43 group. The TrkB expression was significantly reduced in neurons after exposure to ionizing radiation, however, there was no significant correlation with TDP-43 expression. These data indicate that TDP-43 is involved in radiation-induced neuronal synaptic plasticity decline and developmental damage, furthermore, the BDNF/TrkB signaling pathway may not be involved in this process.

The Mechanism of Ubiquitination or Deubiquitination Modifications in Regulating Solid Tumor Radiosensitivity.

Radiotherapy, a treatment method employing radiation to eradicate tumor cells and subsequently reduce or eliminate tumor masses, is widely applied in the management of numerous patients with tumors. However, its therapeutic effectiveness is somewhat constrained by various drug-resistant factors. Recent studies have highlighted the ubiquitination/deubiquitination system, a reversible molecular modification pathway, for its dual role in influencing tumor behaviors. It can either promote or inhibit tumor progression, impacting tumor proliferation, migration, invasion, and associated therapeutic resistance. Consequently, delving into the potential mechanisms through which ubiquitination and deubiquitination systems modulate the response to radiotherapy in malignant tumors holds paramount significance in augmenting its efficacy. In this paper, we comprehensively examine the strides made in research and the pertinent mechanisms of ubiquitination and deubiquitination systems in governing radiotherapy resistance in tumors. This underscores the potential for developing diverse radiosensitizers targeting distinct mechanisms, with the aim of enhancing the effectiveness of radiotherapy.

The hsa_circ_0004805/hsa_miR-149-5p/TGFB2 axis plays critical roles in the pathophysiology of diabetic retinopathy in vitro and in vivo.

The aim of this study was to investigate the mechanism underlying the role of a recently identified hsa_circ_0004805/hsa_miR-149-5p/transforming growth factor beta 2 (TGFB2) axis in the progression of diabetic retinopathy (DR). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis suggested that hsa_circ_0004805 was highly expressed in aqueous humor samples of patients with DR, whereas hsa_miR-149-5p showed the opposite trend. Meanwhile, the results of a dual-luciferase reporter assay indicated that hsa_miR-149-5p directly interacted with both hsa_circ_0004805 and TGFB2. Using a variety of assays (Cell Counting Kit-8, EdU-labeling, Transwell, flow cytometric, wound healing, tube formation assays), we found that the overexpression of hsa_circ_0004805 significantly downregulated the level of hsa_miR-149-5p and promoted DNA synthesis, proliferation, migration, and tube formation in human retinal microvascular epithelial cells (hRECs) cultivated in a high-glucose environment. In contrast, hsa_miR-149-5p mimics inhibited DNA synthesis, proliferation, migration, and tube formation in hRECs by reducing the expression of its downstream target TGFB2 as well as the levels of phosphorylated SMAD2; however, these effects were reversed by the overexpression of hsa_circ_0004805. In a streptozotocin-induced Sprague-Dawley rat model of DR, retinal vascular leakage, capillary decellularization, loss of pericytes, fibrosis, and gliosis were evident, which could be reversed by vitreous microinjection of rat miR-149-5p mimics (rno-miR-149-5p agomir). Combined, our findings indicated that, under hyperglycemia, the hsa_circ_0004805/hsa_miR-149-5p/TGFB2 axis plays a critical role in the retinal pathophysiology associated with the development of DR, and has potential as a therapeutic target in the treatment of this condition.

The therapeutic targets of N6-methyladenosine (m6A) modifications on tumor radioresistance.

Radiation therapy is an important tool for malignant tumors, and its tolerance needs to be addressed. In recent years, several studies have shown that regulators of aberrant m6A methylation play an important role in the formation, development and invasion and metastasis of tumors. A large number of studies have confirmed aberrant m6A methylation as a new target for tumour therapy, but research on whether it can play a role in tumor sensitivity to radiotherapy has not been extensive and thorough enough. Recent studies have shown that all three major enzymes of m6A methylation have significant roles in radioresistance, and that the enzymes that play a role differ in different tumor types and by different mechanisms, including regulating tumor cell stemness, affecting DNA damage and repair, and controlling the cell cycle. Therefore, elucidating the mechanisms of m6A methylation in the radiotherapy of malignant tumors is essential to counteract radioresistance, improve the efficacy of radiotherapy, and even propose targeted treatment plans for specific tumors. The latest research progress on m6A methylation and radioresistance is reviewed in this article.

Immunotherapy combined with radiotherapy to reverse immunosuppression in microsatellite stable colorectal cancer

In recent years, the exploration of immune checkpoint inhibitors (ICIs) has resulted in substantial progress and has changed the pattern of cancer treatment. ICIs have revolutionized the treatment landscape of microsatellite instable colorectal cancer while the efficacy is very limited in patients with microsatellite stable colorectal cancer. Therefore, sensitizing MSS CRC to immunotherapy is a major challenge in the field of CRC immunotherapy. Immunotherapy-based combination therapy is an effective strategy. This review of radiotherapy (RT) as a local treatment has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumor environment by modulating the immune response. Such evidence gives a strong rationale for the synergism of radiotherapy and immunotherapy, introducing the era of ‘immunoradiotherapy’. How to give full play to the synergistic effect of radiotherapy and immunotherapy to improve the therapeutic effect of MSS CRC and bring good prognosis is a hot problem to be solved in the field of cancer treatment.This article reviews the development of CRC immunotherapy, the immune resistance mechanism of MSS CRC, and the impact and potential value of immunotherapy combined with radiotherapy on the immune environment of CRC (AU)

ALKBH5/YTHDF2-mediated m6A modification of circAFF2 enhances radiosensitivity of colorectal cancer by inhibiting Cullin neddylation.

BACKGROUND: Circular RNA (circRNA) and N6-methyladenosine (m6A) play a critical role in tumour occurrence and development, including colorectal cancer (CRC). However, little is known about the interaction between circRNA and m6A in the radiosensitivity of CRC. Here, we investigated the role of a novel m6A-regulated circRNA in CRC. METHODS: Differentially expressed circRNAs from radiosensitive and radioresistant CRC tissues were screened. Modifications of the selected circRNAs were examined by methylated RNA immunoprecipitation assay. Finally, the selected circRNAs were subjected to radiosensitivity assay. RESULTS: We identified that circAFF2 is closely related to both radiosensitivity and m6A in CRC. CircAFF2 was highly expressed in patients with radiosensitive rectal cancer, and patients with high expression of circAFF2 had a better prognosis. In addition, circAFF2 can enhance the radiosensitivity of CRC cells both in vitro and in vivo. The regulation of circAFF2 involves ALKBH5-mediated demethylation, followed by its recognition and degradation via YTHDF2. Rescue experiments revealed that circAFF2 could reverse the radiosensitivity induced by ALKBH5 or YTHDF2. Mechanistically, circAFF2 binds with CAND1, promotes the binding of CAND1 to Cullin1 and inhibits its neddylation, subsequently impacting the radiosensitivity of CRC. CONCLUSION: We identified and characterised circAFF2 as a novel m6A-modified circRNA and validated the ALKBH5/YTHDF2/circAFF2/Cullin-NEDD8 axis as a potential radiotherapy target for CRC.

Recurrence patterns are significantly associated with the 18F­FDG PET/CT radiomic features of patients with locally advanced non­small cell lung cancer treated with chemoradiotherapy.

A model for predicting the recurrence pattern of patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy is of great importance for precision treatment. The present study analyzed whether the comprehensive quantitative values (CVs) of the fluorine-18(18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) radiomic features and metastasis tumor volume (MTV) combined with clinical characteristics could predict the recurrence pattern of patients with LA-NSCLC treated with chemoradiotherapy. Patients with LA-NSCLC treated with chemoradiotherapy were divided into training and validation sets. The recurrence profile of each patient, including locoregional recurrence (LR), distant metastasis (DM) and both LR/DM were recorded. In the training set of patients, the primary tumor prior radiotherapy with 18F-FDG PET/CT and both primary tumors and lymph node metastasis were considered as the regions of interest (ROIs). The CVs of ROIs were calculated using principal component analysis. Additionally, MTVs were obtained from ROIs. The CVs, MTVs and the clinical characteristics of patients were subjected to aforementioned analysis. Furthermore, for the validation set of patients, the CVs and clinical characteristics of patients with LA-NSCLC were also subjected to logistic regression analysis and the area under the curve (AUC) values calculated. A total of 86 patients with LA-NSCLC were included in the analysis, including 59 and 27 patients in the training and validation sets of patients, respectively. The analysis revealed 22 and 12 cases with LR, 24 and 6 cases with DM and 13 and 9 cases with LR/DM in the training and validation sets of patients, respectively. Histological subtype, CV2-5 and CV3-4 were identified as independent variables in the logistic regression analysis (P<0.05). In addition, the AUC values for diagnosing LR, DM and LR/DM were 0.873, 0.711 and 0.826, and 0.675, 0.772 and 0.708 in the training and validation sets of patients, respectively. Overall, the results demonstrated that the spatial and metabolic heterogeneity quantitative values from the primary tumor combined with the histological subtype could predict the recurrence pattern of patients with LA-NSCLC treated with chemoradiotherapy.

Immunotherapy combined with radiotherapy to reverse immunosuppression in microsatellite stable colorectal cancer.

In recent years, the exploration of immune checkpoint inhibitors (ICIs) has resulted in substantial progress and has changed the pattern of cancer treatment. ICIs have revolutionized the treatment landscape of microsatellite instable colorectal cancer while the efficacy is very limited in patients with microsatellite stable colorectal cancer. Therefore, sensitizing MSS CRC to immunotherapy is a major challenge in the field of CRC immunotherapy. Immunotherapy-based combination therapy is an effective strategy. This review of radiotherapy (RT) as a local treatment has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumor environment by modulating the immune response. Such evidence gives a strong rationale for the synergism of radiotherapy and immunotherapy, introducing the era of 'immunoradiotherapy'. How to give full play to the synergistic effect of radiotherapy and immunotherapy to improve the therapeutic effect of MSS CRC and bring good prognosis is a hot problem to be solved in the field of cancer treatment.This article reviews the development of CRC immunotherapy, the immune resistance mechanism of MSS CRC, and the impact and potential value of immunotherapy combined with radiotherapy on the immune environment of CRC.

Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy in Pain Relief for Bone Metastases: A Systematic Review and Meta-Analysis.

PURPOSE: This study aimed to investigate the difference in pain relief between stereotactic body radiation therapy (SBRT) and conventional radiation therapy (cRT) for patients with bone metastases. METHODS AND MATERIALS: Clinical trials and observational studies comparing SBRT versus cRT for bone metastases were retrieved. The main endpoint was pain relief after radiation therapy; the secondary endpoints were pain score change, local progression-free survival, reirradiation rate, and toxic events. When there was a significant heterogeneity, the random-effects model was applied. Otherwise, the fixed-effects model was used. Analyses of all included studies were performed first, followed by analyses of randomized controlled trials (RCTs) only. RESULTS: Six RCTs, 1 prospective cohort study, and 3 retrospective observational studies were enrolled. Between 2004 and 2019, 448 patients received SBRT, and 445 patients received cRT. All prospective studies defined the lesions as oligometastatic. Pooled results based on all included studies indicated that SBRT was generally associated with a higher overall relief rate (P < .001 at 3 months; P = .015 at 6 months) and complete relief rate (P = .029 at 1 month; P < .001 at 6 months). Pooled results based on RCTs indicated that at 3 and 6 months, SBRT was associated with a higher overall relief rate (P < .001 and P = .017, respectively) and complete relief rate (P < .001 and P < .00, respectively). Subgroup analyses indicated that in more cases, the analgesic advantage of SBRT was more obvious when spinal lesions were irradiated, when the difference in the mean biological effective dose (BED) was less, or when intensity modulated radiation therapy was used to deliver SBRT. CONCLUSIONS: Excessive elevation of BED introduces the risk of diminishing the analgesic effect of SBRT. SBRT delivered using intensity modulated radiation therapy is preferred for pain relief in spinal oligometastases. More RCTs are required to determine the most appropriate BED or dose regimen for SBRT.

Mechanism and Function of Circular RNA in Regulating Solid Tumor Radiosensitivity.

Radiotherapy is an important tool in the treatment of malignant tumors, and exploring how to make radiotherapy more effective is a new way to break through the current bottleneck in the development of radiation oncology. Circular RNAs (circRNAs) are a special class of endogenous non-coding RNAs. Numerous studies have shown that circRNAs have shown great potential in regulating the biological functions of tumors, including proliferation, migration, invasion, and treatment resistance, and that differences in their expression levels are closely related to the clinical prognosis of tumor patients. This review systematically compares the mechanisms of circRNAs in the process of tumor development and radiosensitivity and provides insight into the clinical translation of circRNAs in radiotherapy.

Mechanism and clinical value of exosomes and exosomal contents in regulating solid tumor radiosensitivity.

Radiotherapy is among the routine treatment options for malignant tumors. And it damages DNA and other cellular organelles in target cells by using ionizing radiation produced by various rays, killing the cells. In recent years, multiple studies have demonstrated that exosomes are mechanistically involved in regulating tumor formation, development, invasion and metastasis, and immune evasion. The latest research shows that radiation can affect the abundance and composition of exosomes as well as cell-to-cell communication. In the environment, exosome-carried miRNAs, circRNA, mRNA, and proteins are differentially expressed in cancer cells, while these molecules play a role in numerous biological processes, including the regulation of oncogene expression, mediation of signaling pathways in cancer cells, remodeling of tumor-related fibroblasts, regulation of cell radiosensitivity, and so forth. Therefore, elucidation of the mechanism underlying the role of exosomes in radiotherapy of malignant tumors is crucial for improving the efficacy of radiotherapy. This review will summarize the research advances in radiosensitivity of malignant tumors related to exosomes.

Function and clinical significance of N6-methyladenosine in digestive system tumours.

RNA modification, like DNA methylation, histone modification, non-coding RNA modification and chromatin rearrangement, plays an important role in tumours. N6-methyladenosine (m6A) is the most abundant RNA modification in cells, and it regulates RNA transcription, processing, splicing, degradation, and translation. m6A-associated proteins have been used as new biomarkers and therapeutic targets for tumour prediction and monitoring. There are three main types of proteins involved in m6A methylation: methyltransferases (METTL3, METTL14, WTAP, RBM15, ZC3H13 and KIAA1429), demethylases (FTO, ALKBH5 and ALKBH3) and RNA-binding proteins (YTHDF1-3, YTHDC1-2, IGF2BPs and HNRNPs). This article reviews the origins, characteristics and functions of m6A and its relationship with digestive system tumours based on recent research. The expression of m6A regulators can be used as an evaluation indicator of tumour growth and progression and as a prognostic indicator. In-depth research on m6A methylation in digestive system tumours may provide new directions for clinical prediction and further treatment.

Retrospective analysis of the bleeding risk induced by oral antiplatelet drugs during radiotherapy.

ABSTRACT: We conducted this retrospective analysis to assess whether oral antiplatelet drugs (APDs) during radiotherapy increase bleeding risk.Patients who underwent radiotherapy for esophageal cancer (EC) in the Third Affiliated Hospital of Soochow University from January 2015 to December 2019 were screened. After the differences in clinical parameters were eliminated by a propensity-score matched (PSM) analysis at a 1:1 ratio, the thrombocytopenia, consumption of platelet-increasing drugs, suspension of radiotherapy, and bleeding in patients taking APDs were compared with those in the control group.A total of 986 patients were included in the original dataset. Of these, 34 patients took APDs during radiotherapy. After matching, the APD and control groups each retained 31 patients. There was no significant difference in platelet concentrations between the two groups before radiotherapy (P = .524). The lowest platelet concentration during radiotherapy in the APD group was significantly lower (P = .033). The consumption of platelet-increasing drugs in the APD group was higher than that in the control group (P  < .05). However, there was no significant difference in the average number of days of radiotherapy suspension because of thrombocytopenia (P = .933) and no significant difference in the incidence of bleeding between the two groups (P = .605).Oral APDs during radiotherapy lead to a further decrease in platelet concentration, but timely and adequate application of platelet-increasing drugs can avoid the increased risk of bleeding and the reduced efficacy of radiotherapy.

CircNEIL3 promotes cervical cancer cell proliferation by adsorbing miR-137 and upregulating KLF12.

BACKGROUND: CircRNAs play crucial roles in multiple tumours. However, the functions of most circRNAs in cervical cancer remain unclear. METHODS: This study collected GSE113696 data from the GEO database to search for differentially expressed circRNAs in cervical cancer. Quantitative reverse transcription PCR was used to detect the expression level of circNEIL3 in cervical cancer cells and tissues. Then, functional experiments in vitro and in vivo were performed to evaluate the effects of circNEIL3 in cervical cancer. RESULTS: CircNEIL3 was highly expressed in cervical cancer. In vivo and in vitro experiments verified that circNEIL3 enhanced the proliferation capacity of cervical cancer cells. RNA immunoprecipitation, luciferase reporter assay, pull-down assay, and fluorescent in situ hybridization confirmed the interaction between circNEIL3 and miR-137 in cervical cancer. A luciferase reporter assay showed that circNEIL3 adsorbed miR-137 and upregulated KLF12 to regulate the proliferation of cervical cancer cells. CONCLUSIONS: CircNEIL3 is an oncogene in cervical cancer and might serve as a ceRNA that competitively binds to miR-137, thereby indirectly upregulating the expression of KLF12 and promoting the proliferation of cervical cancer cells.

Simultaneous high PD-L1 and low VEGFR2 expression is associated with better overall survival in rectal cancer.

BACKGROUND: The aim of the present study was to analyze the association of programmed cell death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) expression levels with clinicopathological characteristics and survival to provide a treatment strategy for rectal cancer. METHODS: Immunohistochemical staining of VEGFR2 and PD-L1 was carried out, and the association of PD-L1 and VEGFR2 expression levels with clinicopathological characteristics and survival were investigated in 77 pair-matched rectal cancer patients. RESULTS: PD-L1 and VEGFR2 expression levels in surgical tumor tissues were higher than those in paired adjacent normal tissues, respectively (both P<0.05). The results of the 5-year overall survival (OS) analysis showed that patients with low VEGFR2 expression (66.7% vs. 43.5%, P=0.042) and high tumor PD-L1 expression (63.9% vs. 26.1%, P=0.001) in tumor tissues demonstrated significantly better OS. Patients with high TNM stage had poorer OS [hazard ratio (HR): 2.093, 95% confidence interval (CI): 1.027-4.087, P=0.030]. Similar results of poorer OS could be seen in patients with low tumor PD-L1 expression (HR: 3.365, 95% CI:1.747-6.481, P=0.005), as well as patients with high tumor VEGFR2 expression (HR: 0.418, 95% CI: 0.232-0.993, P=0.048). CONCLUSIONS: The results indicated that tumor PD-L1 and VEGFR2 expression levels were associated with OS, and the combination of tumor PD-L1 and VEGFR2 levels might be an independent prognostic factor in rectal cancer.

Application of Optical Laser 3D Surface imaging system (Sentinel) in breast cancer radiotherapy.

It has been clearly confirmed that radiation therapy (RT) after breast conserving surgery (BCS) is an effective treatment modality comparable to mastectomy for early breast cancer. The purpose of this study was to further evaluate the accuracy of 3D surface imaging system (Sentinel) for breast cancer patients received BCS. The optical surface scans and CBCT scans were acquired before and immediately after couch movement correction. The deviation of the CBCT scans from the reference planning CT was considered an estimate for the residual errors for patient setup correction. The planning target volume (PTV) margins for treatment sessions was calculated according to the setup errors. We obtained a total of 245 sets of data collected from 49 breast cancer patients. Compared with Sentinel setup errors, the residual setup errors as determined by the CBCT scans after couch movement correction were reduced in the six directions. The PTV margins derived from the CBCT residual errors were all less than 5 mm in X, Y, and Z directions. Our results suggested that Optical surface imaging can be applied in positioning for breast cancer patient accurately without unnecessary imaging dose.

Salvage treatment for lymph node recurrence after radical resection of esophageal squamous cell carcinoma.

BACKGROUND: Patients with regional lymph node recurrence after radical resection of esophageal cancer have poor therapeutic outcomes. Currently, there is no standard treatment for regional lymph node recurrence, and its prognostic risk factors are not well-understood. This study retrospectively analyzed 83 patients with postoperative regional lymph node recurrence after radical resection of esophageal squamous cell carcinoma. The aim was to evaluate the clinical efficacy and prognostic factors of salvage radiotherapy with or without chemotherapy in these patients. METHODS: The survival and prognostic factors of 83 patients with esophageal squamous cell carcinoma with regional lymph node recurrence after radical surgery were retrospectively analyzed. All patients underwent radiotherapy, of which 74 patients received volumetric modulated arc therapy (VMAT), 9 patients received three-dimensional conformal radiation therapy (3DCRT), administered using a conventional segmentation protocol with a dose distribution range of 50.4-66.2Gy (median dose of 60Gy). In total, 41 patients received radiotherapy alone, 42 received radiotherapy combined with chemotherapy, and the concurrent chemotherapy regimen was mainly composed of either platinum or fluorouracil monotherapy, except for 4 patients who were given 5-fluorouracil plus platinum (FP) or paclitaxel plus platinum (TP). RESULTS: The median follow-up time was 24 (range, 9-75) months. The overall survival (OS) rates at 1 year, 2 years, 3 years, and 5 years were 83.0, 57.1, 40.1, and 35.1%, respectively. The median overall survival (OS) time was 18 (range, 5-75) months. The 3-year survival rate was 47.5% in patients with radiation alone and 41.9% in patients receiving concurrent chemoradiotherapy(p = 0.570), while the response rate (CR + PR) in those two groups was 73.2 and 91.4%, respectively. By multivariate analysis of OS, age (worse in younger patients, p = 0.034) was found to be significantly associated with disease prognosis. The commonly toxicities were esophagitis, neutropenia and anemia. 18% patients experienced grade 3 toxicity and no treatment-related death occurred. CONCLUSIONS: These results of this retrospective analysis suggest that radiotherapy with or without chemotherapy is an effective and feasible salvage treatment for lymph node recurrence after radical resection of esophageal squamous cell carcinoma.

Pim-1 inhibitor SMI-4a suppresses tumor growth in non-small cell lung cancer via PI3K/AKT/mTOR pathway.

Background: In the present study, we aimed to investigate the effect of proviral integration site for moloney murine leukemia virus-1 (Pim-1) inhibitor (SMI-4a) on the progression of non-small cell lung cancer (NSCLC). Materials and methods: The effects of SMI-4a on proliferation, apoptosis, and cell cycle of NSCLC cells were examined by in vitro experiments using human NSCLC cell lines (A549 and Ltep-a-2). The pathway regulated by SMI-4a was detected using Western blot. Furthermore, we performed in vivo experiments to assess the effects of SMI-4a on tumor growth using mouse models with NSCLC. Results: Our data demonstrated that SMI-4a could inhibit the proliferation of A549 and Ltep-a-2 cells markedly in a dose-dependent manner (P<0.05). Treatment with 80 µmol/L of SMI-4a for 48 h significantly induced the apoptosis rate of NSCLC cells (P<0.05), and blocked the cell cycle of NSCLC cells in G2/M phase (P<0.05). The phosphorylation levels of PI3K, AKT, and mTOR in NSCLC cells were significantly downregulated by SMI-4a (P<0.05). Result from in vivo experiments demonstrated that SMI-4a could suppress the tumor growth in mouse models with NSCLC (P<0.05). Conclusions: SMI-4a suppresses the progression of NSCLC by blocking the PI3K/AKT/mTOR pathway.

MicroRNA-621 Acts as a Tumor Radiosensitizer by Directly Targeting SETDB1 in Hepatocellular Carcinoma.

Radiotherapy is one of the most important treatment methods of tumors. However, the application of radiotherapy in hepatocellular carcinoma (HCC) is limited due to the low tolerance of normal liver cells for radiation and inherent radiation resistance in HCC. With the in-depth study of microRNAs (miRNAs) in tumor therapy, the regulation of tumor radiosensitivity by miRNAs has been a research hotspot in recent years. In the present study, the expression of miR-621 was lower in HCC tissues and cells, and such low expression of miR-621 was associated with poor prognosis in HCC patients. In addition, in vivo and in vitro assays confirmed that the high expression of miR-621 could significantly enhance the radiosensitivity of HCC. Moreover, the expressions of miR-621 and SETDB1 in HCC tissues were negatively correlated. Dual-luciferase reporter assays indicated that miR-621 could directly target the 3' UTR of SETDB1. In addition, miR-621 enhanced the radiosensitivity of HCC cells via directly inhibiting SETDB1. Besides, the miR-621 and/or SETDB1 axis improved the radiosensitivity of HCC cells via activating the p53-signaling pathway. Taken together, miR-621 and/or SETDB1 might be used as a novel therapeutic target for the treatment of HCC.