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This study aimed to investigate the effect of neuropilin-1 (NRP-1) silencing on epithelial-mesenchymal transformation (EMT) mediated by transforming growth factor-b1 (TGF-b1) and on the proliferation and migration of colon cancer SW480 cells. After transfection of small interfering ribonucleic acid (siRNA)-NRP-1 into colon cancer SW480 cells, the messenger RNA (mRNA) and protein expression levels of NRP-1 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Four EMT models were induced using 0, 2, 5, and 10 ng/mL TGF-b1, respectively. Cell proliferation was detected using Cell Counting Kit-8, and the protein levels of EMT markers E-cadherin and vimentin were detected using Western blot. EMT was induced in the transfected SW480 cells using TGF-b1, after which four groups were created: a negative control group (siRNA-Ncontrol), a transfection group (siRNA-NRP-1), an induction group (TGF-b1), and a transfection + induction group (siRNA-NRP-1+TGF-b1). Western blot was then used to detect the expression of E-cadherin and vimentin, and cell proliferation and migration were detected using cell counting kit-8 (CCK-8) and scratch assay.After transfection with siRNA-NRP-1, the mRNAand protein expression levels of SW480 cells were significantly decreased (P<0.05). After 48 hours of induction with 10 ng/mL TGF-b1, cell proliferation was obvious, E-cadherin expression decreased, and vimentin expression significantly increased (P<0.05), indicating that EMT had been successfully induced compared with the induction group, the transfection + induction group had significantly increased E-cadherin expression after corresponding treatments (including transfection and induction alone) (P<0.05), and the proliferation and migration of colon cancer cells decreased (P<0.05). In conclusion: silencing, NRP-1 in colon cancer SW480 cells can partially reverse TGF-b1-mediated EMT, reduce the proliferation activity of colon cancer cells, and slow their migration ability. Therefore, NRP-1 may become a new target for the treatment of colon cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: We aimed to assess the clinical outcome of computed tomography (CT)-guided percutaneous microwave ablation (MWA) in patients 75 years of age and older with early stage peripheral nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Twenty-eight patients, aged ≥75 years, with Stage I and lymph node-negative IIa peripheral NSCLC underwent CT-guided percutaneous MWA in our hospital between July 2007 and March 2015. The overall 1-, 2-, 3-, and 4-year survival rates were estimated using Kaplan-Meier analysis. Adverse events were recorded. RESULTS: The median follow-up time was 22.5 months. The overall median survival time (MST) was 35 months (95% confidence interval [CI] 22.3-47.7 months), and the cancer-specific MST was 41.9 months (95% CI 38.8-49.9 months). The 1-, 2-, 3-, and 4-year overall survival rates were 91.7%, 76.5%, 47.9%, and 47.9%, while the cancer-specific survival rates were 94.7%, 73.9%, 64.7%, and 64.7%, respectively. Median time to local progression was 28.0 months (95% CI 17.7-38.3 months). Major complications were included pneumothorax (21.4%, requiring drainage), pleural effusions (3.6%, requiring drainage), and pulmonary infection (3.6%). CONCLUSIONS: CT-guided percutaneous MWA is safe and effective for the treatment of patients 75 years of age and older with medically inoperable early stage peripheral NSCLC. [ABSTRACT FROM AUTHOR]

Background:Aberrant Smad7 expression contributes to the invasion and metastasis of pancreatic cancer cells. However, the potential mechanism underlying aberrant Smad7 expression in human pancreatic ductal adenocarcinoma (PDAC) remains largely unknown.Methods:Bioinformatic prediction programmes and luciferase reporter assay were used to identify microRNAs regulating Smad7. The association between miR-367 expression and the overall survival of PDAC patients was evaluated by Kaplan-Meier analysis. The effects of miR-367 and Smad7 on the invasion and metastasis of pancreatic cancer cells were investigated both in vitro and in vivo.Results:We found that miR-367 downregulated Smad7 expression by directly targeting its 3′-UTR in human pancreatic cancer cells. High level of miR-367 expression correlated with poor prognosis of PDAC patients. Functional studies showed that miR-367 promoted pancreatic cancer invasion in vitro and metastasis in vivo through downregulating Smad7. In addition, we showed that miR-367 promoted epithelial-to-mesenchymal transition by increasing transforming growth factor-β (TGF-β)-induced transcriptional activity.Conclusions:The present study identified and characterised a signalling pathway, the miR-367/Smad7-TGF-β pathway, which is involved in the invasion and metastasis of pancreatic cancer cells. Our results suggest that miR-367 may be a promising therapeutic target for the treatment of human pancreatic cancer. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a fatal disease with great public health impact worldwide. Heme oxygenase (HO)-1 has recently been reported as an important player in tumor angiogenesis and metastasis. However, the role of HO-1 in liver cancer metastasis is unclear. In this study, we explored genetic differences and downstream signal transduction pathways of HO-1 in liver cancer cell lines. HO-1 wild-type and mutant cell lines were generated from human liver cancer cell line HepG2. The overexpression of wild-type HO-1 decreased the migration of HepG2 cells. In contrast, the overexpression of mutant HO-1G143H increased the migration of the cancer cells. Interleukin (IL)-6 is one of the major downstream molecules that mediated this process because IL-6 expression and migration are suppressed by HO-1 and increased when HO-1 is knocked down by shRNA. In addition, we demonstrated carbon monoxide (CO) and p38MAPK are the cofactors in this signal pathway. In vivo animal model demonstrated HO-1 inhibited the tumor growth. In conclusion, in vitro and in vivo data show HO-1 inhibits the human HCC cells migration and tumor growth by suppressing the expression of IL-6. The heme degradation product CO is a cofactor in this process and inhibits p38MAPK phosphorylation. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that a sub-population of cancer cells with stem-like properties, termed tumor-initiating cells (T-ICs), exist in many different kinds of malignancies, which have a pivotal role in tumorigenesis, tumor progression, metastasis and post-treatment relapse. However, how the stem-like properties of T-ICs are regulated remains obscure. Our previous study showed that reduction of let-7 microRNA (miRNA) in breast tumor-initiating cells (BT-ICs) contributes to the maintenance of their self-renewal capacity and undifferentiated status. In this study we show the effect of mir-30 reduction on the stem-like features of BT-ICs. Similar to let-7, mir-30 is reduced in BT-ICs, and the protein level of Ubc9 (ubiquitin-conjugating enzyme 9) and ITGB3 (integrin β3), the target genes of mir-30, is markedly upregulated. Enforced constitutive expression of mir-30 in BT-ICs inhibits their self-renewal capacity by reducing Ubc9, and induces apoptosis through silencing ITGB3. On the contrary, blocking the miRNA with a specific antisense oligonucleotide (ASO) in differentiated breast cancer cells revived their self-renewal capacity. Furthermore, ectopic expression of mir-30 in BT-IC xenografts reduces tumorigenesis and lung metastasis in nonobese diabetic/severe combined immunodeficient mice, whereas blocking mir-30 expression enhances tumorigenesis and metastasis. Together, our data suggest mir-30 as one of the important miRNAs in regulating the stem-like features of T-ICs. [ABSTRACT FROM AUTHOR]

Background:Gold(III) porphyrin 1a is a new class of anticancer drug, which inhibits cell proliferation of wide range of human cancer cell lines and induces apoptosis in human nasopharyngeal carcinoma cells. However, the underlying signalling mechanism by which gold(III) porphyrin 1a modifies the intracellular apoptosis pathways in tumour cells has not been explained in detail in neuroblastoma cells.Methods:Cell proliferation and apoptosis were determined by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Annexin V binding, respectively. Western blot assay was used to detect proteins involved in apoptotic and Akt pathways. In vivo tumour growth was assessed by inoculating tumour cells to nude mice subcutaneously, and gold(III) porphyrin 1a was administrated intravenously.Results:This study assessed the antitumour effect and mechanism of gold(III) porphyrin 1a on neuroblastoma in vitro and in vivo. Gold(III) porphyrin 1a displayed a growth inhibition and induction of apoptosis in neuroblastoma cells effectively in vitro, which was accompanied with release of cytochrome c and Smac/DIABLO and caspases activation. Further studies indicated that gold(III) porphyrin 1a inhibited X-linked inhibitor of apoptosis (XIAP). However, we found that gold(III) porphyrin 1a can induce a survival signal, Akt activation within minutes and could last for at least 24 h. To further confirm association between activation of Akt and the effectiveness of gold(III) porphyrin 1a, neuroblastoma cells were treated with API-2, an Akt-specific inhibitor. API-2 sensitised cells to gold(III) porphyrin 1a-induced apoptosis and growth inhibition.Conclusion:These results suggested that Akt may be considered as a molecular ‘brake’ that neuroblastoma cells rely on to slow down gold(III) porphyrin 1a-induced apoptosis and antiproliferation. Gold(III) porphyrin 1a is a mitochondrial apoptotic stimulus but also activates Akt, suggesting an involvement of Akt in mediating the effectiveness to growth inhibition and apoptosis by gold(III) porphyrin 1a and that inhibition of Akt can enhance the anticancer activity of gold(III) porphyrin 1a in neuroblastoma.British Journal of Cancer (2009) 101, 342–349; doi:10.1038/sj.bjc.6605147 www.bjcancer.com Published online 23 June 2009 [ABSTRACT FROM AUTHOR]

The c-Jun NH2-terminal kinase (JNK) pathway represents one subgroup of MAP kinases that are activated primarily by cytokines and exposure to environmental stress. Autophagy is a protein-degradation system characterized by the formation of double-membrane vacuoles termed autophagosomes. Autophagy-related gene beclin 1 plays a key role in autophagosome formation. However, the relationships between activation of JNK pathway, autophagy induction and Beclin 1 expression remain elusive. In this study, we used human cancer cell lines CNE2 and Hep3B to investigate the role of JNK-mediated Beclin 1 expression in ceramide-induced autophagic cell death. Ceramide-treated cells exhibited the characteristics of autophagy (that is, acidic vesicular organelle formation and the LC3-II generation). JNK was activated in these two cell lines exposed to ceramide and the phosphorylation of c-Jun also increased. In the meantime, we found that ceramide upregulated Beclin 1 expression in cancer cells. The upregulation of Beclin 1 expression could be blocked by SP600125 (a specific inhibitor of JNK) or a small interfering RNA (siRNA) directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was involved in the regulation of beclin 1 transcription in response to ceramide treatment. In addition, inhibition of JNK activity by SP600125 could inhibit autophagy induction by ceramide. Furthermore, Beclin 1 knockdown by siRNA also inhibited ceramide-mediated autophagic cell death. JNK-mediated Beclin 1 expression was also observed in topotecan-induced autophagy. These data suggest that activation of JNK pathway can mediate Beclin 1 expression, which plays a key role in autophagic cell death in cancer cells.Oncogene (2009) 28, 886–898; doi:10.1038/onc.2008.441; published online 8 December 2008 [ABSTRACT FROM AUTHOR]

Extra-pancreatic metastasis is a difficult problem for surgical intervention in pancreatic cancer. CXC chemokine receptor 4 (CXCR4) was considered to have an important role in this process. We hypothesized it may contribute to the pancreatic cancer progression through influencing canonical Wnt pathway. The purpose of this study was to examine the functional role of CXCR4 in the progression of pancreatic cancers and explore the possible mechanism. To this end, the relation between CXCR4 and clinical characteristics was analysed. shRNA against CXCR4 was applied to disrupt the SDF-1/CXCR4 signal transduction pathways in pancreatic cancer cell lines. Our results showed that overall survival in the case of patients positive for CXCR4 expression was significantly lower than that in the case of patients negative for CXCR4 expression. Notably, in vitro studies we observed that the abrogation of CXCR4 could obviously influence the pancreatic cancer cell phenotype including cell proliferation, colony formation, cell invasion and also inhibit the TOPflash activity. In addition, Wnt target genes and mesenchymal markers such as Vimentin and Slug were also inhibited in CXCR4 knockdown cells. Collectively, these data reported here demonstrate CXCR4 could modulate the canonical Wnt pathway and perhaps be a promising therapeutic target for pancreatic cancer progression. [ABSTRACT FROM AUTHOR]

Colour figures can be viewed on http://www.esacp.org/acp/2002/24-4_5/heinmoeller.htm. [ABSTRACT FROM AUTHOR]