MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expression by base-pairing to the 3 0 -UTR of the target mRNA. Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated. Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E-cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression. In the present study, we found that Snai1, a known transcriptional repressor of E-cadherin and modulator of EMT, is post-transcriptionally targeted by miRNA-30a in non-small cell lung cancer (NSCLC). Consistent with this, microRNA30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E-cadherin (epithelial marker) and negatively with N-cadherin (mesenchymal marker) expression. Forced re-introduction of miR-30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E-cadherin expression. Using a chicken embryonic metastasis assay, we found that miR-30a suppresses in vivo distant metastasis to the lungs and liver. Finally, we screened the expression of miR-30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR-30a was downregulated significantly (p < 0.0001) in tumors compared to corresponding normal tissues. These results suggest that miR-30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC.Lung cancer is the most common cancer world wide in terms of both incidence and mortality. 1 The major problem in the management of lung cancer is metastatic disease, highlighting the importance of a better understanding of the biological processes that occur in tumor cells to promote the aggressive neoplastic phenotype. The hallmarks of malignant transformation are the capabilities of invasion and metastasis. In order to acquire these traits, tumor cells must be able to detach from the primary tumor, migrate, and disseminate to distant organs to form metastases. 2 Now it is clear that a transition of tumor cells at the invasive front, which is characterized by the loss of epithelial markers and the gain of a mesenchyme-like phenotype, plays a key role to induce invasion and metastasis. This transition is called epithelial to mesenchymal transition, or EMT.Epithelial cells are generally characterized by their arrangement as a sheet of cells abutting each other in a uniform fashion. As a result of regularly spaced cell-cell junctions between neighboring cells, epithelial cells cannot move away from the monolayer. On the other hand, mesenchymal cells generally lack tight intercellular adhesions and a regimented structure. The transition of epithelial cells into mesenchymal-like cells is orchestrated by a series of events finally leading to the release of epithelial cells from the surround...

Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4, MZB1, NIP7, and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUVmax, and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets.

Propolis and its compounds have been the subject of many studies due to their antimicrobial and antiinflammatory activity; however, it is now known that they also possess antitumor properties. This review aims to summarize the results of studies on the mechanism of activity of propolis and its active compounds such as CAPE and chrysin in the apoptotic process, and their influence on the proliferation of cancer cells. Our review shows that propolis and its presented compounds induce apoptosis pathways in cancer cells. The antiproliferative effects of propolis, CAPE or chrysin in cancer cells are the result of the suppression of complexes of cyclins, as well as cell cycle arrest. The results of in vitro and in vivo studies suggest that propolis, CAPE and chrysin may inhibit tumor cell progression and may be useful as potential chemotherapeutic or chemopreventive anticancer drugs.

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3’ UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3’ UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.

Purpose: Current staging methods are imprecise for predicting prognosis of early-stage nonŝ mall-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis. Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence. Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P < 0.001; n = 103) and in the independent validation set (P < 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response. Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.

Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.

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The polymerization of ␣-and ␤-tubulin into microtubules results in a complex network of microfibrils that have important structural and functional roles in all eukaryotic cells. In addition, microtubules can interact with a diverse family of polypeptides which are believed to directly promote the assembly of microtubules and to modulate their functional activity. We have demonstrated that the c-Myc oncoprotein interacts in vivo and in vitro with ␣-tubulin and with polymerized microtubules and have defined the binding site to the N-terminal region within the transactivation domain of c-Myc. In addition, we have shown that c-Myc colocalizes with microtubules and remains tightly bound to the microtubule network after detergent extraction of intact cells. These findings suggest a potential role for Myc-tubulin interaction in vivo.The product of the c-myc gene is a nuclear phosphoprotein that has been implicated in the regulation of cell differentiation, apoptosis, and the development of human tumors (5,19,28). The c-Myc protein includes multifunctional domains that include an N-terminal transactivation domain within exon II and a C-terminal domain, within exon III, which is necessary for heterodimerization (5, 19). These observations have supported the model that c-Myc functions as a transcription factor whose activity can be regulated by its protein binding partners. In addition, the N-terminal transactivation region of c-Myc binds to the retinoblastoma protein-related tumor suppressor protein p107, and it has been recently shown that this interaction can suppress the activity of the c-Myc transactivation domain (12). Further, the observation that Burkitt's lymphoma frequently contains naturally occurring somatic mutations within the transactivation domain (3, 34) which result in loss of p107 suppression confirms that this is an important functional domain of c-Myc.Although c-Myc is characterized as a nuclear protein (10, 15), it has recently been proposed that the subcellular localization of c-Myc can vary according to the proliferation state of the cell. For example, in actively growing NIH 3T3 cells c-Myc is predominantly found in the nucleus, while a shift to the cytoplasm occurs in contact-inhibited cells (31). An increased cytoplasmic/nuclear ratio for c-Myc has also been noted following monocytic differentiation of human myeloid leukemia cells (8) and in nondividing prefertilized Xenopus oocytes (14). In addition, comparison of c-Myc localization patterns of normal tissue, adenomas, and colorectal tumors showed that tumor progression was associated with an accumulation of cytoplasmic c-Myc protein (27). These experiments suggested that nucleus-cytoplasm exchanges of c-Myc protein play an important functional role in cell proliferation. Since it had been proposed that tubulin mediates the cytoplasm-to-nucleus translocation of the glucocorticoid and vitamin D receptors (2, 25), we examined whether c-Myc could also interact with tubulin and microtubules. This hypothesis was also suggested by the observation tha...