[Application value of CT examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma].

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.

Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations.

Probing binding modes of GDP, GTP and GNP to NRAS are of significance for understanding the regulation mechanism on the activity of RAS proteins. Four separate Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the apo, GDP-, GTP- and GNP-bound NRAS. Dynamics analyses suggest that binding of three ligands highly affects conformational states of the switch domains from NRAS, which disturbs binding of NRAS to its effectors. The analyses of free energy landscapes (FELs) indicate that binding of GDP, GTP and GNP induces more energetic states of NRAS compared to the apo NRAS but the presence of GNP makes the switch domains more ordered than binding of GDP and GNP. The information of interaction networks of ligands with NRAS reveals that the π-π interaction of residue F28 and the salt bridge interactions of K16 and D119 with ligands stabilize binding of GDP, GTP and GNP to NRAS. Meanwhile magnesium ion plays a bridge role in interactions of ligands with NRAS, which is favourable for associations of GDP, GTP and GNP with NRAS. This work is expected to provide useful information for deeply understanding the function and activity of NRAS.

Decoding drug resistant mechanism of V32I, I50V and I84V mutations of HIV-1 protease on amprenavir binding by using molecular dynamics simulations and MM-GBSA calculations.

Mutations V32I, I50V and I84V in the HIV-1 protease (PR) induce drug resistance towards drug amprenavir (APV). Multiple short molecular dynamics (MSMD) simulations and molecular mechanics generalized Born surface area (MM-GBSA) method were utilized to investigate drug-resistant mechanism of V32I, I50V and I84V towards APV. Dynamic information arising from MSMD simulations suggest that V32I, I50V and I84V highly affect structural flexibility, motion modes and conformational behaviours of two flaps in the PR. Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV. This study can provide useful dynamics information for the design of potent inhibitors relieving drug resistance.

Percutaneous vertebral augmentation for osteoporotic vertebral compression fractures will increase the number of subsequent fractures at adjacent vertebral levels: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate whether percutaneous vertebral augmentation (PVA) was associated with clinical and radiological subsequent adjacent fractures in patients with osteoporotic vertebral compression fractures. MATERIALS AND METHODS: The systematic review was performed following PRISMA guidelines. Data were retrieved from PubMed, EMBASE, Cochrane Library, Google Scholar, Web of Science, and ClinicalTrial.gov, from database inception to March 2020. Eligible studies were those that assessed subsequent adjacent fractures after PVA in comparison with conservative treatment (CT). The number of patients with adjacent secondary vertebral fractures was calculated, and the pooled risk ratio (RR) with its 95% confidence intervals (95% CI) was used. Moreover, heterogeneity, sensitivity, and publication bias analyses were performed. RESULTS: Twenty-four studies were included finally. Moreover, 20/421 (4.75%) patients from the PVA group and 25/359 (6.96%) patients from the CT group had clinical subsequent adjacent fractures, and 46/440 (10.45%) patients from the PVA group and 36/444 (8.10%) patients from the CT group had radiological subsequent adjacent fractures. Both had no significant difference between the two groups (RR = 0.67, 95% CI [0.38, 1.19], p = 0.17)/(RR = 1.13, 95% CI [0.75, 1.70], p = 0.576). However, the number of fractured vertebrae was higher in the PVA group than in the CT group (RR = 1.41, 95% CI [1.03, 1.93], p = 0.03). A sensitivity analysis did not identify specific trials that seriously deflected. No obvious publication bias was identified. CONCLUSIONS: The systematic review revealed that PVA did not increase the incidence for subsequent adjacent fractures regardless of whether they were clinical or radiological fractures. However, PVA can increase the number of subsequent fractures at adjacent vertebral levels.

Decoding molecular mechanism underlying binding of drugs to HIV-1 protease with molecular dynamics simulations and MM-GBSA calculations.

HIV-1 protease (PR) is thought to be efficient targets of anti-AIDS drug design. Molecular dynamics (MD) simulations and multiple post-processing analysis technologies were applied to decipher molecular mechanism underlying binding of three drugs Lopinavir (LPV), Nelfinavir (NFV) and Atazanavir (ATV) to the PR. Binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) suggest that compensation between binding enthalpy and entropy plays a vital role in binding of drugs to PR. Dynamics analyses show that binding of LPV, NFV and ATV highly affects structural flexibility, motion modes and dynamics behaviour of the PR, especially for two flaps. Computational alanine scanning and interaction network analysis verify that although three drugs have structural difference, they share similar binding modes to the PR and common interaction clusters with the PR. The current findings also confirm that residues located interaction clusters, such as Asp25/Asp25', Gly27/Gly27', Ala28/Ala28', Asp29, Ile47/Ile47', Gly49/Gly49', Ile50/Ile50', Val82/Val82' and Ile84/Ile84, can be used as efficient targets of clinically available inhibitors towards the PR.

Insights into effect of the Asp25/Asp25' protonation states on binding of inhibitors Amprenavir and MKP97 to HIV-1 protease using molecular dynamics simulations and MM-GBSA calculations.

The protonation states of two aspartic acids in the catalytic strands of HIV-1 protease (PR) remarkably affect bindings of inhibitors to PR. It is requisite for the design of potent inhibitors towards PR to investigate the influences of Asp25/Asp25' protonated states on dynamics behaviour of PR and binding mechanism of inhibitors to PR. In this work, molecular dynamics (MD) simulations, MM-GBSA method and principal component (PC) analysis were coupled to explore the effect of Asp25/Asp25' protonation states on conformational changes of PR and bindings of Amprenavir and MKP97 to PR. The results show that the Asp25/Asp25' protonation states exert different impacts on structural fluctuations, flexibility and motion modes of PR. Dynamics analysis verifies that Asp25/Asp25' protonated states highly affect conformational dynamics of two flaps in PR. The binding free energy calculations results suggest that the Asp25/Asp25' protonated states obviously strengthen bindings of inhibitors to PR compared to the non-protonation state. Calculations of residue-based free energy decomposition indicate that the Asp25/Asp25' protonation not only disturbs the interaction network of inhibitors with PR but also stabilizes bindings of inhibitors to PR by cancelling the electrostatic repulsive interaction. Therefore, special attentions should be paid to the Asp25/Asp25' protonation in the design of potent inhibitors towards PR.

Polyoxometalate SbW9 regulates proliferation and apoptosis of NSCLC cells via PTEN-dependent AKT signaling pathway.

The article "Polyoxometalate SbW9 regulates proliferation and apoptosis of NSCLC cells via PTEN-dependent AKT signaling pathway, by H.-B. Sun, L. Xu, Z.-X. Wang, Y. Zheng, Y. Zhao, Y.-Y. Yin, X.-L. Han, Z.-N. Xu, published in Eur Rev Med Pharmacol Sci 2019; 23 (18): 7959-7967-PMID: 31599421" has been withdrawn from the authors due to some technical reasons (there are some evident errors and incorrect data). The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19012.

MicroRNA-218 regulates the epithelial-to-mesenchymal transition and the PI3K/Akt signaling pathway to suppress lung adenocarcinoma progression by directly targeting BMI-1.

The article "MicroRNA-218 regulates the epithelial-to-mesenchymal transition and the PI3K/Akt signaling pathway to suppress lung adenocarcinoma progression by directly targeting BMI-1, by L. Xu, H.-B. Sun, Z.-N. Xu, X.-L. Han, Y.-Y. Yin, Y. Zheng, Y. Zhao, Z.-X. Wang, published in Eur Rev Med Pharmacol Sci 2019; 23 (18): 7978-7988-DOI: 10.26355/eurrev_201909_19014-PMID: 31599423" has been withdrawn from the authors due to some technical reasons (there are some errors and  incorrect data). The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19014.

LINC01093 promotes proliferation and invasion of non-small cell lung cancer cells via targeting akt signaling pathway.

The article "LINC01093 promotes proliferation and invasion of non-small cell lung cancer cells via targeting akt signaling pathway, by Z.-X. Wang, Z.-N. Xu, H.-B. Sun, Y. Wang, Z.-F. Han, Y. Yu, X.-L. Han, Y.-Y. Yin, L. Xu, published in Eur Rev Med Pharmacol Sci 2020; 24 (1): 222-229- DOI: 10.26355/eurrev_202001_19914-PMID: 31957835" has been withdrawn from the authors due to some technical reasons (there are some errors and incorrect data). The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19914.

Insights into interaction mechanism of inhibitors E3T, E3H and E3B with CREB binding protein by using molecular dynamics simulations and MM-GBSA calculations.

CREB binding protein (CBP) and its paralog E1A binding protein (p300) are related to the development of inflammatory diseases, cancers and other diseases, and have been potential targets for the treatment of human diseases. In this work, interaction mechanism of three small molecules E3T, E3H, and E3B with CBP was investigated by employing molecular dynamics (MD) simulations, principal component analysis (PCA), and molecular mechanics/generalized born surface area (MM-GBSA) method. The results indicate that inhibitor bindings cause the changes of movement modes and structural flexibility of CBP, and van der Waals interactions mostly drive associations of inhibitors with CBP. In the meantime, the results based on inhibitor-residue interactions not only show that eight residues of CBP can strongly interact with E3T, E3H and E3B but also verify that the CH-CH, CH-π, and π-π interactions are responsible for vital contributions in associations of E3T, E3H and E3B with CBP. In addition, the H-O radial distribution functions (RDFs) were computed to assess the stability of hydrogen bonding interactions between inhibitors and CBP, and the obtained information identifies several key hydrogen bonds playing key roles in bindings of E3T, E3H and E3B to CBP. Potential new inhibitors have been proposed.

Forensic Application of Plant Evidence.

ABSTRACT: With the increasingly obvious role of plant evidence in case detection, forensic botany, which provides clues and evidence in crime scene investigation by using botanical research method has attracted growing attention. The common experimental techniques used in forensic botany are morphological examination, physical and chemical examination, molecular genetic examination, and so on. This paper briefly expounds the advantages and disadvantages of different test methods, summarizes the problems that need to be paid attention to in the application of forensic botany by arranging the related literatures and cases of forensic botanical research, in order to provide reference for scene investigation of cases.

Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613, by Z.-N. Xu, Z.-X. Wang, L. Xu, H.-X. Yu, K. Chao, L.-L. Yang, X.-L. Han, H.-B. Sun, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10810-10817-DOI: 10.26355/eurrev_201912_19784-PMID: 31858549" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19784.

Probing molecular mechanism of inhibitor bindings to bromodomain-containing protein 4 based on molecular dynamics simulations and principal component analysis.

It is well known that bromodomain-containing protein 4 (BRD4) has been thought as a promising target utilized for treating various human diseases, such as inflammatory disorders, malignant tumours, acute myelogenous leukaemia (AML), bone diseases, etc. For this study, molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA) were integrated together to uncover binding modes of inhibitors 8P9, 8PU, and 8PX to BRD4(1). The results obtained from binding free energy calculations show that van der Waals interactions act as the main regulator in bindings of inhibitors to BRD4(1). The information stemming from PCA reveals that inhibitor associations extremely affect conformational changes, internal dynamics, and movement patterns of BRD4(1). Residue-based free energy decomposition method was wielded to unveil contributions of independent residues to inhibitor bindings and the data signify that hydrogen bonding interactions and hydrophobic interactions are decisive factors affecting bindings of inhibitors to BRD4(1). Meanwhile, eight residues Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asn140, and Ile146 are recognized as the common hot interaction spots of three inhibitors with BRD4(1). The results from this work are expected to provide a meaningfully theoretical guidance for design and development of effective inhibitors inhibiting of the activity of BRD4.

Linc00703 suppresses non-small cell lung cancer progression by modulating CyclinD1/CDK4 expression.

OBJECTIVE: The aim of this study was to detect the expression of linc00703 in non-small cell lung cancer (NSCLC), and to explore the biological function and potential molecular mechanism of linc00703 in NSCLC using in vitro experiments. PATIENTS AND METHODS: The carcinoma tissues and para-carcinoma tissues were collected from 32 patients diagnosed with NSCLC, from which the RNA was extracted. The relative expression of linc00703 in NSCLC tissues was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The NSCLC cells and normal human bronchial epithelial cells were selected, in which the relative expression of linc00703 was determined via qRT-PCR. Next, the linc00703 overexpression plasmids were designed and synthesized, and then transiently transfected into NSCLC cells. After 48 h, the overexpression efficiency was detected. Finally, the changes in cell proliferation, apoptosis, cycle distribution and expressions of downstream molecular markers were determined using cell counting kit-8 (CCK8) assay, colony formation assay, flow cytometry and Western blotting, respectively, after overexpression of linc00703 in NSCLC cells. RESULTS: The results of qRT-PCR revealed that the expression of linc00703 was down-regulated by 5.14 times on average in 29 out of 32 cases of NSCLC tissues, and it was also down-regulated in NSCLC cells. Besides, it was found through CCK-8 assay, colony formation assay and flow cytometry that after overexpression of linc00703 in NSCLC cells, the cell proliferation was inhibited, the apoptosis was enhanced, and the cell cycle was arrested in G1/G0 phase. Furthermore, the results of Western blotting showed that after overexpression of linc00703, the protein expressions of cyclinD1 and cyclin-dependent kinase 4 (CDK4) declined, while those of cyclinE1 and CDK2 did not change. CONCLUSIONS: The expression of linc00703 is down-regulated in NSCLC, and it suppresses the occurrence and development of NSCLC via mediating the expression of cyclinD1/CDK4.

Revealing binding selectivity of inhibitors toward bromodomain-containing proteins 2 and 4 using multiple short molecular dynamics simulations and free energy analyses.

Emerging evidences indicate bromodomain-containing proteins 2 and 4 (BRD2 and BRD4) play critical roles in cancers, inflammations, cardiovascular diseases and other pathologies. Multiple short molecular dynamics (MSMD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were applied to investigate the binding selectivity of three inhibitors 87D, 88M and 89G towards BRD2 over BRD4. The root-mean-square fluctuation (RMSF) analysis indicates that the structural flexibility of BRD4 is stronger than that of BRD2. Moreover the calculated distances between the Cα atoms in the centres of the ZA_loop and BC_loop of BRD4 are also bigger than that of BRD2. The rank of binding free energies calculated using MM-GBSA method agrees well with that determined by experimental data. The results show that 87D can bind more favourably to BRD2 than BRD4, while 88M has better selectivity on BRD4 over BRD2. Residue-based free-energy decomposition method was utilized to estimate the inhibitor-residue interaction spectrum and the results not only identify the hot interaction spots of inhibitors with BRD2 and BRD4, but also demonstrate that several common residues, including (W370, W374), (P371, P375), (V376, V380) and (L381, L385) belonging to (BRD2, BRD4), generate significant binding difference of inhibitors to BRD2 and BRD4.

LINC01093 promotes proliferation and invasion of non-small cell lung cancer cells via targeting akt signaling pathway.

OBJECTIVE: To explore the expression of LINC01093, a long non-coding ribonucleic acid (lncRNA) in non-small cell lung cancer (NSCLC) tissues, and cells and its regulatory role in NSCLC cell proliferation and invasion. PATIENTS AND METHODS: The expression of LINC01093 in NSCLC tissues and cells was detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) experiment. The specific sequences interfering in LINC01093 were designed and transiently transfected into A549 and SPCA-1 cells using LipofectamineTM 2000, and 48 later, the transfection efficiency was detected. Moreover, the impacts of small interfering (si)-LINC01093 on NSCLC cell proliferation were observed via methyl thiazolyl tetrazolium (MTT) and colony forming assays, the influence of LINC01093 on the cycle distribution of NSCLC cells was determined through flow cytometry, and the changes in the invasion and migration abilities of NSCLC cells were evaluated via transwell assay after interfering in the expression of LINC01093. Finally, the expression changes of the molecular markers in the protein kinase B (Akt) signaling pathway in the downstream of LINC01093 were detected via Western blotting. RESULTS: According to the results of qRT-PCR, the relative expression level of LINC01093 was up-regulated in NSCLC tissues and cells. After interfering in the expression of LINC01093, the results of MTT and colony forming assays revealed that the proliferation ability of NSCLC cells was weakened, according to the findings in the flow cytometry, the cells were arrested in G1/0 phase, the transwell assay results manifested that the cell migration and invasion abilities were weakened, and the results of the Western blotting suggested the changes in the expressions of molecular markers in the Akt signaling pathway. CONCLUSIONS: The expression of LINC01093 is upregulated in NSCLC tissues and cells, and it facilitates the proliferation, invasion, and metastasis of NSCLC cells via the Akt signaling pathway.

Molecular mechanism of inhibitor bindings to bromodomain-containing protein 9 explored based on molecular dynamics simulations and calculations of binding free energies.

Recently, bromodomain-containing protein 9 (BRD9) has been a prospective therapeutic target for anticancer drug design. Molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were adopted to explore binding modes of three inhibitors (5SW, 5U2, and 5U6) to BRD9 and identify the hot spot of the inhibitor-BRD9 binding. The results indicate that the inhibitor 5SW has the strongest binding ability to BRD9 among the current three inhibitors. Furthermore, the rank of the binding free energies predicted by MM-GBSA approach agrees with that determined by the experimental values. In addition, inhibitor-residue interactions were computed by using residue-based free-energy decomposition method and the results suggest that residue His42 produces the CH-H interactions, residues Asn100, Ile53 and Val49 produce the CH-[Formula: see text] interactions with three inhibitors and Tyr106, Phe45 and Phe44 generate the π-π interactions with inhibitors. Notably, the residue Asn140 forms hydrogen bonding interactions with three inhibitors. This research is expected to provide useful molecular basis and dynamics information at atomic levels for the design of potent inhibitors inhibiting the activity of BRD9.

Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613.

OBJECTIVE: Lung adenocarcinoma is one of the most ordinary malignant tumors. Recent researches have proved that long noncoding RNAs (lncRNAs) are vital factors in many diseases. In this work, lncRNA SNHG14 was studied to identify its function in the development of lung adenocarcinoma. PATIENTS AND METHODS: Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to detect SNHG14 expression in paired lung adenocarcinoma patients' tissue samples and cells. Then, the function of SNHG14 was detected through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, colony formation assay, and transwell assay in vitro. Besides, mechanism assays and the interaction between SNHG14 and miR-613 were conducted. RESULTS: SNHG14 was remarkably higher-expressed in lung adenocarcinoma tissues than in adjacent samples. Moreover, cell proliferation and invasion of lung adenocarcinoma were promoted via overexpression of SNHG14, while cell proliferation and invasion of lung adenocarcinoma were inhibited via silence of SNHG14. Moreover, RT-qPCR results revealed that miR-613 was downregulated via overexpression of SNHG14, while miR-613 was upregulated via knockdown of SNHG14. Further experiments showed that miR-613 was also a direct target of SNHG14 in lung adenocarcinoma. CONCLUSIONS: Our study suggests that SNHG14 enhances lung adenocarcinoma cell proliferation and invasion via targeting miR-613, which indicates that SNHG14 may be a potential therapeutic target in lung adenocarcinoma.

MicroRNA-218 regulates the epithelial-to-mesenchymal transition and the PI3K/Akt signaling pathway to suppress lung adenocarcinoma progression by directly targeting BMI-1.

OBJECTIVE: To investigate the role of miR-218 in the development of lung adenocarcinoma (LA) and its underlying mechanism. PATIENTS AND METHODS: Fifty-two pairs of human LA samples and adjacent para-carcinoma tissue samples were collected from our hospital between June 2015 and March 2017. Meanwhile, one normal human pulmonary epithelial cell line BEAS-2B and four human LA cell lines (H1299, PC-9, A549, and SPC-A1) were cultured. The cells' ability of proliferation and migration was detected by MTT assays and Transwell assays, respectively. The target gene was clarified by dual-luciferase reporter assay. The related protein and mRNA expression levels were detected by immunohistochemistry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. At last, the tumor xenograft model was made for further exploring the mechanism. RESULTS: MiR218 expressions were notably reduced in LA tissues in comparison with controls. In addition, the declined miR218 expressions were correlated with the poor OS and worse clinicopathological parameters of LA patients. Furthermore, miR218 overexpression could suppress the proliferation, migration and invasion capacities of LA cells via regulation of PI3K/Akt signaling pathway and epithelial-mesenchymal transition (EMT) respectively. Results in the current study also revealed that miR-218 upregulation could suppress the tumor growth rate and tumor size of LA mice. B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was confirmed to be a direct target for miR-218 and upregulated in LA tissues, which indicated the poor prognosis of LA patients. CONCLUSIONS: MiR-218 exerted anti-tumor functions in LA partially via the regulation of BMI-1, suggesting that BMI-1/miR-218 axis may provide a novel insight into tumorigenesis and the basis for the development of miRNA-targeting therapies against LA.