Lihua Shang

Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.

The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. However, it remains unclear how IL-17 might contribute to tumor angiogenesis. In our study, IL-17 enhanced the formation of vessel-like tubes in HUVECs both directly (when HUVECs were incubated with IL-17) and indirectly (when HUVECs were incubated in conditioned cell media (CCM) from IL-17-treated cancer cells). Our results from experiments using siRNA-mediated knockdowns of STAT3 and GIV suggest that the effects of IL-17 were mediated by activating STAT3/GIV signaling in NSCLC cells and subsequently up-regulating its downstream target VEGF. Consistent with these findings, immunostaining experiments on human NSCLC tissues indicated that IL-17 and GIV expression were significantly and positively associated with increased tumor vascularity. The clinical significance of IL-17 was authenticated by our finding that the combination of intratumoral IL-17 + cells and GIV expression served as a better prognosticator for survival than either marker alone. Therefore, our finding highlights a novel aspect of STAT3/GIV pathway in the IL-17 promotes tumor angiogenesis of NSCLC.

Polymorphisms of ERCC1 C118T/C8092A and MDR1 C3435T predict outcome of platinum-based chemotherapies in advanced non-small cell lung cancer: a meta-analysis.

BACKGROUND AND AIMS With great progress made in individualized chemotherapy, pharmacogenetics is gradually put on the agenda. We performed this meta-analysis to compare outcome to platinum-based chemotherapies in advanced non-small cell lung cancer (NSCLC) with different ERCC1 C118T/C8092A and MDR1 C3435T polymorphisms. METHODS Relevant studies were identified according to search strategy in this meta-analysis. Inclusion criteria were patients with advanced NSCLC who were receiving platinum-based chemotherapies. We evaluated the relationship between single nucleotide polymorphisms (SNP) and outcome of platinum-based chemotherapies. RevMan and STATA package were used for the comprehensive quantitative analyses. RESULTS Twenty studies were included in the meta-analysis. There was no significant association between SNPs and objective response or overall survival of platinum-based chemotherapies with CC vs. CT/TT: ERCC1 C118T (OR 1.21, 95% CI 0.81-1.82 for objective response; HR 1.09, 95% CI 0.79-1.51 for overall survival); ERCC1 C8092A SNP (OR 0.84, 95% CI 0.59-1.18; HR 1.26, 95% CI 0.68-2.36) and MDR1 C3435T SNP (HR 1.11, 95% CI 0.78-1.56). Ethnic stratification provided the same results. We found a significant difference for MDR1 C3435T (OR 2.22, 95% CI 1.46-3.37; OR 2.63, 95% CI 1.56-4.45 for Asians; OR 1.61, 95% CI 0.79-3.28 for Caucasians). CONCLUSIONS We found no evidence to support the use of ERCC1 C118T/C8092A polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC. For the MDR1 C3435T SNP, a significant association with objective response was detected for CC genotype in overall and Asian populations stratified. Multiple and large-scale studies with ethnic stratification are required for the correlation between biomarkers and tumor prognosis.

Luffa echinata Roxb. induces human colon cancer cell (HT-29) death by triggering the mitochondrial apoptosis pathway.

The antiproliferative properties and cell death mechanism induced by the extract of the fruits of Luffa echinata Roxb. (LER) were investigated. The methanolic extract of LER inhibited the proliferation of human colon cancer cells (HT-29) in both dose-dependent and time-dependent manners and caused a significant increase in the population of apoptotic cells. In addition, obvious shrinkage and destruction of the monolayer were observed in LER-treated cells, but not in untreated cells. Analysis of the cell cycle after treatment of HT-29 cells with various concentrations indicated that LER extracts inhibited the cellular proliferation of HT-29 cells via G2/M phase arrest of the cell cycle. The Reactive oxygen species (ROS) level determination revealed that LER extracts induced apoptotic cell death via ROS generation. In addition, LER treatment led to a rapid drop in mitochondrial membrane potential (MMP) as a decrease in fluorescence. The transcripts of several apoptosis-related genes were investigated by RT-PCR analysis. The caspase-3 transcripts of HT-29 cells significantly accumulated and the level of Bcl-XL mRNA was decreased after treatment with LER extract. Furthermore, the ratio of mitochondria-dependent apoptosis genes (Bax and Bcl-2) was sharply increased from 1.6 to 54.1. These experiments suggest that LER has anticancer properties via inducing the apoptosis in colon cancer cells, which provided the impetus for further studies on the therapeutic potential of LER against human colon carcinoma.

The efficacy and safety of low-molecular-weight heparin use for cancer treatment: A meta-analysis

BACKGROUND Low-molecular-weight heparin (LMWH) has an anti-tumour effect in-vitro and in animal models of malignancy; however, the evidence from clinical trials is controversial. Thus, we performed a meta-analysis from the results of randomised controlled trials (RCTs) to assess LMWH efficacy and safety in cancer patients who had no venous thromboembolism (VTE). METHODS We searched the MEDLINE, EMBASE and CENTRAL (The Cochrane Central Register of Controlled Trails) databases covering all papers published up until April 2012. Two reviewers (D. H. Che and J. Y. Cao) extracted the data independently. The inclusion criteria used were patients with cancer who had no VTE and were treated with LMWH. The outcomes of interest included the 1-year mortality rate, VTE, bleeding and major bleeding complications. The results were presented as a relative risk (RR), and the STATA 11.0 package was used for comprehensive quantitative analysis. RESULTS A total of 11 studies with 3835 cases and 3449 controls were included. The meta-analysis showed significant differences in the rates of bleeding with an RR: 1.32 [95% confidence interval (95% CI, 1.08-1.62)] and VTE with an RR: 0.53 (95% CI, 0.42-0.67) in cancer patients when LMWH was compared with placebo or no anticoagulant. There were no significant differences in the 1-year mortality rate with an RR: 0.97 (95% CI, 0.92-1.02) and major bleeding with an RR: 1.22 (95% CI, 0.87-1.71). CONCLUSION LMWH does not significantly reduce the 1-year mortality rate for cancer patients. Although LMWH can prevent VTE, we should consider the risk-effect ratio (in case of an increased bleeding event) when we use LMWH in the patients with cancer. Thus, further research is still needed to confirm these results.

Tumor-associated macrophages promote tumor metastasis via the TGF-β/SOX9 axis in non-small cell lung cancer

Tumor-associated macrophages (TAMs), most of which display the immunosuppressive M2 phenotype, affect the tumor microenvironment and promote progression and metastasis in lung carcinoma. In this study, we analyzed clinical non-small cell lung cancer (NSCLC) samples and found that high densities of TAMs were associated with a poor prognosis in NSCLC patients. Moreover, the number of TAMs present correlated positively with expression of sex determining region Y (SRY)-related high mobility group box 9 (SOX9) in NSCLC tissues. TAMs secreted TGF-β, which increased SOX9 expression and promoted epithelial-to-mesenchymal transition (EMT) in lung cancer cells, thereby promoting tumor proliferation, migration, and invasion. SOX9 knockdown inhibited EMT, indicating that TGF-β-mediated EMT is SOX9-dependent. TGF-β induced SOX9 expression by upregulating the C-jun/SMAD3 pathway. These results indicate that TGF-β secreted by TAMs promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis. The TGF-β/SOX9 axis may therefore be an effective target for the treatment of lung cancer.

Interleukin-17 levels correlate with poor prognosis and vascular endothelial growth factor concentration in the serum of patients with non-small cell lung cancer

Abstract Objective: The aim of this study was to explore the clinical role of serum interleukin-17 in patients with non-small-cell lung cancer (NSCLC). Materials and method: IL-17 expression and microvessel density (MVD) were measured via immunohistochemistry in 58 NSCLC tissues. Serum IL-17 and VEGF levels in NSCLC patients (n = 43) and healthy controls (n = 37) were analyzed via enzyme-linked immunosorbent assay. Results: Serum IL-17 was elevated and the levels positively correlated with VEGF concentration in NSCLC patients. Multivariate analyses revealed that serum IL-17 levels were an independent prognostic factor in NSCLC. Conclusion: IL-17 may play a role in NSCLC progression by promoting angiogenesis.

Combination of four gene markers to detect circulating tumor cells in the peripheral blood of patients with advanced lung adenocarcinoma using real-time PCR

The aim of this study was to establish a robust and reliable assay for the detection of circulating tumor cells (CTCs) in the peripheral blood (PB) of patients with advanced lung adenocarcinoma. We used real-time reverse transcription PCR (RT-PCR) to detect survivin, human telomerase reverse transcriptase (hTERT), cytokeratin-7 (CK-7) and thyroid transcription factor 1 (TTF-1) mRNA expression levels in 68 advanced lung adenocarcinoma patients and 30 healthy patients. Statistical analyses were additionally performed to examine the correlation between the mRNA expression levels of these markers with the clinicopathological features of advanced lung adenocarcinoma patients. The sensitivity of these four mRNA markers in the PB of advanced lung adenocarcinoma patients was 41.18, 61.76, 41.18 and 35.29%, respectively. The sensitivity of these four markers combined was 82.35%, which was significantly higher compared with single marker detection. Statistical analysis demonstrated that high expression levels of survivin, hTERT and TTF-1 mRNA are positively correlated with lymph node classification, and high expression levels of survivin, hTERT, CK7 and TTF-1 mRNA are positively correlated with distant metastasis (P<0.05). In addition, overexpression of these four mRNA markers is positively correlated with disease progression (P<0.05). Our data suggest that the combination of survivin, hTERT, CK-7 and TTF-1 mRNA markers may provide a valuable tool for CTC detection and is associated with disease progression in advanced lung adenocarcinoma patients.

Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6-mediated COX-2/PGE2/β-catenin signalling pathway

Infiltration of macrophages plays a critical role in the connection between inflammation and cancer invasion; however, the molecular mechanism that enables this crosstalk remains unclear. This paper investigates a molecular link between infiltration of macrophages and metastasis of lung cancer cells. In this study, the macrophage density and cyclooxygenase-2 (COX-2) protein were examined in surgical specimens by immunohistochemistry (IHC), and the prostaglandin E2 (PGE2) levels were determined in the blood of 30 non-small cell lung cancer (NSCLC) patients using enzyme-linked immunosorbent assay (ELISA). We demonstrated that macrophage infiltration was significantly associated with elevated tumour COX-2 expression and serum PGE2 levels in NSCLC patients. Interestingly, the COX-2 and PGE2 levels as well as macrophages were poor predictors of NSCLC patient survival. THP-1-derived macrophages were co-cultured in vitro with A549 and H1299 lung cancer cells. In the co-culture process, interleukin-6 (IL-6) induced the COX-2/PGE2 pathway in lung cancer cells, which subsequently promoted β-catenin translocation from the cytoplasm to the nucleus, resulting in epithelial-mesenchymal transition (EMT) and lung cancer cell invasion. Our findings show that the IL-6-dependent COX-2/PGE2 pathway induces EMT to promote invasion of tumour cells through β-catenin activation during the interaction between macrophages and lung cancer cells, which suggests that inhibition of COX-2/PGE2 or macrophages has the potential to suppress metastasis of lung cancer cells.

Luffa echinata Roxb. induced apoptosis in human colon cancer cell (SW-480) in the caspase-dependent manner and through a mitochondrial apoptosis pathway

Background: Luffa echinata Roxb. (LER) (Cucurbitaceae) showed tremendous medicinal importance and are being used for the treatment of different ailments. Objective: In this study, the antiproliferative properties and cell death mechanism induced by the extract of the fruits of LER were investigated. Materials and Methods: MTT and LDH assay were used to test the antiproliferative and cytotoxicity of LER extract, respectively. The intracellular ROS were measured by a fluorometric assay. The expression of several apoptotic-related proteins in SW-480 cells treated by LER was evaluated by Western blot analysis. Results: The methanolic extract of LER fruits inhibited the proliferation of human colon cancer cells (SW-480) in both dose- and time-dependent manners. The LER-treated cells showed obvious characteristics of cell apoptosis, including cell shrinkage, destruction of the monolayer, and condensed chromatin. In addition, treatments of various concentrations of LER extracts caused the release of lactate dehydrogenase as a dose-dependent manner via stimulation of the intracellular metabolic system. LER induced apoptosis, DNA fragmentation, and cellular ROS accumulation in SW-480 cells. Treatment of LER on SW-480 cells promoted the expression of caspases, Bax, Bad, and p53 proteins and decreased the levels of Bcl-2 and Bcl-XL. Conclusions: These results indicated that treatment with LER-induced cell death in mitochondrial apoptosis pathway by regulating pro-apoptotic proteins via the up regulation of the p53 protein. These findings highlight the potentials of LER in the treatment of human colon cancer.

Distant Metastasis and Survival Outcomes after Computed Tomography-Guided Needle Biopsy in Resected Stage I-III Non-Small Cell Lung Cancer

Background and objective Several reports describe the needle-tract implantation after percutaneous needle lung biopsy. The present study evaluated whether preoperative computed tomography-guided needle biopsy (CTNB) affected the distant metastasis and overall survival in patients with early non-small cell lung cancer (NSCLC). Methods A total of 1667 patients with pathological stage I-III NSCLC were assimilated. Of these, 168 patients received preoperative CTNB, whereas 1499 patients were not subjected to any biopsy before surgical resection. Propensity score matching method was adopted to balance the observed covariates between the two groups. Cox regression analysis and Kaplan-Meier estimations were used for survival analysis. Subset analysis was performed in the p-stage ≤ II cases. Results The distant metastasis and mortality were not significantly increased for all patients with preoperative CTNB (P = 0.142 and P = 0.125, respectively). The subset analysis of p-stage ≤ II cases showed that CTNB increased the risk of distant metastasis (P = 0.032) while not increasing the risk of mortality (P = 0.086). Conclusion CTNB can increase the risk of distant metastasis in the p-stage ≤ II patients.