HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma.

High-mobility group box 1 (HMGB1) can enhance the stability and accessibility of nucleus binding sites to nucleosomes and transcription factors. Recently, HMGB1 has been recognized as a positive regulator of tumor glutamine, and its overexpression has been correlated with tumorigenesis and cancer progression. However, functions and mechanisms of HMGB1 in regulation of glycolysis during cancer progression in lung adenocarcinoma (LUAD) is still unclear. Here, we found that intracellular HMGB1 was consistently upregulated in LUAD specimens, and positively relevant to tumor grade and poor survival. HMGB1 facilitated glycolysis and promoted metastasis through physical interaction with SET and HAT1, forming HMGB1/SET/HAT1 complex that inhibited H3K9 and H3K27 acetylation in LUAD. The functional proteins complex coordinated histone modification to suppress the expression of SASH1, thus further facilitating glycolysis and inducing the metastasis in vitro and in vivo. Consistent with this, the expression of SASH1 was negatively correlated with HMGB1, SET and GLUT1, and positively correlated with HAT1 in human LUAD specimens. Clinically, LUAD patients with high expression of HMGB1 and low expression of SASH1 exhibited the worst clinical outcomes. Overall, the findings of this study revealed the critical role of HMGB1 in glycolysis and metastasis by attenuating H3K9ace and H3K27ace through physical interacted with SET and HAT1, which may facilitate future targeted therapies.

The malignancy suppression and ferroptosis facilitation of BCL6 in gastric cancer mediated by FZD7 repression are strengthened by RNF180/RhoC pathway.

BACKGROUND: B-cell lymphoma 6 (BCL6) is a transcription repressor that plays a tumor suppressor or promoting role in various tumors. However, its function and molecular mechanism in gastric cancer (GC) remain unclear. Ferroptosis, a novel programmed cell death, is closely related to tumor development. In this research, we aimed to explore the role and mechanism of BCL6 in malignant progression and ferroptosis of gastric cancer. METHODS: Firstly, BCL6 was identified as an important biomarker that attenuated the proliferation and metastasis of GC through tumor microarrays and confirmed in GC cell lines. RNA sequence was performed to explore the downstream genes of BCL6. The underlying mechanisms were further investigated by ChIP, dual luciferase reporter assays and rescue experiments. Cell death, lipid peroxidation, MDA and Fe2+ level were detected to determine the effect of BCL6 on ferroptosis and the mechanism was revealed. CHX, MG132 treatment and rescue experiments were used to explore the upstream regulatory mechanism of BCL6. RESULTS: Here we showed that BCL6 expression was significantly decreased in GC tissues, and patients with low BCL6 expression showed more malignant clinical features and poor prognosis. The upregulation of BCL6 may significantly inhibited the proliferation and metastasis of GC cells in vitro and in vivo. In addition, we found that BCL6 directly binds and transcriptionally represses Wnt receptor Frizzled 7 (FZD7) to inhibit the proliferation, metastasis of GC cells. We also found that BCL6 promoted lipid peroxidation, MDA and Fe2+ level to facilitate ferroptosis of GC cells by FZD7/ß-catenin/TP63/GPX4 pathway. Furthermore, the expression and function of BCL6 in GC were regulated by the ring finger protein 180 (RNF180)/ras homolog gene family member C (RhoC) pathway, which had been elucidated to be involved in significantly mediating the proliferation and metastasis of GC cells. CONCLUSIONS: In summary, BCL6 should be considered a potential intermediate tumor suppressor to inhibit the malignant progression and induce ferroptosis, which might be a promising molecular biomarker for further mechanistic investigation of GC.

[1,1'-Dibenzyl-2,2'-(2-oxapropane-1,3-diyl)di(1H-benzimidazole)-κ³N³,O,N³']bis(2,4,6-trinitrophenolato-κO¹)manganese(II).

In the title complex, [Mn(C6H2N3O7)2(C30H26N4O)], the Mn(II) atom is coordinated by the tridentate bis-benzimidazole ligand and two atoms of the picrate anions, in a distorted square-pyramidal geometry (τ = 0.038). One nitro O atom of one picrate ion is disordered over two sites with occupancies of 0.54 (5) and 0.46 (5).

Synthesis, Crystal Structure, and DNA-Binding Studies of a Nickel(II) Complex with the Bis(2-benzimidazolymethyl)amine Ligand.

A V-shaped ligand Bis(2-benzimidazolymethyl)amine (bba) and its nickel(II) picrate (pic) complex, with composition [Ni(bba)(2)](pic)(2)·3MeOH, have been synthesized and characterized on the basis of elemental analyses, molar conductivities, IR spectra, and UV/vis measurements. In the complex, the Ni(II) ion is six-coordinated with a N(2)O(4) ligand set, resulting in a distorted octahedron coordination geometry. In addition, the DNA-binding properties of the Ni(II) complex have been investigated by electronic absorption, fluorescence, and viscosity measurements. The experimental results suggest that the nickel(II) complex binds to DNA by partial intercalation binding mode.

Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy.

Somatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.

1-Methyl-2-({[(1-methyl-1H-benzimid-azol-2-yl)meth-yl](phen-yl)amino}-meth-yl)1H-benzimidazol-3-ium picrate.

In the title molecular salt, C(24)H(24)N(5) (+)·C(6)H(2)N(3)O(7) (-), the dihedral angle between the benzimidazole rings of the cation is 5.041 (2)°. In the anion, the three nitro groups make dihedral angles of 2.468 (3), 12.795 (3) and 24.958 (4)° with respect to the central ring. In the crystal, weak aromatic π-π stacking [centroid-centroid distance = 3.599 (15) Å] consolidates the packing. In addition, an intra-molecular N-H⋯N hydrogen bond is observed.

Bis[1,3-bis(1-propyl-1H-benzimidazol-2-yl)-2-oxapropane]-cadmium(II) dipicrate dimethyl-formamide monosolvate.

In the title compound, [Cd(C(22)H(26)N(4)O)(2)](C(6)H(2)N(3)O(7))(2)·C(3)H(7)NO, the Cd(II) ion is coordinated by four N atoms and two O atoms from two tridentate 1,3-bis-(1-propyl-1H-benzimidazol-2-yl)-2-oxopropane ligands in a distorted octa-hedral coordination environment. There are significant differences in the chemically equivalent Cd-O bond lengths [2.618 (2) Šand 2.561 (2) Å].

Bis[1,3-bis-(1-methyl-1H-benzimidazol-2-yl)-2-oxapropane]-cadmium dipicrate acetonitrile sesquisolvate 0.25-hydrate.

In the title compound, [Cd(C(18)H(18)N(4)O)(2)](C(6)H(2)N(3)O(7))(2)·1.5CH(3)CN·0.25H(2)O, the Cd(II) ion is coordinated by four N atoms and two O atoms from two tridentate 1,3-bis-(1-methyl-1H-benzimidazol-2-yl)-2-oxopropane ligands in a distorted octa-hedral coordination environment. The lengths of the chemically equivalent Cd-O bonds [2.4850 (16) and 2.5488 (16)Å] are signiificantly different. One of the picrate anions is disordered over two sets of sites, with refined occupancies of 0.504 (15) and 0.496 (15). A 0.5-occupancy acetonitrile solvent mol-ecule is disordered over two sites with equal occupancies. The H atoms of a 0.25-occupancy solvent water mol-ecule were neither located nor included in the refinement.

Bis[1,3-bis-(1-ethyl-1H-benzimidazol-2-yl)-2-oxapropane]-cadmium(II) dipicrate dimethyl-formamide disolvate.

In the title compound, [Cd(C(20)H(22)N(4)O)(2)](C(6)H(2)N(3)O(7))(2)·2C(3)H(7)NO, the Cd(II) ion is coordinated by four N atoms and two O atoms from two tridentate 1,3-bis-(1-ethyl-1H-benzimid-azol-2-yl)-2-oxapropane ligands in a distorted octa-hedral environment.

1,3-Bis(1-methyl-1H-benzimidazol-2-yl)-2-oxapropane.

In the title mol-ecule, C(18)H(18)N(4)O, the dihedral angle between the mean planes of the two benzimidazole ring systems is 61.5 (1)°.

Bis(nitrato-κO)(3-oxapentane-1,5-diamine-κN,O,N')zinc(II).

In the title compound, [Zn(NO(3))(2)(C(4)H(12)N(2)O)], the Zn(II) atom is N,O,N'-chelated by a 3-oxapentane-1,5-diamine ligand and is further coordinated by two nitrate anions in a distorted trigonal-bipyramidal geometry. Inter-molecular N-H⋯O hydrogen bonding is present in the crystal structure. A short O⋯O contact of 2.816 (8) Šis observed between the nitrate anions of adjacent mol-ecules.

Bis[N,N-bis-(1-allyl-1H-benzimidazol-2-ylmethyl-κN)benzyl-amine-κN]cadmium dipicrate.

The crystal structure of the title compound, [Cd(C(29)H(29)N(5))(2)](C(6)H(2)N(3)O(7))(2), consists of Cd(II) complex cations and picrate anions. In the complex cation, the Cd(II) ion is chelated by two bis-(1-allyl-benzimidazol-2-ylmeth-yl)benzyl-amine (babb) ligands in a distorted octa-hedral geometry. Extensive C-H⋯O hydrogen bonding occurs between cations and anions in the crystal structure.

Synthesis, Crystal Structure, and Spectra Properties of the Cadmium (II) Complex with Bis(N-allylbenzimidazol-2-ylmethyl)benzylamine.

A novel complex of cadmium (II) picrate (pic) with V-shaped ligand bis(N-allylbenzimidazol-2-ylmethyl)benzylamine (babb), with composition [Cd(babb)(2)](pic)(2), was synthesized and characterized by elemental analyses and electrical conductivity, IR, and UV/visible spectra. The crystal structure of the complex has been determined by the single-crystal X-ray diffraction. In the complex, the coordination sphere around Cd (II) is distorted octahedral, six nitrogen atoms involved in coordination afforded by two tridentate ligand babb. Moreover, The DNA-binding properties of the ligand babb and Cd (II) complex were investigated by spectrophotometric methods and viscosity measurements, and the results suggest that they bind to DNA via an intercalation binding mode, and the Cd (II) complex shows higher affinity than the ligand.

Synthesis and characterization of the ligand based on benzimidazole and its copper complex: DNA binding and antioxidant activity.

A new copper(II) complex with formulae of [Cu(buobb)(2)](pic)(2), where buobb stands for the ligand of 1,3-bis(1- butylbenzimidazol-2-yl)-2-oxopropane and pic represents 2,4,6-trinitrophenol, has been synthesized and characterized by elemental analyses, molar conductivity, IR, UV-Vis spectra measurements, and cyclic voltammetry. The crystal structure of the copper(II) complex has been determined by X-ray single-crystal diffraction. The coordination environment around each copper(II) atom can be described as a distorted octahedral geometry. The π-π stacking interactions link the copper(II) complex into a 1D infinite network. The interactions of the ligand and the copper(II) complex with calf thymus DNA (CT-DNA) are investigated by using electronic absorption titration, ethidium bromide-DNA displacement experiments, and viscosity measurements. Additionally, the copper(II) complex's antioxidant properties have been investigated in vitro.

Signatures of Multi-Omics Reveal Distinct Tumor Immune Microenvironment Contributing to Immunotherapy in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) contains a variety of genomic and epigenomic abnormalities; the effective tumor markers related to these abnormalities need to be further explored. Methods: Clustering analysis was performed based on DNA methylation (MET), DNA copy number variation (CNV), and mRNA expression data, and the differences in survival and tumor immune microenvironment (TIME) between subtypes were compared. Further, we evaluated the signatures in terms of both prognostic value and immunological characteristics. Results: There was a positive correlation between MET and CNV in LUAD. Integrative analysis of multi-omics data from 443 samples determined molecular subtypes, iC1 and iC2. The fractions of CD8+ T cells and activated CD4+ T cells were higher, the fraction of Tregs was lower, and the expression level of programmed death-ligand 1 (PD-L1) was higher in iC2 with a poor prognosis showing a higher TIDE score. We selected PTTG1, SLC2A1, and FAM83A as signatures of molecular subtypes to build a prognostic risk model and divided patients into high-risk group and low-risk group representing poor prognosis and good prognosis, respectively, which were validated in 180 patients with LUAD. Further, the low-risk group with lower TIDE score had more infiltrating immune cells. In 100 patients with LUAD, the high-risk group with an immunosuppressive state had a higher expression of PD-L1 and lower counts of CD8+ T cells and dendritic cells. Conclusions: These findings demonstrated that combined multi-omics data could determine molecular subtypes with significant differences of prognosis and TIME in LUAD and suggested potent utility of the signatures to guide immunotherapy.

SMYD2 promotes tumorigenesis and metastasis of lung adenocarcinoma through RPS7.

The protein methyltransferase SET and MYND domain-containing protein 2 (SMYD2) is a transcriptional regulator that methylates histones and nonhistone proteins. As an oncogene, SMYD2 has been investigated in numerous types of cancer. However, its involvement in lung cancer remains elusive. The prognostic value of SMYD2 expression in lung adenocarcinoma (LUAD) was determined through bioinformatics analysis, reverse-transcription polymerase chain reaction, western blotting, and immunohistochemistry. The effect of SMYD2 on LUAD cell proliferation and metastasis was explored in vivo and in vitro, and the underlying mechanisms were investigated via RNA-seq, and chromatin immunoprecipitation-quantitative PCR. SMYD2 expression was significantly upregulated in LUAD cell lines and tissues. High SMYD2 expression was associated with shorter overall and disease-free survival in LUAD patients. Inhibition of SMYD2 with SMYD2 knockdown or AZ505 dramatically inhibited the proliferation, migration, and invasion ability of GLC-82 and SPC-A1 cells and remarkably reduced tumor growth in mice. Mechanically, SMYD2 may activate the transcription of ribosomal small subunit protein 7 (RPS7) by binding to its promoter. Following overexpression of SMYD2, the proliferation, migration, and invasion of cells increased, which was partially reversed by RPS7. Thus, SMYD2 might modulate tumorigenesis and metastasis mediated by RPS7 LUAD. SMYD2 might be a prognostic biomarker and therapeutic target in LUAD.

Somatic copy number alterations are predictive of progression-free survival in patients with lung adenocarcinoma undergoing radiotherapy.

OBJECTIVE: Lung cancer is the most common cause of cancer-related deaths worldwide. Somatic copy number alterations (SCNAs) have been used to predict responses to therapies in many cancers, including lung cancer. However, little is known about whether they are predictive of radiotherapy outcomes. We aimed to understand the prognostic value and biological functions of SCNAs. METHODS: We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy. Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response. Our results were validated in 20 patients with lung adenocarcinoma (LUAD) receiving radiotherapy. RESULTS: SCNAs were a better predictor of progression-free survival (PFS) in LUAD (P = 0.024) than in lung squamous carcinoma (P = 0.18) in patients treated with radiotherapy. Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD. Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels (P = 0.022). Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS. Additionally, high SCNA may activate the cell cycle pathway and induce tumorigenesis. CONCLUSIONS: SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy, in combination with TNM, with the aim of predicting long-term PFS. Therefore, SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.

Molecular subtypes based on CNVs related gene signatures identify candidate prognostic biomarkers in lung adenocarcinoma.

The classical factors for predicting prognosis currently cannot meet the developing requirements of individualized and accurate prognostic evaluation in lung adenocarcinoma (LUAD). With the rapid development of high-throughput DNA sequencing technologies, genomic changes have been discovered. These sequencing data provide unprecedented opportunities for identifying cancer molecular subtypes. In this article, we classified LUAD into two distinct molecular subtypes (Cluster 1 and Cluster 2) based on Copy Number Variations (CNVs) and mRNA expression data from the Cancer Genome Atlas (TCGA) based on non-negative matrix factorization. Patients in Cluster 1 had worse outcomes than that in Cluster 2. Molecular features in subtypes were assessed to explain this phenomenon by analyzing differential expression genes expression pattern, which involved in cellular processes and environmental information processing. Analysis of immune cell populations suggested different distributions of CD4+ T cells, CD8+ T cells, and dendritic cells in the two subtypes. Subsequently, two novel genes, TROAP and RASGRF1, were discovered to be prognostic biomarkers in TCGA, which were confirmed in GSE31210 and Tianjin Medical University Cancer Institute and Hospital LUAD cohorts. We further proved their crucial roles in cancers by vitro experiments. TROAP mediates tumor cell proliferation, cycle, invasion, and migration, not apoptosis. RASGRF1 has a significant effect on tumor microenvironment. In conclusion, our study provides a novel insight into molecular classification based on CNVs related genes in LUAD, which may contribute to identify new molecular subtypes and target genes.

(Dimethyl-formamide)(2-methyl-propen-oato)[tris-(1-methyl-1H-benzimidazol-2-ylmeth-yl)amine]-manganese(II) perchlorate dimethyl-formamide solvate.

In the title complex, [Mn(C(4)H(5)O(2))(C(27)H(27)N(7))(C(3)H(7)NO)]ClO(4)·C(3)H(7)NO, the Mn(II) ion is seven-coordinated in a distorted monocapped trigonal-prismatic geometry formed by a tetra-dentate tris-(1-methyl-1H-benzimidazol-2-ylmeth-yl)amine mol-ecule, a bidentate 2-methacrylate anion and a dimethyl-formamide mol-ecule. The methyl groups of the coordinated dimethyl-formamide mol-ecule and the perchlorate anions are disordered over two positions with occupancy factors of 0.640 (8) and 0.360 (8).

Bis[2,6-bis-(1H-benzimidazol-2-yl)pyridine]-nickel(II) dipicrate dimethyl-formamide disolvate.

In the title compound, [Ni(C(19)H(13)N(5))(2)](C(6)H(2)N(3)O(7))(2)·2C(3)H(7)NO, the Ni(II) ion is coordinated by two tridentate 2,6-bis-(1H-benzimidazol-2-yl)pyridine ligands in a distorted octa-hedral geometry. In the crystal structure, the picrate anions and solvent dimethyl-formamide (DMF) mol-ecules are connected to the cation via inter-molecular N-H⋯O hydrogen bonds. Further stabilization is provided by weak inter-molecular C-H⋯O hydrogen bonds. One of the DMF moleclues is disordered over two sites with refined occupancies of 0.737 (3) and 0.263 (3).