Prognostic predictive modeling of non-small cell lung cancer associated with cadmium-related pathogenic genes.

Persistent exposure to low-dose of cadmium is strongly linked to both the development and prognosis of non-small cell lung cancer (NSCLC), yet the precise molecular mechanism behind this relationship remains uncertain. In this study, cadmium-related pathogenic genes (CRPGs) in NSCLC were identified via differential expression analysis. NSCLC patient clusters related to CRPGs were constructed through univariate Cox and K-means clustering algorithms. Multivariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were employed to determine the prognosis. Sixteen CRPGs showed a significant association with NSCLC. We found biological and prognostic differences between patients in clusters A and B. A predictive prognostic risk model for NSCLC revealed that FAM83H, MSMO1, and SNAI1 are central. Hence, the 3 hub genes were named. To further elucidate the role of CRPGs in NSCLC, A549 cells were exposed to CdCl2. The mRNA and protein expression levels of the 3 hub genes and cell invasion were detected. Moreover, 10 µM CdCl2 may increase the protein expression of 3 hub genes and enhance the invasive ability of A549 cells. This risk model may have established a theoretical foundation for investigating the mechanisms, treatment, and prognosis of NSCLC.

Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment.

Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.

Bibliometric Analysis Reveals the Progress of PM2.5 in Health Research, Especially in Cancer Research.

PM2.5 has an aerodynamic diameter of less than or equal to 2.5 microns due to its inherent physical and chemical properties so that it can enter the alveoli through the respiratory tract for blood gas exchange. Numerous studies have shown that PM2.5 is a serious air pollutant that poses a wide range of health risks, especially for cancer. Bibliometric methods were employed to have comprehensively analyzed the research of PM2.5 in cancer for about a decade in Web of Science to identify hotspots and trends using VOSviewer, CiteSpace, and R. The field has undergone overall growth in the past decade. As research on PM2.5 in health deepens, cancer related to it expanded beyond the respiratory system to the digestive system, urinary system, female gonadal axis, breast cancer and other cancers. Another observation is that research on PM2.5 in cancer has progressed in the mechanisms of deterioration, such as the role of matrix metalloproteinases in cancer. In addition, research on the risks of PM2.5 in combination with polycyclic aromatic hydrocarbons and heavy metals has also emerged. Results showed that there are relatively more studies on PM2.5 in high-latitude countries, which may be due to different national conditions, such as climate and coal combustion. Our research has combed through the progress of PM2.5 in cancer research and provided a supplement for developing pollution prevention ideas with different national conditions in this field.

Lycium barbarum polysaccharides promoted proliferation and differentiation in osteoblasts.

Osteoblasts have the capacity to differentiate into several different cell types, including adipocyte, chondrocyte, and muscle lineages. Therefore, osteoblast can be potentially applied in the treatment of bone diseases. The factors controlling osteoblast differentiation is complex. Recently, it has been reported that some natural products regulate the differentiation in osteoblasts and promote bone formation. Based on these findings, this study demonstrated that Lycium barbarum polysaccharides (LBP) could promote proliferation of osteoblast MC3T3-E1 cells through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Besides, expression of key proteins correlated with cellular proliferation such as proliferating cell nuclear antigen (PCNA) and Ki67 was enhanced in the presence of LBP. We also detected the increased expression of bone-specific matrix proteins such as morphogenetic protein 2 (BMP2), bone Gla protein (BGP), osteopontin (OPN), and α-1 type-I collagen (COL1A1) when treated with LBP. This process was mediated by some signals, such as smad1, smad8, Runt-related transcription factor 2 (RUNX2), and Osterix. Furthermore, RUNX2 silencing inhibited osteoblast differentiation by decreasing expression of bone-specific matrix proteins. Collectively, we proposed a previously unidentified function of LBP in osteoblast differentiation, suggesting its potential clinical role in bone disease treatment.

Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma.

E2F is a group of genes that encode a family of transcription factors (TFs) in higher eukaryotes and participate in cell cycle regulation and DNA synthesis in mammalian cells. Evidence from cell lines, mouse models, and human tissues indicates that TFs are implicated in lung cancer (LC) tumorigenesis. However, the diverse expression patterns and prognostic values of eight E2Fs have yet to be elucidated. In the current study, we examined the transcriptional and survival data of E2Fs in patients with LC from ONCOMINE, GEPIA, Kaplan-Meier Plotter, and cBioPortal databases. We found that the expression levels of E2F1/2/3/5/6/7/8 were higher in lung adenocarcinoma and squamous cell lung carcinoma tissues than in lung tissues, whereas the expression level of E2F4 was lower in the former than in the latter. The expression levels of E2F2/4/5/7/8 were correlated with advanced tumor stage. Survival analysis using the Kaplan-Meier Plotter database revealed that the high transcription levels of E2F1/2/4/5/7/8 were associated with low relapse-free survival (RFS) in all of the patients with LC. Conversely, high E2F3/6 levels predicted high RFS in these patients. This study implied that E2F3/6/7 are potential targets of precision therapy for patients with LC and that E2F1/2/4/5/8 are new biomarkers for the prognosis of LC.

miR-134: A Human Cancer Suppressor?

MicroRNAs (miRNAs) are small noncoding RNAs approximately 20-25 nt in length, which play crucial roles through directly binding to corresponding 3' UTR of targeted mRNAs. It has been reported that miRNAs are involved in numerous of diseases, including cancers. Recently, miR-134 has been identified to dysregulate in handles of human cancers, such as lung cancer, glioma, breast cancer, colorectal cancer, and so on. Increasing evidence indicates that miR-134 is essential for human carcinoma and participates in tumor cell proliferation, apoptosis, invasion and metastasis, drug resistance, as well as cancer diagnosis, treatment, and prognosis. Nevertheless, its roles in human cancer are still ambiguous, and its mechanisms are sophisticated as well, referring to a variety of targets and signal pathways, such as STAT5B, KRAS, MAPK/ERK signal pathway, Notch pathway, etc. Herein, we review the crucial roles of miR-134 in scores of human cancers via analyzing latest investigations, which might provide evidence for cancer diagnose, treatment, prognosis, or further investigations.

MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E-cadherin pathway.

Determinants of growth and metastasis in cancer remain of great interest to define. MicroRNAs (miRNAs) have frequently emerged as tumor metastatic regulator by acting on multiple signaling pathways. Here we report the definition of miR-346 as a novel oncogenic microRNA that facilitates non-small cell lung cancer (NSCLC) cell growth and metastasis. XPC, an important DNA damage recognition factor in nucleotide excision repair was defined as a target for down-regulation by miR-346, functioning through direct interaction with the 3'-UTR of XPC mRNA. Blocking miR-346 by an antagomiR was sufficient to inhibit NSCLC cell growth and metastasis, an effect that could be phenol-copied by RNAi-mediated silencing of XPC. In vivo studies established that miR-346 overexpression was sufficient to promote tumor growth by A549 cells in xenografts mice, relative to control cells. Overall, our results defined miR-346 as an oncogenic miRNA in NSCLC, the levels of which contributed to tumor growth and invasive aggressiveness.

SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position.

A series of C4-N-substituted podophyllum derivatives were synthesized and tested for cytotoxicity in HeLa, BGC-823, A549, Huh7 and MCF-7 cells by MTT assay. Pharmacologically, most derivatives displayed potent cytotoxicity against at least one of the tested tumor cell lines. Structure activity relationship (SAR) analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position>4-position>5-position>6-position. Specifically, two compounds, 3g and 3h, with 2-amino-3-chloropyridine substituted into the podophyllotoxin (PPT) and 4'-O-demethylepipodophyllotoxin (DMEP) scaffolds were shown to have the most potent HeLa cells cytotoxicity compared to other synthesized derivatives or reference compounds PPT, DMEP and etoposide (VP-16). The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation. As a result of this work, we conclude that compounds 3g and 3h are more potent anticancer agents than VP-16, and that they work by different antitumor mechanisms.

A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4'-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation.

A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4'-demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH- bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4'-demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity. All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4'-demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 ± 0.20 µM), A549 (i.e., the IC50 value of 3.83 ± 0.08 µM), HepG2 (i.e., the IC50 value of 1.21 ± 0.05 µM), and BGC-823 (i.e., the IC50 value of 4.15 ± 1.13 µM) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 ± 0.10, 59.38 ± 0.77, 67.25 ± 7.05, and 30.74 ± 5.13 µM), respectively. Compound 1 could arrest HeLa cell cycle G2/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test.

Isolation and characterization of polysaccharides with the antitumor activity from Tuber fruiting bodies and fermentation system.

Fifty-two polysaccharides were isolated from the fermentation systems of Tuber melanosporum, Tuber indicum, Tuber sinense, Tuber aestivum and the fruiting bodies of Tuber indicum, Tuber himalayense, Tuber sinense by elution with an activated carbon column. Polysaccharides from Tuber fermentation system exhibited relatively higher in vitro antitumor activity against HepG2, A549, HCT-116, SK-BR-3, and HL-60 cells than those from Tuber fruiting bodies. All polysaccharides were mainly composed of D-mannose, D-glucose, and D-galactose, which suggested that the polysaccharides from Tuber fruiting bodies and fermentation system have identical chemical compositions. The results of antitumor activity and structural identification indicated that the polysaccharide fractions could promote antitumor activity. Tuber polysaccharides from Tuber fermentation system exhibited relatively higher than that from Tuber fruiting bodies. These results confirm the potential of Tuber fermentation mycelia for use as an alternative resource for its fruiting bodies.