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Tanshinone IIA (Tan IIA), as a bioactive compound extracted from the dried roots of Salvia miltiorrhiza (also known as Danshen), is known to inhibit cancer cell proliferation and induce apoptosis. However, the mechanisms underlying the function of Tan IIA in cancer cell apoptosis remain to be elucidated The aim of the present study was to identify the molecular mechanisms underlying the anti-cancer effects of Tan IIA in p53-deficient H1299 cells. Tan IIA was demonstrated to suppress murine double minute 4 (MDM4) expression in a time- and dose-dependent manner through the inhibition of MDM4 mRNA synthesis. Tan IIA-induced downregulation of MDM4 resulted in an increase of P73a and a decrease of inhibitor of apoptosis 3 (IAP3). However, P73a was not activated as two P73a target genes, BCL2 binding component 3 and phorbol-12-myristate-13-acetate-induced protein 1, were not significantly induced. Tan IIA-induced inhibition of IAP3 expression may be involved in Tan IIA-induced apoptosis and inhibition of H1299 cell viability. Notably, a combination of Tan IIA and doxorubicin (DOX) exposure resulted in further MDM4 overexpression in H1299 cells, indicating that Tan IIA sensitized p53-deficient and MDM4-overexpressing H1299 cells to DOX-induced apoptosis. [ABSTRACT FROM AUTHOR]

Lung cancer causes serious health problems. Clinical diagnosis of lung cancer relies on histopathological evalution of tissue specimen. However, extensive knowledge of the metabolic biochemistry of tumors can potentially provide important information for accurate diagnosis of lung cancer. High resolution magic-angle spinning NMR spectroscopy has emerged and be widely acknowledged as an excellent tool in investigating tissue metabolism. Moreover, the combination of high resolution magic-angle spinning NMR technique and multivariate data analysis has become an important metabonomics platform for studying the intact biological tissues. This study reported the metabonomic characteristics of 51 lung tissues from 17 patients with lung cancer using the high resolution magic-angle spinning 1H NMR spectroscopy and the multivariate data analysis methods including principal component analysis and orthogonal partial least squares-discriminant analysis. Clear differences among the metabonomic characteristics of lung cancer tissues at various sites were disclosed. Compared with the adjacent noninvolved tissues, the lung cancer tissues had significantly high levels of aspartate, phosphocholine, glycerophosphocholine and lactate but significantly low levels of glucose and valine. Furthermore, significantly positive (or negative) correlations were observed between the levels of some metabolites such as lactate, fatty acids, valine, phosphocholine, and glycerophosphocholine. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: SETD1A is upregulated in non-small cell lung cancer (NSCLC) tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP axis in NSCLC., Methods: Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation, which is regulated by multiple cellular metabolic pathways, including REDOX homeostasis, iron metabolism, mitochondrial activity and metabolism of amino acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were measured in vitro , and NSCLC cell behaviors were assessed. SETD1A-mediated H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor growth in vivo were verified in nude mouse models., Results: SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis. WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis. Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude mice through the WTAPP1/WTAP axis., Conclusion: SETD1A amplified WTAP expression through WTAPP1 upregulation by mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC cell proliferation and migration and inhibiting ferroptosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tumor development is accompanied by high hypoxia and a dense network of immature vessels. The hypoxia-inducible factor/vascular endothelial growth factor (HIF/VEGF) signaling pathway is activated in various solid tumors. It is thought that HIF/VEGF signaling activation results from intratumoral hypoxia partly. Multiple studies have reported that VEGF is a common target gene for both transcription factors STAT3 and HIF1. KDM4C has also been reported to function as a co-activation factor for HIF-1β/VEGF signaling activation. In this manuscript. Our results demonstrate that KDM4C promotes NSCLC tumor angiogenesis by transcriptionally activating HIF1α/VEGFA signaling pathway. We also find that STAT3 functions as a costimulatory factor in this process. This pathway opens a potential therapeutic window for the treatment of NSCLC., Competing Interests: None., (AJCR Copyright © 2020.)

Esophageal cancer is one of the most common malignant cancers worldwide. Long non-coding RNAs (lncRNAs) have been reported to be associated with different types of cancer; however, the precise function of lncRNAs in tumorigenesis remains largely unknown. Herein, we found that lncRNA NBAT-1 levels were lower in EC clinic tissues than in normal samples, and lncRNA NBAT-1 expression was negatively associated with prognosis and TNM stage in EC patients. More importantly, in EC cancer cells, lncRNA NBAT-1 overexpression strongly inhibited cell proliferation, cell growth and tumor glycolysis. Furthermore, a series of rescue experiments were performed to demonstrate that the role of lncRNA NBAT-1 in EC cell proliferation, cell growth and tumor glycolysis was partially dependent on the PKM2 protein, which is a key metabolic enzyme in tumor development. Taken together, our data illustrate a functional role for lncRNA NBAT-1 in metabolic reprogramming in EC cancer; thus, lncRNA NBAT-1 might be a potential clinical therapeutic target in EC patients., Competing Interests: None., (AJTR Copyright © 2019.)

Emerging evidence suggests toll-like receptor 4 (TLR4) signaling contributes to cancer development and progression. However, the consequences of signaling via the TLR4 pathway in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the impact of Lipopolysaccharide (LPS)-induced TLR4 signaling on ESCC cell proliferation, inflammatory cytokines expression, and downstream molecular mechanisms. Seventy-eight ESCC and 26 normal esophageal specimens were analyzed by immunohistochemistry, and two cell lines (Eca-109 and TE-1) were used for in vitro studies. LPS, a natural agonist of TLR4, was used to activate TLR4 signaling. The effects of LPS-TLR4 signaling on cell proliferation and inflammatory cytokines regulation were examined. Specific inhibitors of mitogen-activated protein kinase (MAPK) (extracellular regulated protein kinase [ERK] and p38) signaling pathways were used to investigate the role of each pathway in LPS-TLR4 signaling. TLR4 protein was increased in ESCC tumor tissues compared with the adjacent normal tissues. TLR4 over-expression was significantly correlated with tumor differentiation grade, lymph node metastasis, and UICC stage. LPS-induced activation of TLR4 signaling promoted cancer cell proliferation, increased production of proinflammatory or immunosuppressive cytokines TNF-α, TGF-β and inhibited the anti-inflammatory cytokine IL-10. LPS-TLR4 signaling was associated with the activation of ERK and p38 MAPK signaling pathways. Further inactivation of the two pathways by specific inhibitors attenuated cell proliferation and inflammatory cytokines expression induced by LPS. Our results indicate that LPS-TLR4 signaling in cancer cells contributes to the progression of human ESCC., (© 2016 International Society for Diseases of the Esophagus.)

Lysyl oxidase (LOX) has been reported to regulate tumor metastasis and has been found to involve in modification of extracellular matrix (ECM) in the context of tumorigenesis. The aim of this study is to determine the prognostic significance of LOX in non-small cell lung cancer (NSCLC) patients and to examine the correlation between LOX expression and ECM remodeling-associated MMP2/MMP9 in NSCLC tissues. The mRNA expression of LOX, MMP2 and MMP9 was investigated by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) in 30 NSCLC patients. The protein expression of LOX was measured by immunohistochemistry (IHC) in 110 paraffin-embedded tissues with NSCLC and the protein expression of MMP2/MMP9 was measured by in 30 NSCLC patients. The correlation between LOX expression and clinical parameters and MMP2/MMP9 was analyzed by appropriate statistics. The Kaplan-Meier method, univariate and multivariate regression analysis was used to analyze the correlation between LOX expression and overall survival (OS). The relative mRNA expression or protein expression of LOX were significantly higher in NSCLC tumor tissues than in the corresponding noncancerous tissues (P < 0.05). High LOX expression was significantly associated with MMP2, MMP9, tumor size, lymph node metastasis, pathological stage and OS (P < 0.05). Univariate and multivariate analysis showed that LOX was an independent prognostic factor for OS. Our results indicate that LOX may play a role in the metastasis of NSCLC by promoting MMP2/MMP9 expression. LOX expression is an independent prognostic factor in OS in NSCLC.

The heat shock proteins (HSPs) 70 and HSP 27 expression in patients with non-small cell lung cancer (NSCLC) was studied and the relationship between HSP 70 and HSP 27 with the clinicopathological features of NSCLC was investigated. The expression of HSP 70 and HSP 27 was detected in tumor tissues from 60 patients with NSCLC by S-P immunohistochemistry. The findings were analyzed in combination with the histological types, histopathological differentiation, lymph node metastasis, patients' clinical stages, smoking history and gender. The results showed that of the 60 NSCLC tissue specimens studied, the immunoreactivity of HSP 70 and HSP 27 was detected in 47 (78.3%) and 43 (71.7%) specimens, respectively. A positive correlation was found between the overexpression of HSP 70 and HSP 27. The histopathological differentiation, lymph node metastasis, clinical stages and smoking history were correlated to the expression of HSP 70, but not to the expression of HSP 27. No statistical significance was observed in histological types and gender with respect to both HSP 70 and HSP 27 expression. It is suggested that the HSP 70 expression is a powerful and significant prognostic indicator and is related to histopathological differentiation, lymph node metastasis, patients' clinical stages, smoking history, whereas HSP 27 expression is not.