The ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Pleiotropic Roles in Cancer.

Cancer remains one of the most common causes of death and disability and represents a major economic burden in industrialized nations. The renin-angiotensin system (RAS) has been well-recognized as one of the most important regulators of both normal and pathological physiological processes in the brain, kidney, heart, and blood vessels. The activation of the angiotensin-converting enzyme 2/angiotensin-(1-7)/mitochondrial assembly receptor [ACE2/Ang-(1-7)/MasR] axis, which is one component of the RAS, has recently been identified as a critical component of pulmonary systems, gastric mucosa, and cancer. However, the ability of the ACE2/Ang-(1-7)/MasR axis to suppress or promote cancer has not been fully elucidated. In this review, we focus on recent experimental and clinical studies investigating the basic properties, roles, and mechanisms of ACE2, Ang-(1-7), and the MasR, as well as the axis pathway, to provide insights into possible therapeutic strategies for treating cancer that target the ACE2/Ang-(1-7)/MasR axis.

The Role of Interleukin-17 in Lung Cancer.

Tumour-associated inflammation is a hallmark of malignant carcinomas, and lung cancer is a typical inflammation-associated carcinoma. Interleukin-17 (IL-17) is an important inflammatory cytokine that plays an important role in chronic inflammatory and autoimmune diseases and in inflammation-associated tumours. Numerous studies have shown that IL-17 directly or indirectly promotes tumour angiogenesis and cell proliferation and that it inhibits apoptosis via the activation of inflammatory signalling pathways. Therefore, IL-17 contributes to the metastasis and progression of lung cancer. Research advances with respect to the role of IL-17 in lung cancer will be presented as a review in this paper.

IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma.

Inflammation and angiogenesis are two hallmarks of carcinoma. The proinflammatory cytokine interleukin-17 (IL-17) facilitates angiogenesis in lung cancer; however, the underlying mechanism is not fully understood. In this study, tumour microvessel density (MVD) was positively associated with IL-17, interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial cell growth factor (VEGF) expression in human lung adenocarcinoma tissues, and it was increased in tumour tissues of A549-IL-17 cell-bearing nude mice. Importantly, positive correlations were also detected between IL-17 expression and IL-6, IL-8 and VEGF expression in human lung adenocarcinoma tissues. Furthermore, IL-6, IL-8 and VEGF production, as well as STAT1 phosphorylation, were increased in tumour tissues of A549-IL-17 cell-bearing nude mice in vivo and in A549 and H292 cells following IL-17 stimulation in vitro. In addition, STAT1 knockdown using an inhibitor and siRNA attenuated the IL-17-mediated increases in IL-6, IL-8 and VEGF expression in A549 and H292 cells. In conclusion, IL-17 may promote the production of the angiogenic inducers IL-6, IL-8 and VEGF via STAT1 signalling in lung adenocarcinoma.

IL-17 induces EMT via Stat3 in lung adenocarcinoma.

Epithelial-mesenchymal transition (EMT) plays a vital role in lung inflammatory diseases, including lung cancer. However, the role and mechanism of action of the proinflammatory cytokine IL-17 in EMT in lung adenocarcinoma remain unresolved. In our study, we discovered that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively correlated with IL-17 expression, while E-cadherin expression was negatively correlated with IL-17 expression in human lung adenocarcinoma tissues. Moreover, we confirmed that IL-17 promoted EMT in A549 and Lewis lung carcinoma (LLC) cells in vitro by upregulating N-cadherin, Vimentin, Snail1, Snail2, and Twist1 expression and downregulating E-cadherin expression. Stat3 was activated in IL-17-treated A549 and LLC cells, and Stat3 inhibition or siRNA knockdown notably reduced IL-17-induced EMT in A549 and LLC cells. Thus, IL-17 promotes EMT in lung adenocarcinoma via Stat3 signaling; these observations suggest that targeting IL-17 and EMT are potential novel therapeutic strategies for lung cancer.

Prognostic significance of serum LDH in small cell lung cancer: A systematic review with meta-analysis.

BACKGROUND: Lactare dehydrogenase (LDH) has been proven to be a prognostic and a potential pro-tumor factor in patients with lung cancer. But the prognostic value of serum LDH in small cell lung cancer (SCLC) has not been quantified systematically. OBJECTIVE: Thus, this study was to evaluate the correlations between serum LDH and overall survival of SLCLC by systematic review with meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science databases were searched from inception to October 2014 and references in those publications would be included if the association between serum LDH and overall survival of SCLC can be derived. Quality assessment and data extraction were performed in the articles selected according to inclusion and exclusion criteria. RESULTS: Twenty-eight studies including 4785 patients with SCLC were deemed eligible. Pooled results showed that SCLC patients with elevated LDH levels were associated with an increased hazard ratio (HR 1.45, 95%CI 1.27∼ 1.66) of overall survival. CONCLUSIONS: The study suggests significant correlations between elevated serum LDH levels and poor overall survival in patients with SCLC. And serum LDH levels can be measured combining with other tools for assessing the risk stratification and prognosis of SCLC, which shows directions for treatments of SCLC.

Retinoic acid-related orphan receptor C isoform 2 expression and its prognostic significance for non-small cell lung cancer.

BACKGROUND: Retinoic acid-related orphan receptor C isoform 2 (RORC2) is regarded as a pathogenic factor for autoimmune and inflammatory diseases and tumours. Previous studies have primarily focused on RORC2 expression in IL-17-producing immune cells but not in carcinoma cells; thus, little is known about the roles of RORC2 in the progression of human non-small cell lung cancer (NSCLC). In this study, we analysed the expression of RORC2 and its participation in tumour progression in NSCLC. METHODS: RORC2 expression in NSCLC and adjacent normal lung tissues was assessed via quantitative real-time PCR (qRT-PCR) and immunohistochemistry. RORC2 expression in NSCLC cell lines was examined by qRT-PCR, Western blotting and flow cytometry. The effects of inhibiting RORC2 activity on the proliferation of NSCLC cells were evaluated. The prognostic value of RORC2 for NSCLC was revealed based on Kaplan-Meier analysis. RESULTS: High RORC2 expression was observed in lung cancer tissues and was significantly related to age (p = 0.013) and regional lymph node metastasis (p = 0.009). RORC2 expression was higher in the A549, H460, SPC-A1 and H1299 cell lines than in a control cell line. In addition, cell proliferation was decreased in NSCLC cells upon the blocking of RORC2 activity using a specific inhibitor. High RORC2 expression correlated with worse overall survival (p = 0.030). CONCLUSIONS: Our study suggests that RORC2 is expressed by lung cancer cells and greatly contributes to tumour cell proliferation and overall survival in NSCLC. These findings strongly imply that RORC2 is associated with tumour progression.

Integrative genomic analysis of interleukin-36RN and its prognostic value in cancer.

Interleukin (IL)-36RN, previously known as IL1-F5 and IL-1δ, shares a 360-kb region of chromosome 2q13 with members of IL-1 systems. IL-36RN encodes an anti-inflammatory cytokine, IL-36 receptor antagonist (IL-36Ra). In spite of IL-36Ra showing the highest homology to IL-1 receptor (IL-1R) antagonist, it differs from the latter in aspects including its binding to IL-lRrp2 but not to IL-1R1. IL-36RN is mainly expressed in epithelial cells and has important roles in inflammatory diseases. In the present study, IL-36RN was identified in the genomes of 27 species, including human, chimpanzee, mouse, horse and dolphin. Human IL-36RN was mainly expressed in the eye, head and neck, fetal heart, lung, testis, cervix and placenta; furthermore, it was highly expressed in bladder and parathyroid tumors. Furthermore, a total of 30 single nucleotide polymorphisms causing missense mutations were determined, which are considered to be the causes of various diseases, such as generalized pustular psoriasis. In addition, the link between IL-36RN and the prognosis of certain cancer types was revealed through meta-analysis. Tumor-associated transcriptional factors c-Fos, activator protein-1, c-Jun and nuclear factor κB were found to bind to the upstream region in the IL-36RN gene. This may indicate that IL-36RN is involved in tumorigenesis and tumor progression through the regulation of tumor-associated transcriptional factors. The present study identified IL-36RN in various species and investigated the associations between IL-36RN and cancer prognosis, which would determine whether IL-36RN drove the evolution of the various species with regard to tumorigenesis.

The effect of proinflammatory cytokines on IL-17RA expression in NSCLC.

Interleukin-17 receptor (IL-17RA) is essential for proinflammatory cytokine IL-17-mediated pathogenesis of various tumors. IL-17RA is upregulated by some proinflammatory cytokines such as IL-21 and IL-15 and downregulated by IL-2, while the effect of IL-1ß, IL-6, IL-8, TNF-α on IL-17RA expression in non-small cell lung caner (NSCLC) remains unknown. Our findings revealed that IL-17RA mRNA was increased in NSCLC tissues compared with the corresponding peritumor tissues (P = 0.0039) and high expression of IL-17RA protein in human NSCLC tissues was significantly associated with histological subtype, primary tumor size and clinical stages (P = 0.033, 0.033 and 0.011, respectively). IL-17RA mRNA expression was positively related to IL-1ß, IL-6, IL-8, TNF-α mRNA expression (P = 0.013, 0.0001, 0.002 and 0.010 respectively) in NSCLC tissues. Furthermore, IL-1ß, IL-6, IL-8, TNF-α upregulated IL-17RA mRNA and protein in A549 and H460 cells (all P < 0.05). It is suggested that IL-1ß, IL-6, IL-8, TNF-α promoted IL-17RA expression in NSCLC and they may involve in IL-17RA signaling in NSCLC.