Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor ß- and p53-Mediated Apoptosis.

Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor ß (ERß) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERß and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERß and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN.

The effect of Fe2O3 and ZnO nanoparticles on cytotoxicity and glucose metabolism in lung epithelial cells.

Metallic nanoparticles (NPs) have potential applications in industry and medicine, but they also have the potential to cause many chronic pulmonary diseases. Mechanisms for their cytotoxicity, glucose and energy metabolism responses need to be fully explained in lung epithelial cells after treatment with metallic nanoparticles. In our study, two different metallic nanoparticles (Fe2 O3 and ZnO) and two cell-based assays (BEAS-2B and A549 cell lines) were used. Our findings demonstrate that ZnO nanoparticles, but not Fe2 O3 nanoparticles, induce cell cycle arrest, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial dysfunction and glucose metabolism perturbation, which are responsible for cytotoxicity. These results also suggest that the glucose metabolism and bioenergetics had a great potential in evaluating the cytotoxicity and thus were very helpful in understanding their underlying molecular mechanisms.

Intra-tumoral microbial community profiling and associated metabolites alterations of TNBC.

Triple-negative breast cancer (TNBC) presents significant challenges to female health owing to the lack of therapeutic targets and its poor prognosis. In recent years, in the field of molecular pathology, there has been a growing focus on the role of intra-tumoral microbial communities and metabolic alterations in tumor cells. However, the precise mechanism through which microbiota and their metabolites influence TNBC remains unclear and warrants further investigation. In this study, we analyzed the microbial community composition in various subtypes of breast cancer through 16S rRNA MiSeq sequencing of formalin-fixed, paraffin-embedded (FFPE) tissue samples. Notably, Turicibacter, a microbe associated with cancer response, exhibited a significantly higher abundance in TNBC. Similarly, mass spectrometry-based metabolomic analysis revealed substantial differences in specific metabolites, such as nutriacholic, pregnanetriol, and cortol. Furthermore, we observed significant correlations between the intra-tumoral microbiome, clinicopathological characteristics, and human epidermal growth factor receptor-2 expression(HER2). Three microbial taxa (Cytophagaceae, Conexibacteraceae, and Flavobacteriaceae) were associated with tumor-infiltrating lymphocytes(TILs), which are indicative of antitumor immunity. This study creatively utilized FFPE tissue samples to assess intra-tumoral microbial communities and their related metabolic correlations, presenting avenues for the identification of novel diagnostic biomarkers, the development of therapeutic strategies, and the early clinical diagnosis of TNBC.

Intratumoral Microbiome of Human Primary Liver Cancer.

Primary liver tumors (PLCs) and liver metastasis currently represent the leading cause of cancer-related deaths worldwide due to poor outcomes, high incidence, and postsurgical recurrence. Hence, novel diagnostic markers and therapeutic strategies for PLCs are urgently needed. The human microbiome can directly or indirectly impact cancer initiation, progression, and response to therapy, including cancer immunotherapy; however, the roles of the microbiota in the tumor microenvironment are not clear and require more investigation. Here, we investigated intratumoral microbial community profiling on formalin-fixed paraffin-embedded tissue samples of patients with PLC by 16S ribosomal RNA using the MiSeq platform. We characterized the microbial communities in different histopathological subtypes and in the different prognoses of patients with PLC. The study revealed microbial population differences not only in carcinoma tissue and the matched adjacent nontumor tissue but in different histopathological subtypes, even in patients with PLC with different prognoses. Interestingly, the abundance of certain bacteria that have antitumor effects at family and genus level, such as Pseudomonadaceae, decreased in tumor tissue and was linearly associated with prognosis of patients with PLC. Conclusion: We provide a potential novel diagnostic biomarker and therapeutic strategy for early clinical diagnosis and treatment of PLC.

[Corrigendum] miR­647 and miR­1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer.

Subsequently to the publication of this paper, an interested reader drew to the authors' attention that, in the scratch­wound assays shown in Fig. 3A on p. 8195, the data shown for the '0 h/NC' and '0 h/miR­1914 antagomir' data panels appeared to be strikingly similar, such that they may have been derived from the same original source. The authors have consulted their original data, and realize that the '0 h/miR­1914 antagomir' data panel was inadvertently selected incorrectly for Fig. 3A. The corrected version of Fig. 3, now showing the correct data for the '0 h/miR­1914 antagomir' data panel in Fig. 3A, is shown on the next page. Note that the errors in Fig. 3 did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 16, 8189­8199, 2017; DOI: 10.3892/mmr.2017.7675].

Metabolic reprogramming links chronic intestinal inflammation and the oncogenic transformation in colorectal tumorigenesis.

The causal connections between chronic inflammation and tumorigenesis are well established and supported by a great deal of evidence and research results over recent decades. Still, many mysteries remain in our understanding of tumor metabolism, not to mention inflammatory-oncogenic transformation. In this review, we examined the Warburg effect and the process of inflammation during tumorigenesis and attempted to extend the knowledge about metabolic reprogramming. This review may establish a useful conceptual framework for understanding the complex pathophysiological process of inflammatory-oncogenic transformation from the metabolic perspective.

miR­647 and miR­1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer.

MicroRNAs (miRNAs/miRs) have been investigated as diagnostic and prognostic biomarkers for cancer; however, the significance of miRNAs in colorectal cancer (CRC) remains to be elucidated. The aim of the present study was to determine the genetic profiles of CRC tissue, and screen for miRNAs implicated in CRC cell proliferation and migration. RNA sequencing of 10 paired specimens was performed to for screen genes that were upregulated or downregulated in CRC. miRNA expression in CRC specimens and cell lines was confirmed using qPCR analysis. The significance of indicated miRNAs in CRC cell proliferation and migration was evaluated using MTT and scratch wound­healing assays. Online computational prediction, isobaric tags for relative and absolute quantification analysis and a luciferase reporter assay were applied to determine candidate targeted genes for the miRNAs. RNA­seq data revealed miR­1914 as the most prominent miRNA in CRC specimens. qPCR analysis also suggested that the expression of miR­1914, as well as its counterpart miR­647 were elevated in CRC specimens and cell lines. Suppression of miR­647/1914 using small interfering RNAs inhibited CRC SW480 and SW620 cell proliferation, and migration. Nuclear factor I/X (NFIX) was demonstrated to be a candidate for miR­647/1914 and mediated the oncogenic activity of miR­647/1914. In all, miR­647 and miR­1914 were demonstrated to promote the proliferation and migration of CRC cells by directly targeting NFIX. Therapeutic delivery of siRNAs targeting miR­647/1914 and overexpression of NFIX may be feasible approaches for CRC treatment.

Chronic inflammation confers to the metabolic reprogramming associated with tumorigenesis of colorectal cancer.

It's well known that microenvironment inflammatory signals could promote cancer development and progression. In colorectal cancer (CRC), chronic inflammation is a major driving mechanism for the development of CRC in patients having long-standing inflammatory bowel disease (IBD). Though it has been addressed that cancer cells ferment much of their glucose supply into lactate regardless of the presence of oxygen, it is unclear whether cell metabolism has been reprogramed during the process from IBD to CRC. Herein, with dextran sulfate sodium (DSS)-induced mouse colitis model, we found that inflammation upregulated key glycolytic enzymes expression via activation of STAT3/c-Myc signaling pathway. Interestingly, during the whole phase of chronic inflammation, the key metabolic enzymes demonstrated increased expression constantly, indicating the metabolic reprogramming was induced by long-term inflammatory signal. Moreover, either the inhibition of STAT3 signaling or c-Myc activity could block the glycolytic enzymes expression induced by interleukin 6 (IL-6). Thus, we presented the view that inflammation could induce the metabolic reprogramming and promote the progression from chronic colitis to colorectal cancer.