Discovery of novel FUT8 inhibitors with promising affinity and in vivo efficacy for colorectal cancer therapy.

As a member of glycosyltransferases, fucosyltransferase 8 (FUT8) is essential to core fucosylation and has been considered as a potential therapeutic target for malignant tumors, including colorectal cancer (CRC). Based on the identification of key binding residues and probable conformation of FUT8, an integrated strategy that combines virtual screening and chemical optimization was carried out and compound 15 was identified as a potent FUT8 inhibitor with novel chemical structure and in vitro antitumor activity. Moreover, chemical pulldown experiments and binding assays confirmed that compound 15 selectively bound to FUT8. In vivo, compound 15 showed promising anti-CRC effects in SW480 xenografts. These data support that compound 15 is a potential FUT8 inhibitor for CRC treatment and deserve further optimization studies.

Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.

One-pot preparation of bi-functional POSS-based hybrid monolith via photo-initiated polymerization for isolation of extracellular vesicles.

Extracellular vesicles (EVs) are important participants in numerous pathophysiological processes, and could be used as valuable biomarkers to detect and monitor various diseases. However, facile EV isolation methods are the essential and preliminary issue for their downstream analysis and function investigation. In this work, a polyhedral oligomeric silsesquioxanes (POSS) based hybrid monolith combined metal affinity chromatography (MAC) and distearoyl phospholipid ethanolamine (DSPE) function was developed via photo-initiated thiol-ene polymerization. This synthesis process was facile, simple and convenient, and the obtained hybrid monolith could be applied to efficiently isolate EVs from bio-samples by taking advantages of the specific bond of Ti4+ and phosphate groups on the phospholipid membrane of EVs and the synergistic effect of DSPE insertion. Meanwhile, the eluted EVs could maintain their structural integrity and biological activity, suggesting they could be used for downstream application. Furthermore, 75 up-regulated proteins and 56 down-regulated proteins were identified by comparing the urinary EVs of colorectal cancer (CRC) patients and healthy donors, and these proteins might be used as potential biomarkers for early screening of CRC. These results demonstrated that this hybrid monolith could be used as a simple and convenient tool for isolating EVs from bio-samples and for wider applications in biomarker discovery.

FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities.

Ti3C2 and Ti2C MXene materials for high-performance isolation of extracellular vesicles via coprecipitation.

Two-dimensional (2D) materials such as MXenes, are usually well utilized in the field of catalysts and battery due to their good hydrophilicity and diversified surface terminals. However, their potential applications in the treatment of biological samples have not been widely concerned. Extracellular vesicles (EVs) contain unique molecular signatures and could be used as biomarkers for the detection of severe diseases such as cancer, as well as monitoring the therapeutic response. In this work, two kinds of MXene materials (Ti3C2 and Ti2C) were successfully synthesized and employed in the isolation of EVs from the biological samples by taking advantage of the affinity interaction between the titanium (Ti) in MXenes and the phospholipid membrane of EVs. Compared with Ti2C MXene materials, TiO2 beads and the other EVs isolation methods, Ti3C2 MXene materials exhibited excellent isolation performance via the coprecipitation with EVs due to the abundant unsaturated coordination of Ti2+/Ti3+, and the dosage of materials was the lowest. Meanwhile, the whole isolation process could be done within 30 min and integrated well with the following analysis of proteins and ribonucleic acids (RNAs), which was also convenient and economic. Furthermore, the Ti3C2 MXene materials were used to isolate the EVs from the blood plasma of colorectal cancer (CRC) patients and healthy donors. Proteomics analysis of EVs showed that 67 proteins were up-regulated, in which most of them were closely related to CRC progression. These findings indicate that the MXene material-based EVs isolation method via coprecipitation provides an efficient tool for early diagnosis of diseases.

A new neurosurgical adjustable pressure suction apparatus with a mechanically controlled air inlet: the study of precise regulation and atraumatic suction.

Background: An essential surgical tool in neurosurgery is the suction tube. The skillful and accurate use of a suction tube facilitates the neurosurgical operation. Objective: This study is to verify the practicality of an adjustable pressure suction tube (APS tube) and to explore the ideal APS tube diameter and tip negative pressure for different intracranial structures. Methods: APS tubes were used to aspirate brain tissues and carotid arteries of rats. Laser speckle contrast imaging (LSCI) was used to record the blood flow velocity (BFV). We measured APS tube diameter, air inlet size, tip negative pressure and central negative pressure and calculated the correlation between them. In our department, intraoperative real-time parameters including APS tube diameter, length, air inlet size, and central negative pressure were recorded, and the tube tip negative pressure suitable for different intracranial structures and parts was calculated. Results: All experiments were carried out using APS tubes. Experiments on rats objectively reflected a severe structural damage to the brain and blood vessels by the suction tube, which might even result in an irreversible reduction in blood flow., Rat carotid arteries and brain tissue suffered severe damage when the tip negative pressure exceeded 33.4 ± 1.8 and 29.2 ± 2.0 kPa, respectively. BFV failed to return to the preoperative level 3 min after the operation (p < 0.05), and this decrease was more pronounced when the suction tube diameter was large (p < 0.05). The tip negative pressure was positively and negatively correlated with central negative pressure and the air inlet size, and was independent of APS tube diameter. A total of 50 operations including 39 tumor resection operations and 11 moyamoya disease bypass operations were recorded. Large-diameter APS tubes (3.5 mm) with an closed air inlet were frequently used to maintain a greater tip negative pressure before the incision of dura mater. When important structures such as motor cortex and brainstem were involved, 1.5- or 2.0-mm-diameter APS tubes were mostly used, and an air inlet was opened up to 0.7-2.1 mm to maintain a safe tip negative pressure (7.4-27.9 kPa). Conclusion: APS tubes with a mechanical knob provide stable and precise adjustment of the tip negative pressure, avoiding excessive negative pressure that causes serious damage to the intracranial structure. And, this allows the surgeon to hold the suction tube more freely and operate at any angle with an appropriate fulcrum near the incision to achieve efficient atraumatic suction and enhance surgical safety.

Synergistic antitumor activity of 5-fluorouracil and atosiban against microsatellite stable colorectal cancer through restoring GATA3.

Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban, an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo. Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu.

Microsatellite Instability Analysis and Its Prognostic Value in Invasive Nonampullary Duodenal Adenocarcinoma.

PURPOSE: Nonampullary duodenal adenocarcinoma (NADA) is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to their rarity. In this study, we retrospectively analyzed 54 cases of invasive NADA, focusing on the microsatellite instability (MSI) phenotype, programmed cell death-ligand 1 (PD-L1) expression, and prognostic factors. METHODS: Expression of the PD-L1 protein and cell differentiation markers in tumors was detected by immunohistochemistry. Microsatellite markers (NR-21, NR-22, NR-24, BAT-25, and BAT-26) were amplified for MSI assessment by PCR. RESULTS: The incidence of MSI in invasive NADA was 35.2%. No significant correlation between the MSI phenotype and clinicopathological factors was observed. Positive expression of PD-L1 by immune cells was common in advanced-stage disease (p = 0.054), and positive expression of PD-L1 in cancer cells correlated significantly with the histologically undifferentiated type (p = 0.016). Kaplan-Meier survival analysis demonstrated a significantly better overall survival (OS) in patients with MSI (p = 0.013) and at early-stage disease (p = 0.000) than in those with microsatellite-stable or at late tumor stages. Univariate and multivariate analyses showed that MSI (hazard ratio [HR]: 0.282, 95% confidence interval [CI]: 0.106-0.751, p = 0.011) and early tumor stage (stage I-II) (HR: 8.81, 95% CI: 2.545-30.500, p = 0.001) were independent better prognostic factors of OS. CONCLUSIONS: MSI and early tumor stage (stage I-II) were independent better prognostic factors of OS. A high proportion of MSI phenotypes and positive PD-L1 expression may be helpful for identifying immune checkpoint inhibitors as a novel therapeutic strategy.

Photoactivated DNA Walker Based on DNA Nanoflares for Signal-Amplified MicroRNA Imaging in Single Living Cells.

Specific and sensitive detection and imaging of cancer-related miRNA in living cells are desirable for cancer diagnosis and treatment. Because of the spatiotemporal variability of miRNA expression level during different cell cycles, signal amplification strategies that can be activated by external stimuli are required to image miRNAs on demand at desired times and selected locations. Herein, we develop a signal amplification strategy termed as the photoactivated DNA walker based on DNA nanoflares, which enables photocontrollable signal amplification imaging of cancer-related miRNA in single living cells. The developed method is achieved via combining photoactivated nucleic acid displacement reaction with the traditional exonuclease III (EXO III)-assisted DNA walker based on DNA nanoflares. This method is capable of on-demand activation of the DNA walker for dictated signal amplification imaging of cancer-related miRNA in single living cells. The developed method was demonstrated as a proof of concept to achieve photoactivated signal amplification imaging of miRNA-21 in single living HeLa cells via selective two-photon irradiation (λ = 740 nm) of single living HeLa cells by using confocal microscopy equipped with a femtosecond laser.

Photoactivated Biosensing Process for Dictated ATP Detection in Single Living Cells.

The subcellular distribution of adenosine 5'-triphosphate (ATP) and the concentration of ATP in living cells dynamically fluctuate with time during different cell cycles. The dictated activation of the biosensing process in living cells enables the spatiotemporal target detection in single living cells. Herein, a kind of o-nitrobenzylphosphate ester hairpin nucleic acid was introduced as a photoresponsive DNA probe for light-activated ATP detection in single living cells. Two methods to spatiotemporally activate the probe in single living cells were discussed. One method was the usage of the micrometer-sized optical fiber (about 5 µm) to guide the UV light (λ = 365 nm) to selectively activate the photoresponsive DNA probe in single living cells. The second method involved a two-photon laser confocal scanning microscope to selectively irradiate the photoresponsive DNA probes confined in single living cells via two-photon irradiation (λ = 740 nm). ATP aptamer integrated in the activated DNA probes selectively interacted with the target ATP, resulting in dictated signal generation. Furthermore, the photoactivated biosensing process enables dictated dual-model ATP detection in single living cells with "Signal-ON" fluorescence signal and "Signal-OFF" electrochemical signal outputs. The developed photoactivated biosensor for dictated ATP detection with high spatiotemporal resolution in single living cells at a desired time and desired place suggests the possibility to monitor biomarkers during different cell cycles.

Mechanism of PKM2 affecting cancer immunity and metabolism in Tumor Microenvironment.

PKM2 is the enzyme that regulates the final rate-limiting step of glycolysis. PKM2 expression can reinforce the utilization of oxygen and synthesis of growth substances in cancer cells by enhancing OXPHOS and the Warburg effect. In cancer immunity, PKM2 can modulate the expression of PD-L1 in M2 macrophage and decrease the amount and activity of CD8+ T cells. This affects cancer cell killing and immune escape sequentially. How PKM2 regulates PD-L1 expression through immunometabolism is summarized. PKM2 builds a bridge between energy metabolism and cancer immunity. The activator and inhibitor of PKM2 both promote the anti-cancer immune response and inhibit cancer growth and metastasis by regulating the metabolism of cancer cells and immune cells in the tumor microenvironment through HIF-1α/PKM2 pathway. This review focuses on the precise role of PKM2 modulating immunometabolism, providing valuable suggestions for further study in this field.

Influencing factors for peripheral and posterior lesions in mild non-proliferative diabetic retinopathy-the Kailuan Eye Study.

AIM: To explore the influencing factors of diabetes type 2 patients with mild non-proliferative diabetic retinopathy (NPDR) in the Kailuan area of Tangshan, Hebei Province, China. METHODS: In this non-interventional, retrospective study, 683 patients with type 2 diabetes were included in the Kailuan Diabetic Retinopathy Study involving participants with diabetes in the community-based longitudinal Kailuan Study. Based on the undilated ultra-wide field (200°; UWF) images and partial dilated digital fundus images, the diabetic retinopathy (DR) of the surveyed population was graded. Interobserver agreement was estimated by using Cohen's Kappa statistics. The main outcome indicators included gender, age, weight, height, body mass index, blood pressure, circumferences of neck, waist and hip, current smoking, levels of fasting plasma glucose (FPG), hypersensitive C-reactive protein, creatinine, and cholesterol, etc. According to different lesions' locations of patients with mild NPDR, logistic regression models were used to estimate the odds ratios (ORs) and their 95%CIs of each risk factor. RESULTS: The study group of 683 patients included 570 males and 113 females. The mean age of the patients was 62.18±9.41y. Compared with dilated fundus examinations, there was fair agreement with the level of DR identified on UWF images in 63.91% of eyes (k=0.369, 95%CI, 0.00-0.00). Detected by UWF images, there were 98 patients with mild NPDR having peripheral retinal lesions, 35 patients with mild NPDR having posterior lesions, 44 patients with mild NPDR whose lesions were detected both in and out the standard two fields area, and 336 patients with non obvious DR. Parameters that conferred a statistically significant increased risks for mild NPDR with having peripheral retinal lesions were neck circumstance (OR, 1.124; 95%CI, 1.044-1.211), and with posterior lesions were FPG (OR, 1.052; 95%CI, 1.007-1.099). CONCLUSION: UWF is an effectiveness means of DR screening. Moreover, it is necessary to evaluate peripheral diabetic retinal lesions which can help to estimate the severity of DR. The phenomenon that nonuniform and inhomogeneous distribution of DR lesions has been found. And the influencing factors in mild NPDR are differing by different lesions' locations.

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

Background: Immunotherapy targeting PD-1/PD-L1 represents a breakthrough in the treatment of lung cancer. Pyruvate kinase M2 (PKM2) is not only a critical player in glycolysis, but also conducive to tumor progression and immune response. While both have been linked to lung adenocarcinoma (AC), the correlation and clinical significance of PKM2 and PD-L1 expression in human lung AC tissues remains not entirely explored. Methods: Expression of PKM2 and PD-L1 proteins were detected by immunohistochemistry in 74 lung AC cases and the corresponding noncancerous tissues. Simultaneously, multiplex immunofluorescence was used to detect PKM2, PD-L1, CK, CD3, and CD68 in the lung AC tissues. We measured expression patterns and co-localization of these markers, evaluating their association with clinicopathological features and overall survival. Validation of findings was conducted using mRNA expression data from The Cancer Genome Atlas (TCGA) of 515 lung AC cases. Results: High expression of PKM2 in tumor cells was significantly related with lymph node metastasis and TNM stage (p=0.035, p=0.017, respectively). Moreover, PKM2 expression in tumor cells was positively correlated with tumor PD-L1 expression. High expression of PKM2, PD-L1 in tumor cells and immune cells predicted high mortality rate and poorer survival rates, respectively. Additionally, multivariate Cox regression models indicated that high expression of PKM2 in tumor cells was an independent prognostic factor. Based on TCGA genomic data, high PKM2 mRNA expression was significantly associated with poorer survival (p=0.001). Conclusion: High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict poorer survival rates in patients with lung AC.

Elevated VEGF-A & PLGF concentration in aqueous humor of patients with uveal melanoma following Iodine-125 plaque radiotherapy.

AIM: To measure the concentration of vascular endothelial growth factor-A (VEGF-A), and placental growth factor (PLGF) in aqueous humor of uveal melanoma patients before and after Iodine-125 plaque therapy (IPT), determine the postoperative fluctuation and evaluate associated factors in vivo. METHODS: Participants were 18 Chinese patients with uveal melanoma who were elected to IPT. Undiluted aqueous humor samples were collected at Iodine plaque implant and removal time, then stored immediately at -80°C until assayed. The concentration of VEGF-A, PLGF and other 7 cytokines comprising interleukin-2 (IL-2), IL-8, IL-10, interferon (IFN)-γ, programmed death (PD)-1, transforming growth factor (TGF)-ß1 and insulin-like growth factor (IGF)-1 in aqueous humor was measured using Raybiotech immunoassay kit, a high throughput strategy. The VEGF-A and PLGF levels were compared across preoperation and postoperation subgroups, as well as those of other 7 interleukins. Correlation and grouped analyses were conducted to determine the independent effects of clinical parameters and other cytokines on VEGF-A and PLGF concentration or fluctuation. This study set a self-control design. RESULTS: VEGF-A (P=0.038) and PLGF (P=0.026) were the only two increased cytokines after IPT. Preoperative and postoperative level of VEGF-A and PLGF (r=0.575, P=0.013; r=0.987, P<0.001) correlated with each other significantly. Level of VEGF-A (r=0.626, P=0.005; r=0.588, P=0.01) and PLGF (r=0.616, P=0.007; r=0.588, P=0.01) had positive correlation with tumor thickness consistently. Elevated VEGF-A or PLGF level were strong predictive factors of each other (P=0.007, OR=60.0). The elevated VEGF-A group showed a higher postoperative level of IFN-γ (P=0.005), IL-2 (P<0.001) and IL-10 (P=0.004) in aqueous humor. When the elevated PLGF group got similar results that a higher postoperative level of IFN-γ (P=0.007), IL-2 (P<0.001) and IL-10 (P=0.013) in aqueous humor. CONCLUSION: This study reveals that VEGF-A and PLGF in aqueous humor significantly increased with tumor thickness and radiation process in uveal melanoma patients. VEGF-A and PLGF may be crucial in uveal melanoma genesis and radiotherapy reactions. Immune mediators comprised IFN-γ, IL-2 and IL-10 could play roles in the link between inflammation and angiogenesis in uveal melanoma when exposed to radiotherapy.

Clinicopathological and prognostic significance of caveolin-1 and ATG4C expression in the epithelial ovarian cancer.

OBJECTIVE: Altered expression of caveolin-1 (CAV1) and autophagy marker ATG4C is observed in various types of human cancers. However, the clinical significance of CAV1 and ATG4C expression in epithelial ovarian cancer (EOC) remains largely unknown. The present study aims to explore the clinicopathological value and prognostic significance of CAV1 and ATG4C expression in EOC. METHODS: The expression pattern and prognostic value of CAV1 and ATG4C mRNA in EOC were analyzed using data from the Cancer Genome Atlas (TCGA) database (N = 373). In addition, immunohistochemistry analysis was performed to detect and assay the expression of CAV1 and ATG4C proteins in tissue microarray of EOC. RESULTS: Based on TCGA data, Kaplan-Meier analysis indicated that patients with low CAV1 mRNA (p = 0.021) and high ATG4C mRNA (p = 0.018) expression had a significantly shorter overall survival (OS). Cox regression analysis demonstrated that the expression levels of CAV1 (p = 0.023) and ATG4C mRNA (p = 0.040) were independent prognostic factors for OS in EOC. In addition, the Concordance Index of the nomogram for OS prediction was 0.660. Immunohistochemical analysis showed the expression levels of stromal CAV1 and cancerous ATG4C proteins, and high expression of both CAV1 and ATG4C protein in the stroma were found to significantly correlate with the histologic subtypes of EOC, especially with serous subtype. CONCLUSIONS: Decreased expression of CAV1 mRNA and increased expression of ATG4C mRNA in EOC can predict poor overall survival. The expression levels of CAV1 protein in stromal cells and ATG4C protein in cancer cells are significantly associated with histologic subtypes of EOC. These findings suggest that CAV1 and ATG4C serve as useful prognostic biomarkers and candidate therapeutic targets in EOC.

Application of a double-colour upconversion nanofluorescent probe for targeted imaging of mantle cell lymphoma.

Upconversion nanoparticles are a new type of fluorescent marker in biomedical imaging that can convert a longer wavelength (such as near-infrared fluorescence) into a shorter wavelength (such as visible light). Mantle cell lymphoma, which is derived from B-cell lymphoma, is a subtype of non-Hodgkin's lymphoma, and the immune phenotype is a mature B-cell phenotype (CD20+, CD5+). To develop the use of nanomaterials as specific markers for the medical imaging of mantle cell lymphoma, we modified the surface of UCNPs by oxidation so that the CD20 or CD5 antibody could covalently attach to the upconversion nanoparticles to form antibody-UCNP conjugates. These antibody-UCNP conjugates were used as fluorescent probes to detect the CD20 or CD5 antigen. Due to the excessive expression of these antigens on the surface of MCL cells and successful strong connection between the antibody and UCNPs, the latter could specifically combine with mantle cell lymphoma cells. Upon near-infrared excitation at 980 nm, cells labelled with UCNPs emitted bright upconversion fluorescence.

A polymorphism in miR-1262 regulatory region confers the risk of lung cancer in Chinese population.

It has been proposed that the majority of disease-associated loci identified by genome-wide association studies (GWAS) are enriched in non-coding regions, such as the promoter, enhancer or non-coding RNA genes. Thus, we performed a two-stage case-control study to systematically evaluate the association of genetic variants in miRNA regulatory regions (promoter and enhancer) with lung cancer risk in 7,763 subjects (discovery stage: 2,331 cases and 3,077 controls; validation stage: 1,065 cases and 1,290 controls). As a result, we identified that rs12740674 (C > T) in miR-1262 enhancer was significantly associated with the increased risk of lung cancer (additive model in discovery stage: adjusted OR = 1.31, 95%CI = 1.13-1.53, p = 3.846 × 10-4 in Nanjing GWAS; adjusted OR = 1.20, 95%CI = 1.00-1.44, p = 0.041 in Beijing GWAS; validation stage: adjusted OR = 1.20, 95%CI = 1.03-1.41, p = 0.024). In meta-analysis, the p value for the association between rs12740674 and lung cancer risk reached 6.204 × 10-6 (adjusted OR = 1.24, 95%CI = 1.13-1.36). Using 3DSNP database, The Cancer Genome Atlas (TCGA) data and functional assays, we observed that the risk T allele of rs12740674 reduced the expression level of miR-1262 in lung tissue through chromosomal looping, and overexpression of miR-1262 inhibited lung cancer cell proliferation probably through targeting the expression levels of ULK1 and RAB3D. Our findings confirmed the important role that genetic variants of noncoding sequence play in lung cancer susceptibility and indicated that rs12740674 in miR-1262 may be biologically relevant to lung carcinogenesis.