PI3Kß controls immune evasion in PTEN-deficient breast tumours.

Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3Kß isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kß activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kß led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kß inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kß inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kß controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kß inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.

TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer.

Despite progress in the application of checkpoint immunotherapy against various tumors, attempts to utilize immune checkpoint blockade (ICB) agents in triple negative breast cancer (TNBC) have yielded limited clinical benefits. The low overall response rate of checkpoint immunotherapy in TNBC may be attributed to the immunosuppressive tumor microenvironment (TME). In this study, we investigated the role of mitogen-associated kinase TTK in reprogramming immune microenvironment in TNBC. Notably, TTK inhibition by BAY-1217389 induced DNA damage and the formation of micronuclei containing dsDNA in the cytosol, resulting in elicition of STING signal pathway and promoted antitumor immunity via the infiltration and activation of CD8+ T cells. Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials.

G-Quadruplex-Programmed Versatile Nanorobot Combined with Chemotherapy and Gene Therapy for Synergistic Targeted Therapy.

Developing synergistic targeted therapeutics to improve treatment efficacy while reducing side effects has proven promising for anticancer therapies, but how to conveniently modulate multidrug cooperation remains a challenge. Here, a novel synergistic strategy using a G-quadruplex-programmed versatile nanorobot (G4VN) containing two subunits of DNAzyme (DzG4) and ligand-drug conjugates (LDCs) is proposed to precisely target tumors and then execute both gene silencing and chemotherapy. As the core module of this nanorobot, a well-designed G4 responding to a high level of K+ in tumor microenvironment smartly kills three birds with one stone, which makes two TfR aptamers proximate to improve their efficiency of targeting tumor cells, and in situ activates a split 10-23 DNAzyme to downregulate target mRNA expression, meanwhile promotes the cell uptake of a GSH-responsive LDCs to enhance drug efficacy. Such a design enables a potently synergistic anticancer therapy with low side effects in vivo, showing great promise for broad applications in precision disease treatment.

A Tumor-Specific Cascade-Activating Smart Prodrug System for Enhanced Targeted Therapy.

Developing intelligently targeted drugs with low side effects is urgent for cancer treatment. Toward this goal, a tumor-specific cascade-activating smart prodrug system consisting of a G-quadruplex(G4)-modulated tumor-targeted DNA vehicle and a well-designed cellular stimuli-responsive ligand-drug conjugates (LDCs) is proposed. An original "donor-acceptor" binary fluorescent ligand, with ultrahigh affinity, brightness, and photostability, is engineered to tightly bind G4 structures and significantly improve the nuclease resistance of the DNA vehicle, which serves as a bridge contributing to the construction of the prodrug system, named ApG4/LDCs. Sodium nitroprusside and doxorubicin are loaded into ApG4/LDCs in one pot and generate nitric oxide and superoxide anion in response to cancer cellular environments, which in cascade generates peroxynitrite to cause DNA damage while promoting the self-monitored drug release to achieve enhanced targeted therapy. Such a cascade activation and self-reinforcement process is executed only when the prodrug system targets the tumor tissue followed by cell uptake, showing significant antitumor efficacy and greatly weakening the damage to normal tissues. Given the unique features, the innovative strategy for prodrug design may open a new door to precision disease treatment.

Strengthening Sn-MOF with SiO2/GeO2 Nanoparticles for Synergistically Enhanced High Capacity and Cycle Stability.

Metal-organic frameworks (MOFs) based on tin (Sn) have shown great potential as materials for lithium storage, thanks to their ability to alleviate volume expansion due to the homogeneous distribution of Sn in a porous matrix framework. However, the weak mechanical strength of the porous Sn-MOF structure has been a major challenge, leading to pulverization during the discharging/charging process. To overcome this issue, we have developed a feasible strategy to strengthen the Sn-MOF mechanical properties by incorporating SiO2/GeO2 nanoparticles during the synthesis process. The resulting composites of Sn-Si and Sn-Ge exhibited high energy density and long-term cycle stability, thanks to their synergistic effect in alloying and conversion reactions. Our density functional theory (DFT) calculations have revealed that the rigid SiO2/GeO2 nanoparticles enhance the Sn-MOF mechanical properties, including Young's and shear moduli, which contribute to the long-term cycle stability of these composites.

Global burden of diabetes mellitus from 1990 to 2019 attributable to dietary factors: An analysis of the Global Burden of Disease Study 2019.

AIMS: To analyse spatial and temporal changes in the global burden of diabetes mellitus (DM) attributable to dietary factors from 1990 to 2019. MATERIALS AND METHODS: The burden of DM was analysed in terms of age-standardized disability-adjusted life-year (DALY) rates and age-standardized death rates (ASDRs), which were obtained from the Global Burden of Disease Study 2019, and their corresponding estimated annual percentage changes (EAPCs). RESULTS: The ASDR exhibited a decreasing trend (EAPC = -0.02), while the age-standardized DALY rate exhibited an increasing trend (EAPC = 0.65). Forty-four percent of the burden of DM was attributable to dietary factors, with the three largest contributors being high intake of red meat, high intake of processed meat, and low intake of fruit. Residence in a region with a high sociodemographic index (SDI) was associated with a diet low in whole grains and high in red meat and processed meat, while residence in a low-SDI region was associated with a diet low in whole grains and fruits, and high in red meat. CONCLUSIONS: The age-standardized DALYs of DM attributable to dietary factors increased between 1990 and 2019 but differed among areas. The three largest dietary contributors to the burden of DM were high intake of red meat, high intake of processed meat, and low intake of fruit.

Malignant tumor increases the risk of all causes in-hospital mortality in critically ill patients with ischemic stroke: analysis of the MIMIC-IV database.

BACKGROUND: Ischemic stroke (IS) and malignant tumor (MT) have high morbidity and mortality rates worldwide, and several associations exist between them. This study aimed to determine the effect of MT on hospital mortality in patients with IS. METHODS: Based on their MT status, participants with IS in the Medical Information Mart for Intensive Care IV (MIMIC-IV) were divided into two groups. The primary outcome was in-hospital all causes mortality. Kaplan-Meier survival analysis was performed to evaluate the intergroup in-hospital mortality, and three Cox regression models were used to determine the association between MT and in-hospital mortality. RESULTS: A total of 1605 participants (749 males and 856 females) were included in the study. The mean age was 72.030 ± 15.463 years. Of these, 257 (16%) patients died in the hospital. Kaplan-Meier analysis showed that the MT group had a significantly lower possibility of in-hospital survival than the non-MT group. In the unadjusted model, in-hospital mortality among MT patients had a higher odds ratio (OR) of 1.905 (95% CI, 1.320-2.748; P < 0.001) than the non-MT group. After adjusting for basic information, vital signs, and laboratory data, MT was also associated with increased in-hospital mortality (OR = 1.844, 95% CI: 1.255-2.708; P = 0.002). CONCLUSIONS: Among the patients with IS, the risk of all causes in-hospital mortality was higher for MT than for patients non-MT. This finding can assist clinicians in more accurately assessing prognosis and making informed treatment decisions.

Hydrogel-based microenvironment engineering of haematopoietic stem cells.

Haematopoietic Stem cells (HSCs) have the potential for self-renewal and multilineage differentiation, and their behaviours are finely tuned by the microenvironment. HSC transplantation (HSCT) is widely used in the treatment of haematologic malignancies while limited by the quantity of available HSCs. With the development of tissue engineering, hydrogels have been deployed to mimic the HSC microenvironment in vitro. Engineered hydrogels influence HSC behaviour by regulating mechanical strength, extracellular matrix microstructure, cellular ligands and cytokines, cell-cell interaction, and oxygen concentration, which ultimately facilitate the acquisition of sufficient HSCs. Here, we review recent advances in the application of hydrogel-based microenvironment engineering of HSCs, and provide future perspectives on challenges in basic research and clinical practice.

Association of birth weight with type 2 diabetes mellitus and the mediating role of fatty acids traits: a two-step mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors. METHODS: Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness. RESULTS: The IVW method showed that lower birth weight raised the risk of T2DM (ß: -1.113, 95% CI: -1.573 ∼ -0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%). CONCLUSIONS: Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.

[Hepatocellular Carcinoma-Derived Exosomes: Key Players in Intercellular Communication Within the Tumor Microenvironment]. / 肝癌外泌体在肿瘤微环境细胞间通讯中的作用.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.

Investigating the association between serum ADAM/ADAMTS levels and bone mineral density by mendelian randomization study.

PURPOSE: A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders. METHODS: The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship. RESULTS: The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (ß = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship. CONCLUSION: Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

Proximity-Enhanced Electrochemiluminescence Sensing Platform for Effective Capturing of Exosomes and Probing Internal MicroRNAs Involved in Cancer Cell Apoptosis.

Exosomal microRNAs (miRNAs) play critical regulatory roles in many cellular processes, and so how to probe them has attracted increasing interest. Here we propose an aptamer-functionalized dimeric framework nucleic acid (FNA) nanoplatform for effective capture of exosomes and directly probing internal miRNAs with electrochemiluminescence (ECL) detection, not requiring RNA extraction in conventional counterparts. A CD63 protein-binding aptamer is tethered to one of the FNA structures, allowing exosomes to be immobilized there and release internal miRNAs after lysis. The target miRNA induces the formation of a Y-shaped junction on another FNA structure in a close proximity state, which benefits the loading of covalently hemin-modified spherical nucleic acid enzymes for enhanced ECL readout in the luminol-H2O2 system. In this facile way, the ultrasensitive detection of exosomal miR-21 from cancer cells is accomplished and then used for cell apoptosis analysis, indicating that the oncogene miR-21 negatively participates in the regulation of the apoptotic process; namely, downregulating the miR-21 level is unbeneficial for cancer cell growth.

The membrane protein Raw regulates dendrite pruning via the secretory pathway.

Neuronal pruning is essential for proper wiring of the nervous systems in invertebrates and vertebrates. Drosophila ddaC sensory neurons selectively prune their larval dendrites to sculpt the nervous system during early metamorphosis. However, the molecular mechanisms underlying ddaC dendrite pruning remain elusive. Here, we identify an important and cell-autonomous role of the membrane protein Raw in dendrite pruning of ddaC neurons. Raw appears to regulate dendrite pruning via a novel mechanism, which is independent of JNK signaling. Importantly, we show that Raw promotes endocytosis and downregulation of the conserved L1-type cell-adhesion molecule Neuroglian (Nrg) prior to dendrite pruning. Moreover, Raw is required to modulate the secretory pathway by regulating the integrity of secretory organelles and efficient protein secretion. Mechanistically, Raw facilitates Nrg downregulation and dendrite pruning in part through regulation of the secretory pathway. Thus, this study reveals a JNK-independent role of Raw in regulating the secretory pathway and thereby promoting dendrite pruning.

Moiré enhanced charge density wave state in twisted 1T-TiTe2/1T-TiSe2 heterostructures.

Nanoscale periodic moiré patterns, for example those formed at the interface of a twisted bilayer of two-dimensional materials, provide opportunities for engineering the electronic properties of van der Waals heterostructures1-11. In this work, we synthesized the epitaxial heterostructure of 1T-TiTe2/1T-TiSe2 with various twist angles using molecular beam epitaxy and investigated the moiré pattern induced/enhanced charge density wave (CDW) states with scanning tunnelling microscopy. When the twist angle is near zero degrees, 2 × 2 CDW domains are formed in 1T-TiTe2, separated by 1 × 1 normal state domains, and trapped in the moiré pattern. The formation of the moiré-trapped CDW state is ascribed to the local strain variation due to atomic reconstruction. Furthermore, this CDW state persists at room temperature, suggesting its potential for future CDW-based applications. Such moiré-trapped CDW patterns were not observed at larger twist angles. Our study paves the way for constructing metallic twist van der Waals bilayers and tuning many-body effects via moiré engineering.

Observation of Electronic Strong Correlation in VTe_{2}-2sqrt[3]×2sqrt[3] Monolayer.

Strong electron correlation under two-dimensional limit is intensely studied in the transition metal dichalcogenides monolayers, mostly within their charge density wave (CDW) states that host a star of David period. Here, by using scanning tunneling microscopy and spectroscopy and density functional theory calculations with on-site Hubbard corrections, we study the VTe_{2} monolayer with a different 2sqrt[3]×2sqrt[3] CDW period. We find that the dimerization of neighboring Te-Te and V-V atoms occurs during the CDW transition, and that the strong correlation effect opens a Mott-like full gap at Fermi energy (E_{F}). We further demonstrate that such a Mott phenomenon is ascribed to the combination of the CDW transition and on-site Coulomb interactions. Our work provides a new platform for exploring Mott physics in 2D materials.

Transparent Oil-Water Separating Hydrophobic Sponge Prepared from a Pickering High Internal Phase Emulsion Stabilized by Octadecyltrichlorosilane Grafting Carbon Nanotubes.

Increasingly, oil spills and industrial discharges are wreaking havoc on the water environment; in order to efficiently separate oil and water from sewage containing oil or organic solvents, a novel porous polymer (P(EHA-co-BA)) was prepared by Pickering high internal phase emulsion (HIPE) template method. To obtain polyHIPE with better oil/water separation capacities, octadecyltrichlorosilane (OTS)-modified carbon nanotubes (CNTs) and surfactants were used as costabilizers for HIPE, which improved the stability of HIPE as well as the mechanical properties and the separation efficiency of polyHIPE. In the presence of 1 wt % OTS-CNT adding in the oil phase, 1%OTS-CNT polyHIPE has high porosity (92.21%), favorable hydrophobicity (a water contact angle of 128°), and excellent mechanical properties. As a result, 1%OTS-CNT polyHIPE has high absorption of oils and oily solvents, e.g., dichloromethane up to 36 g/g, and maintains an absorption efficiency of >97% after 20 reapplications. In the formulation of polyHIPE, cinnamaldehyde (CA) has been added to provide superior antibacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). It appears that the novel polyHIPE proposed in this work is a reusable antibacterial porous polymer with promising applications for oil-water separation.

Sensitively detecting endogenous homocysteine in human serum and cardiomyocytes with a specific fluorescent probe.

The elevated level of homocysteine (Hcy) in circulating blood is generally regarded as a risk factor for a variety of diseases including acute myocardial infarction (AMI), but there is no clear answer to whether circulating Hcy can be used for AMI diagnosis. To address it, here we have designed a tetraazacycle-based fluorescent probe for sensitive detection of endogenous Hcy in AMI patients' serum and cardiomyocytes, showing a perfect selectivity over other biothiols (e.g. Cys and GSH). It mainly relies on the formation of a stable six-membered ring structure when this probe responds to Hcy, which is accompanied by a weakening of photoinduced electron transfer (PET) that induces a sharp increase in the fluorescence emission. In this way, Hcy can be probed in biofluids with high sensitivity. We then employed this fluorescent sensor to statistically analyze the levels of Hcy in human circulating blood, indicating a big difference between AMI patients and the healthy participants. To tell whether such a difference is applicable to AMI diagnosis, we further compare the expression levels of Hcy in cardiomyocytes and other tissue cells. It reveals a lower level of endogenous Hcy in cardiomyocytes, implying no direct relationship between the elevated Hcy and cardiomyocyte damage. This observation suggests that Hcy in circulating blood cannot be utilized as a potential biomarker for AMI diagnosis, although it is proven as a risk factor for this disease.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

MiR-125 family improves the radiosensitivity of head and neck squamous cell carcinoma.

BACKGROUND: MiRNAs can affect the radiosensitization of head and neck squamous cell carcinoma (HNSCC). We aimed to analyze the function of miR-125 family members in HNSCC using The Cancer Genome Atlas (TCGA) and determine their effect on radiation in laryngeal squamous cell cancer (LSCC). METHODS: First, we systematically analyzed the role of the miR-125 family in HNSCC using the TCGA database and found that miR-125a-5p is associated with radiotherapy. We then performed comprehensive enrichment analysis of miR-125a-5p and predicted target genes. Then, we performed transfection, cell proliferation assays, reverse transcription polymerase chain reaction, apoptosis assays, micronucleus tests, and western blotting on hep-2 cells selected with puromycin. RESULTS: MiR-125 family members exhibited significantly different expression in HNSCC. They were significantly associated with tumor-node-metastasis staging, clinical stages, and histological grades. Radiation therapy had a statistically effect on miR-125 family members, except miR-125a-3p. Moreover, miR-125a-5p was related to overall survival in LSCC. Thus, we predicted 110 target genes and seven hub genes of miR-125a-5p. The proliferation rate of cells transfected with lentivirus vector expressing miR-125a-5p was significantly reduced compared to the other groups. The radiation effect was enhanced in cells transfected with miR-125a-5p. The ratio of apoptotic cells transfected and exposed to X-rays (10 Gy) was distinctly higher than that of the Ad-control group. Western blotting analysis revealed that miR-125a-5p upregulated the apoptotic regulators P53 and rH2AX. Thus, miR-125a-5p may increase radiosensitivity in LSCC via upregulation of pro-apoptotic genes. CONCLUSIONS: MiR-125 family members could be prognostic biomarkers of HNSCC and improve HNSCC sensitivity to radiotherapy by activating P53. Upregulating miR-125a-5p via lentivirus vectors may be a novel strategy to strengthen the effect of radiotherapy on LSCC.