Exosome miR-101-3p derived from bone marrow mesenchymal stem cells promotes radiotherapy sensitivity in non-small cell lung cancer by regulating DNA damage repair and autophagy levels through EZH2.

BACKGROUND AND OBJECTIVE: The morbidity rate of non-small cell lung cancer (NSCLC) increases with age, highlighting that NSCLC is a serious threat to human health. The aim of this study was mainly to describe the role of exosomal miR-101-3p derived from bone marrow mesenchymal stem cells (BMSCs) in NSCLC. METHODS: A549 or NCI-H1703 cells (1×105/mouse) were injected into nude mice to establish an NSCLC animal model. RTqPCR, Western blotting and comet assays were used to assess the changes in gene expression, proteins and DNA damage repair. RESULTS: miR-101-3p and RAI2 were found to be expressed at low levels in NSCLC, while EZH2 was highly expressed. In terms of function, miR-101-3p downregulated EZH2. In addition, exosomal miR-101-3p derived from BMSCs promoted the expression of RAI2, inhibited DNA damage repair, and inhibited the activation of the PI3K/AKT/mTOR signaling pathway by inhibiting EZH2, thereby promoting autophagy and decreasing cell viability and finally enhancing the sensitivity of NSCLC to radiotherapy and inhibiting the malignant biological behavior of NSCLC. CONCLUSION: Exosomal miR-101-3p derived from BMSCs can inhibit DNA damage repair, promote autophagy, enhance the radiosensitivity of NSCLC, and inhibit the progression of NSCLC by inhibiting EZH2.

Development and validation of a radiosensitivity model to evaluate radiotherapy benefits in pan-cancer.

Radiotherapy, one of the most fundamental cancer treatments, is confronted with the dilemma of treatment failure due to radioresistance. To predict the radiosensitivity and improve tumor treatment efficiency in pan-cancer, we developed a model called Radiation Intrinsic Sensitivity Evaluation (RISE). The RISE model was built using cell line-based mRNA sequencing data from five tumor types with varying radiation sensitivity. Through four cell-derived datasets, two public tissue-derived cohorts, and one local cohort of 42 nasopharyngeal carcinoma patients, we demonstrated that RISE could effectively predict the level of radiation sensitivity (area under the ROC curve [AUC] from 0.666 to 1 across different datasets). After the verification by the colony formation assay and flow cytometric analysis of apoptosis, our four well-established radioresistant cell models successfully proved higher RISE values in radioresistant cells by RT-qPCR experiments. We also explored the prognostic value of RISE in five independent TCGA cohorts consisting of 1137 patients who received radiation therapy and found that RISE was an independent adverse prognostic factor (pooled multivariate Cox regression hazard ratio [HR]: 1.84, 95% CI 1.39-2.42; p < 0.01). RISE showed a promising ability to evaluate the radiotherapy benefit while predicting the prognosis of cancer patients, enabling clinicians to make individualized radiotherapy strategies in the future and improve the success rate of radiotherapy.

The pivotal role of irradiation-induced apoptosis in the pathogenesis and therapy of medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is a rare primitive neuroectodermal tumors originating from the cerebellum. MB is the most common malignant primary brain tumor of childhood. MB originates from neural precursor cells in distinctive regions of the rhombic lip, and their maturation occurs in the cerebellum or the brain stem during embryonal development. Also, apoptosis is a programmed cell death associated with numerous physiological as well as pathological regulations. RECENT FINDINGS: Irradiation (IR)-induce apoptosis triggers cell death, with or without intervening mitosis within a few hours of IR and these share different morphologic alteration such as, loss of normal nuclear structure as well as degradation of DNA. Moreover, MB is strikingly sensitive to DNA-damaging therapies and the role of apoptosis a key treatment modality. Furthermore, in MB, the apoptotic pathways are made up of several triggers, modulators, as well as effectors. Notably, IR-induced apoptotic mechanisms in MB therapy are very complex and they either induce radiosensitivity or inhibit radioresistance leading to potential effective treatment strategies for MB. CONCLUSION: This review explicitly explores the pivotal roles of IR-induced apoptosis in the pathogenesis and therapy of MB.

Uncovering a novel DNA repair-related radiosensitivity model for evaluation of radiotherapy susceptibility in uterine corpus endometrial cancer.

Background: Uterine corpus endometrial cancer (UCEC) exhibit heterogeneity in their DNA repair capacity, which can impact their response to radiotherapy. Our study aimed to identify potential DNA repair-related biomarkers for predicting radiation response in UCEC. Methods: We conducted a thorough analysis of 497 UCEC samples obtained from TCGA database. Using LASSO-COX regression analysis, we constructed a radiosensitivity signature and subsequently divided patients into the radiosensitive (RS) and the radioresistant (RR) groups based on their radiosensitivity index. The GSVA and GSEA were performed to explore functional annotations. The CIBERSORT and ESTIMATE algorithms were utilized to investigate the immune infiltration status of the two groups. Additionally, we utilized the Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenotype Score (IPS), and pRRophetic algorithms to predict the effectiveness of different treatment modalities. Results: We constructed a radiosensitivity index consists of four DNA repair-related genes. Patients in the RS group demonstrated significantly improved prognosis compared to patients in the RR group when treated with radiotherapy. We observed that the RS group exhibited a higher proportion of the POLE ultra-mutated subtype, while the RR group had a higher proportion of the copy number high subtype. GSVA enrichment analysis revealed that the RS group exhibited enrichment in DNA damage repair pathways. Notably, the RS group demonstrated a higher proportion of naïve B cells and follicular helper T cells, while regulatory T cells (Tregs) and memory B cells were more abundant in the RR group. Furthermore, patients in the RS-PD-L1-high subgroup exhibited enrichment in immune-related pathways and increased sensitivity to immunotherapy, which is likely to contribute to their improved prognosis. Additionally, we conducted in vitro experiments to validate the expression of radiosensitivity genes in non-radioresistant (AN3CA) and radioresistant (AN3CA/IR) endometrial cancer cells. Conclusions: In conclusion, our research successfully constructed a radiosensitivity signature with robust predictive capacity. These findings shed light on the association between immune activation, PD-L1 expression, and the response to immunotherapy in the context of radiotherapy.

Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning.

OBJECTIVE: Treatment plans of charged-particle therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study was to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for charged-particle therapy treatment planning. Approach. The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned to a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account. Main results: The cell survival fraction and corresponding RBE weighted dose w- ere formulated basedon the HMK model. The first derivative of the RBE-weighted dose distribution was also derived,which is needed for fast biological optimization. For the patient plan, the biological optimization increasedthe dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-inducedreduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness dueto the heterogeneity waspronouncedfor low-LET beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam. Significance. The optimal treatment plans that consider the intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model. .

Sustained activation of the FGF1-MEK-ERK pathway inhibits proliferation, invasion and migration and enhances radiosensitivity in mouse angiosarcoma cells.

Angiosarcoma is a rare refractory soft-tissue tumor with a poor prognosis and is treated by radiotherapy. The fibroblast growth factor 1 (FGF1) mutant, with enhanced thermostability due to several substituted amino acids, inhibits angiosarcoma cell metastasis, yet the mechanism of action is unclear. This study aims to clarify the FGF1 mutant mechanism of action using ISOS-1 mouse angiosarcoma cells. The wild-type FGF1 or FGF1 mutant was added to ISOS-1 cells and cultured, evaluating cell numbers over time. The invasive and migratory capacity of ISOS-1 cells was assessed by transwell analysis. ISOS-1 cell radiosensitivity was assessed by colony formation assay after X-ray irradiation. To examine whether mitogen-activated protein kinase (MEK) inhibitor counteracts the FGF1 mutant effects, a combination of MEK inhibitor and FGF1 mutant was added to ISOS-1 cells and cultured. The FGF1 mutant was observed to inhibit ISOS-1 cell proliferation, invasion and migration by sustained FGF1 signaling activation. A MEK inhibitor suppressed the FGF1 mutant-induced inhibition of proliferation, invasion and migration of ISOS-1 cells. Furthermore, the FGF1 mutant enhanced radiosensitivity of ISOS-1 cells, but MEK inhibition suppressed the increased radiosensitivity. In addition, we found that the FGF1 mutant strongly inhibits actin polymerization, suggesting that actin cytoskeletal dynamics are closely related to ISOS-1 cell radiosensitivity. Overall, this study demonstrated that in ISOS-1 cells, the FGF1 mutant inhibits proliferation, invasion and migration while enhancing radiosensitivity through sustained activation of the MEK-mediated signaling pathway.

Mechanism of Musashi2 affecting radiosensitivity of lung cancer by modulating DNA damage repair.

Identifying new targets for overcoming radioresistance is crucial for improving the efficacy of lung cancer radiotherapy, given that tumor cell resistance is a leading cause of treatment failure. Recent research has spotlighted the significance of Musashi2 (MSI2) in cancer biology. In this study, we first demonstrated that MSI2 plays a key function in regulating the radiosensitivity of lung cancer. The expression of MSI2 is negatively correlated with overall survival in cancer patients, and the knockdown of MSI2 inhibits tumorigenesis and increases radiosensitivity of lung cancer cells. Cellular radiosensitivity, which is closely linked to DNA damage, is influenced by MSI2 interaction with ataxia telangiectasia mutated and Rad3-related kinase (ATR) and checkpoint kinase 1 (CHK1) post-irradiation; moreover, knockdown of MSI2 inhibits the ATR-mediated DNA damage response pathway. RNA-binding motif protein 17 (RBM17), which is implicated in DNA damage repair, exhibits increased interaction with MSI2 post-irradiation. We found that knockdown of RBM17 disrupted the interaction between MSI2 and ATR post-irradiation and increased the radiosensitivity of lung cancer cells. Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy.

In vitro study of radiosensitivity in colorectal cancer cell lines associated with Lynch syndrome.

Introduction: Lynch syndrome patients have an inherited predisposition to cancer due to a deficiency in DNA mismatch repair (MMR) genes which could lead to a higher risk of developing cancer if exposed to ionizing radiation. This pilot study aims to reveal the association between MMR deficiency and radiosensitivity at both a CT relevant low dose (20 mGy) and a therapeutic higher dose (2 Gy). Methods: Human colorectal cancer cell lines with (dMMR) or without MMR deficiency (pMMR) were analyzed before and after exposure to radiation using cellular and cytogenetic analyses i.e., clonogenic assay to determine cell reproductive death; sister chromatid exchange (SCE) assay to detect the exchange of DNA between sister chromatids; γH2AX assay to analyze DNA damage repair; and apoptosis analysis to compare cell death response. The advantages and limitations of these assays were assessed in vitro, and their applicability and feasibility investigated for their potential to be used for further studies using clinical samples. Results: Results from the clonogenic assay indicated that the pMMR cell line (HT29) was significantly more radio-resistant than the dMMR cell lines (HCT116, SW48, and LoVo) after 2 Gy X-irradiation. Both cell type and radiation dose had a significant effect on the yield of SCEs/chromosome. When the yield of SCEs/chromosome for the irradiated samples (2 Gy) was normalized against the controls, no significant difference was observed between the cell lines. For the γH2AX assay, 0, 20 mGy and 2 Gy were examined at post-exposure time points of 30 min (min), 4 and 24 h (h). Statistical analysis revealed that HT29 was only significantly more radio-resistant than the MLH1-deficient cells lines, but not the MSH2-deficient cell line. Apoptosis analysis (4 Gy) revealed that HT29 was significantly more radio-resistant than HCT116 albeit with very few apoptotic cells observed. Discussion: Overall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.

Single-cell transcriptomic sequencing data reveal aberrant DNA methylation in SMAD3 promoter region in tumor-associated fibroblasts affecting molecular mechanism of radiosensitivity in non-small cell lung cancer.

OBJECTIVE: Non-small cell lung cancer (NSCLC) often exhibits resistance to radiotherapy, posing significant treatment challenges. This study investigates the role of SMAD3 in NSCLC, focusing on its potential in influencing radiosensitivity via the ITGA6/PI3K/Akt pathway. METHODS: The study utilized gene expression data from the GEO database to identify differentially expressed genes related to radiotherapy resistance in NSCLC. Using the GSE37745 dataset, prognostic genes were identified through Cox regression and survival analysis. Functional roles of target genes were explored using Gene Set Enrichment Analysis (GSEA) and co-expression analyses. Gene promoter methylation levels were assessed using databases like UALCAN, DNMIVD, and UCSC Xena, while the TISCH database provided insights into the correlation between target genes and CAFs. Experiments included RT-qPCR, Western blot, and immunohistochemistry on NSCLC patient samples, in vitro studies on isolated CAFs cells, and in vivo nude mouse tumor models. RESULTS: Fifteen key genes associated with radiotherapy resistance in NSCLC cells were identified. SMAD3 was recognized as an independent prognostic factor for NSCLC, linked to poor patient outcomes. High expression of SMAD3 was correlated with low DNA methylation in its promoter region and was enriched in CAFs. In vitro and in vivo experiments confirmed that SMAD3 promotes radiotherapy resistance by activating the ITGA6/PI3K/Akt signaling pathway. CONCLUSION: High expression of SMAD3 in NSCLC tissues, cells, and CAFs is closely associated with poor prognosis and increased radiotherapy resistance. SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway.

Compound Taxus exerts marked anti-tumor activity and radiosensitization effect on hepatocellular carcinoma cells.

Background: Compound Taxus capsule, as an antineoplastic Chinese patent drug, has been increasingly applied as an adjunctive treatment for the management of non-small-cell lung cancer (NSCLC) and some other malignancies, but research about its antitumor activity and radiosensitization effect on hepatocellular carcinoma (HCC) cells is very rare. Purpose: To investigate the antitumor activity and radiosensitization effect of Compound Taxus on HCC cells and to preliminarily explore the possible molecule mechanisms involved. Methods: Cell viability, cell cycle distribution, apoptosis, DNA damage repair and protein expression levels were detected by CCK-8 assay, flow cytometry, immunofluorescence staining, western blotting analysis and immunohistochemical staining, respectively. The migration and invasion activities and vasculogenic mimicry (VM) formation and angiogenesis were evaluated by tube formation and VM formation assay. Radiation survival curves were obtained from the colony formation assay in human HCC cell lines, Smmc7721 and Bel7402 cells, pretreated with or without Compound Taxus before receiving X-ray irradiation. A Bel7402 tumor-bearing mouse model was established and the radiosensitization effect of Compound Taxus in vivo was evaluated by analyzing tumor volume and tumor weight in different groups receiving different treatments. Results: Compound Taxus decreased viability, induced G2/M arrest, promoted apoptosis, suppressed migration and invasion, and inhibited VM formation and angiogenesis in Smmc7721 and Bel7402 cells. Furthermore, Compound Taxus inhibited irradiation-induced DNA damage repair, enhanced the radiosensitivity of Smmc7721 and Bel7402 cells and improved the anti-tumor therapeutic efficacy of irradiation in Bel7402 tumor-bearing mice. Radiotherapy in combination with Compound Taxus showed the best tumor inhibition compared to that of Compound Taxus alone or irradiation alone. In addition, Compound Taxus significantly down-regulated NF-κB p65, p-NF-κB p65 and Bcl-2, and up-regulated Bax in vitro and in vivo, yet NF-κB p65 overexpression reversed the proapoptotic effect of Taxus on HCC cells, indicating that the NF-κB signaling pathway might be an important signal mediator in the Compound-Taxus-modulated biological responses. Conclusion: Our findings suggest that Compound Taxus shows marked antitumor activity and significant radiosensitization effect on HCC cells, making it possible for Compound Taxus to become a promising auxiliary modality for HCC management and a potential radiosensitizer of HCC in the future.

Hsa-miR-92b-3p Targeting FHL2 to Enhance Radiosensitivity of Nasopharyngeal Carcinoma.

Radiotherapy resistance is a major cause of treatment failure and leads to poor prognosis in nasopharyngeal carcinoma (NPC). Evidences indicate that microRNA (miRNAs) are closely associated with radiotherapy for NPC. In this study, we found that the expression level of miR-92b-3p was significantly higher in radiotherapy-sensitive NPC patients than in radiotherapy-resistant patients. High expression of miR-92b-3p was associated with good prognosis in patients with NPC, and high expression of FHL2 was associated with poor prognosis in patients with NPC. It was predicted that miR-92b-3p could directly target and bind FHL2. Overexpression of miR-92b-3p significantly inhibited FHL2 expression at the mRNA as well as protein levels, while inhibition of miR-92b-3p expression significantly upregulated FHL2 expression. Overexpression of miR-92b-3p significantly reduced proliferation and colony formation in NPC cells. Inhibition of miR-92b-3p attenuated the sensitivity of nasopharyngeal carcinoma to radiotherapy, while simultaneous inhibition of miR-92b-3p and FHL2 increased the sensitivity of NPC to radiotherapy. Our findings highlighted that miR-92b-3p is closely associated with radiotherapy sensitivity and prognosis in NPC patients and may improve the sensitivity of NPC to radiotherapy by targeting FHL2.

CircNOP14 increases the radiosensitivity of hepatocellular carcinoma via inhibition of Ku70-dependent DNA damage repair.

Circular RNAs (circRNAs) are profoundly affected in hepatocellular carcinoma (HCC) through various pathways. However, the role of circRNAs in the radiosensitivity of HCC cells is yet to be explored. In this study, we identified a circRNA-hsa_circ_0006737 (circNOP14) involved in the radiosensitivity of HCC. We found that circNOP14 increased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified Ku70 as a novel and robust interacting protein of circNOP14. Mechanistically, circNOP14 interacts with Ku70 and prevents its nuclear translocation, thereby increasing irradiation-induced DNA damage. Therefore, our findings may provide a predictive indicator and intervention option for 125I brachytherapy or external radiotherapy in HCC.

Enhancing radiosensitivity in triple-negative breast cancer through targeting ELOB.

Enhancing radiotherapy sensitivity is crucial for improving treatment outcomes in triple-negative breast cancer (TNBC) patients. In this study, we investigated the potential of targeting Elongin B (ELOB) to enhance radiotherapy efficacy in TNBC. Analysis of TNBC patient cohorts revealed a significant association between high ELOB expression and poor prognosis in patients who received radiation therapy. Mechanistically, we found that ELOB plays a pivotal role in regulating mitochondrial function via modulating mitochondrial DNA expression and activities of respiratory chain complexes. Targeting ELOB effectively modulated mitochondrial function, leading to enhanced radiosensitivity in TNBC cells. Our findings highlight the importance of ELOB as a potential therapeutic target for improving radiotherapy outcomes in TNBC. Further exploration of ELOB's role in enhancing radiotherapy efficacy may provide valuable insights for developing novel treatment strategies for TNBC patients.

Persons chronically exposed to low doses of ionizing radiation: A cytogenetic dosimetry study.

The dosimetry and control of exposure for individuals chronically exposed to ionizing radiation are important and complex issues. Assessment may be optimized by evaluating individual adaptation and radiosensitivity, but it is not possible for a single model to account for all relevant parameters. Our goal was to develop approaches for the calculation of doses for persons chronically exposed to ionizing radiation, taking their radiosensitivities into consideration. On the basis of ex vivo radiation of blood samples, dose-effect models were constructed for dose ranges 0.01-2.0 and 0.01-0.4 Gy, using different cytogenetic criteria. The frequencies of "dicentric chromosomes and rings" at low doses are too low to have predictive value. The different responses of subjects to radiation made it possible to categorize them according to their radiosensitivities and to generate separate dose-effect curves for radiosensitive, average, and radioresistant individuals, reducing the amount of error in retrospective dosimetry.

Silencing PinX1 enhances radiosensitivity and antitumor-immunity of radiotherapy in non-small cell lung cancer.

BACKGROUND: We aimed to investigate the effects of PinX1 on non-small cell lung cancer(NSCLC) radiosensitivity and radiotherapy-associated tumor immune microenvironment and its mechanisms. METHODS: The effect of PinX1 silencing on radiosensitivity in NSCLC was assessed by colony formation and CCK8 assay, immunofluorescence detection of γ- H2AX and micronucleus assay. Western blot was used to assess the effect of PinX1 silencing on DNA damage repair pathway and cGAS-STING pathway. The nude mouse and Lewis lung cancer mouse model were used to assess the combined efficacy of PinX1 silencing and radiotherapy in vivo. Changes in the tumor immune microenvironment were assessed by flow cytometry for different treatment modalities in the Lewis luuse model. The interaction protein RBM10 was screened by immunoprecipitation-mass spectrometry. RESULTS: Silencing PinX1 enhanced radiosensitivity and activation of the cGAS-STING pathway while attenuating the DNA damage repair pathway. Silencing PinX1 further increases radiotherapy-stimulated CD8+ T cell infiltration and activation, enhances tumor control and improves survival in vivo; Moreover, PinX1 downregulation improves the anti-tumor efficacy of radioimmunotherapy, increases radioimmune-stimulated CD8+ T cell infiltration, and reprograms M2-type macrophages into M1-type macrophages in tumor tissues. The interaction of PinX1 and RBM10 may promote telomere maintenance by assisting telomerase localization to telomeres, thereby inhibiting the immunostimulatory effects of IR. CONCLUSIONS: In NSCLC, silencing PinX1 significantly contributed to the radiosensitivity and promoted the efficacy of radioimmunotherapy. Mechanistically, PinX1 may regulate the transport of telomerase to telomeres through interacting with RBM10, which promotes telomere maintenance and DNA stabilization. Our findings reveal that PinX1 is a potential target to enhance the efficacy of radioimmunotherapy in NSCLC patients.

Corrigendum: ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway.

[This corrects the article DOI: 10.3389/fonc.2022.887068.].

Long non-coding RNA CCAT1 acts as an oncogene to promote radiation resistance in lung adenocarcinoma: an epigenomics-based investigation.

Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. As one of the LncRNAs, LncRNA CCAT1 has been reported to be closely associated with the progression multiple cancers, but its role in modulating the radioresistance of lung adenocarcinoma (LUAD) remains unclear. In our present study, we screened the potential radioresistance related LncRNAs in LUAD based on the data from The Cancer Genome Atlas (TCGA) database. Data suggested that CCAT1 was abundantly expressed in LUAD and CCAT1 was significantly associated with poor prognosis and radioresistance. Moreover, our in vitro experiments showed that radiation treatment could trigger elevated expression of CCAT1 in the human LUAD cell lines. Further loss/gain-of-function investigations indicated that CCAT1 knockdown significantly inhibited cell proliferation, migration and promoted cell apoptosis in NCI-H1299 cells under irradiation, whereas CCAT1 overexpression in A549 cells yield the opposite effects. In summary, we identified the promoting role of CCAT1 in radioresistance of LUAD, which may provide a theoretical basis for radiotherapy sensitization of LUAD.

Roseburia intestinalis sensitizes colorectal cancer to radiotherapy through the butyrate/OR51E1/RALB axis.

The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.

[Circ_0026134 regulates the miR-1270/GRB2 pathway to affect the radiosensitivity of hepatoma cells].

Objective: To investigate whether circular RNA 0026134 (circ_0026134) affects the radiosensitivity of hepatoma cells by regulating the miR-1270/growth factor receptor-bound protein 2 (GRB2) pathway. Methods: Real-time quantitative PCR (RT-qPCR) was used to detect the expression levels of circ_0026134, miR-1270, and GRB2 in liver cancer tissues and cells. Bioinformatics analysis, a dual-luciferase gene reporter assay, RT-qPCR, and western blot were used to analyze the targeting relationships between circ_0026134 and miR-1270 and miR-1270 and GRB2. The effects of circ_0026134, miR-1270, and GRB2 expression combined with 6 Gy on the proliferation, invasion, migration, and apoptosis of Huh7 and SK-HEP-1 cells were detected by a cell counting kit, a transwell assay, a scratch assay, and flow cytometry. The tumorigenesis experiment was used to detect the effect of silencing circ_0026134 in nude mice. Measurement data are expressed as the mean ± standard deviation. The independent sample t-test was used for comparison between two groups, and the one-way analysis of variance and SNK-q test were used for comparison between multiple groups. P < 0.05 was considered statistically significant. Results: The expression levels of circ_0026134 and GRB2, Huh7, and SK-HEP-1 cells in liver cancer tissues were significantly increased, while the expression levels of miR-1270 were significantly decreased (P < 0.05). The expression of circ_0026134 in Huh7 and SK-HEP-1 decreased significantly after radiotherapy (P < 0.05). circ_0026134 binds directly to miR-1270 and negatively regulates miR-1270 expression (P < 0.05). miR-1270 binds directly to GRB2 and negatively regulates GRB2 expression (P < 0.05). 6 Gy radiation significantly inhibited the proliferation, migration, and invasion of Huh7 and SK-HEP-1 cells and induced apoptosis (P < 0.05). Silencing circ_0026134 or overexpression of miR-1270 significantly enhanced the anti-proliferation, anti-migration, invasion, and pro-apoptosis effects of 6 Gy treatment on hepatoma cells (P < 0.05). Inhibition of miR-1270 significantly weakened the effects of silencing circ_0026134 combined with 6 Gy radiation on proliferation, migration, invasion, and apoptosis of hepatoma cells (P < 0.05). Overexpression of GRB2 significantly weakened the effects of miR-1270 overexpression combined with 6 Gy radiation on proliferation, migration, invasion, and apoptosis of hepatoma cells (P < 0.05). circ_0026134 knockdown significantly delayed tumor growth in vivo (P < 0.05). Conclusion: Silencing circ_0026134 strengthens radiation treatment's anti-proliferation, anti-migration, invasion, and pro-apoptotic effects in hepatoma cells by negatively regulating the miR-1270/GRB2 pathway, thereby enhancing radiosensitivity.

Cytotoxicity Enhancement in Osteosarcoma with Multifunctional I-131 Radiotherapeutic Nanoparticles: In Vitro Three-Dimensional Spheroid Model and Release Kinetics Modeling.

This novel radiolabeled chitosan nanoparticle, facilitated with curcumin, increased doxorubicin cytotoxicity and radiosensitivity to MG-63 osteosarcoma cells in a three-dimensional model. Delivery of the anti-epidermal growth factor receptor (EGFR) targeted carboxymethyl chitosan nanoparticles, directly labeled with Na131I (ICED-N), achieved deep tumor penetration in a three-dimensional model. Of three kinetic models, the Higuchi model more closely matched the experimental curve and release profiles. The anti-EGFR targeting resulted in a 513-fold greater targeting efficacy to MG-63 (EGFR+) cells than the control fibroblast (EGFR-) cells. The curcumin-enhanced ICED-N (4 × 0.925 MBq) fractionated-dose regime achieved an 18.3-fold increase in cell cytotoxicity compared to the single-dose (1 × 3.70 MBq) doxorubicin-loaded nanoparticle, and a 13.6-fold increase in cell cytotoxicity compared to the single-dose Na131I nanoparticle. Moreover, the ICED-N fractionated dose increased cells in the G2/M phase 8.78-fold, indicating the cell cycle arrest in the G2/M phase is associated with DNA fragmentation, and the intracellular damage is unable to be repaired. Overall, the results indicate that the fractionated dose was more efficacious than a single dose, and curcumin substantially increased doxorubicin cytotoxicity and amplified osteosarcoma cell radiosensitivity to Na131I.