br Our ROC analysis revealed

Our ROC analysis revealed that a combination of H19, MEG3 and miR-675-5p able to discriminate controls and GC subjects with 88.87% sensitivity and 85% specificity. It has been demonstrated that due to the
Parameter n ncRNAs gene expression
MEG3
Low High
Low High
Low High
Low High Low High
Low High
Gender 62
Female
Male
P value
Smoking 62
Yes
No
P value
P value
Lymph-node metastasis 40
Yes
no
P value
TNM stage 46
I and II
III and IV
P value
P value
P values was computed by χ2 tests. Bold values are statistically significant. P < 0.05.
Fig. 4. KEGG pathways enrichment analysis of genes regulated by miR-675, miR-148a, miR-181a and miR-141. Each column represents one miRNA and each row reveals one pathway. Darker colors represent lower significance values, and higher interaction of each miRNA with a specific molecular pathway.
Fig. 5. MEG3 and H19 lncRNAs inter-active miRNAs. Deregulated level of MEG3 functioned as a “molecular sponge” for miR-181a, miR-148a and miR-141 and thereby modulates the inhibitory effects of these miRNAs on the KX2-391 of target genes involved in GC-related pathways. In addition, H19 lncRNA generates miR-675, as well as acts as a sponge for miR-141, thus indirectly regulate gene expres-sion. Orange and blue nodes represent genes that targeted by three and two miRNAs, respectively. (For interpreta-tion of the references to colour in this figure legend, the reader is referred to the web version of this article.)
possible overlap in miRNA targets, the use of a combination of several miRNAs provided a powerful diagnostic tool compared with using a single marker (Ajit, 2012). Zhu et al. (2014) reported that a panel of five miRNAs may serve as a potential biomarker in detecting early stage GC.
In conclusion, the present study demonstrated that the H19 and miR-675-5p expression levels were elevated in plasma samples of GC patients compared to healthy participants, whereas, MEG3 and miR-141-3p expression were down-regulated in GC cases. Furthermore, ROC analysis revealed that a combination of H19, MEG3 and miR-675-5p expression levels able to discriminate controls and GC subjects. These results could provide useful information to apply ncRNAs as the po-tential biomarkers for GC. However, further in vivo studies with a larger sample size are needed to confirm our results.
Acknowledgments
We greatly appreciate all volunteers for their participation in the study. 
Funding
This work was financially supported by a grant (23.2.36) from the Deputy of Research, Yasuj University of Medical Sciences.
Conflict of interest
The authors declare that they have no conflict of interest.
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Contents lists available at ScienceDirect
Journal of Controlled Release
journal homepage: www.elsevier.com/locate/jconrel
Coated cationic lipid-nanoparticles entrapping miR-660 inhibit tumor T
growth in patient-derived xenografts lung cancer models
Massimo Moroa,1, Daniela Di Paolob,1, Massimo Milionec, Giovanni Centonzea, Viviana Bornaghia, Cristina Borzia, Paolo Gandellinid, Patrizia Perrib, Ugo Pastorinoe, Mirco Ponzonib, Gabriella Sozzia,2, Orazio Fortunatoa,2,
a Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
b Laboratory of Experimental Therapy in Oncology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
c Anatomic Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
d Department of Biosciences, University of Milan, Milan 20133, Italy
e Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
Keywords:
microRNA
Lung cancer
Lipid-nanoparticles
Patient-derived xenografts  r> Lung cancer is the leading cause of cancer-related deaths. Late diagnosis and inadequate therapies contribute to poor outcomes. MicroRNAs (miRNAs) are small non-coding RNAs and are involved in lung cancer development. Because miRNAs simultaneously regulate several cancer-related genes, they represent an interesting therapeutic approach for cancer treatment. We have developed Coated Cationic Lipid-nanoparticles entrapping miR-660 (CCL660) and intraperitoneally administered (1.5 mg/Kg) twice a week for four weeks into SCID mice carrying subcutaneously lung cancer Patients Derived Xenografts (PDXs). Obtained data demonstrated that miR-660 is down-regulated in lung cancer patients and that its replacement inhibited lung cancer growth by inhibiting the MDM2-P53 axis. Furthermore, systemic delivery of CCL660 increased miRNA levels in tumors and significantly reduced tumor growth in two different P53 wild-type PDXs without off-target effects. MiR-660 administration reduced cancer cells proliferation by inhibiting MDM2 and restoring P53 function and its downstream effectors such as p21. Interestingly, anti-tumoral effects of CCL660 also in P53 mutant PDXs but with a functional p21 pathway were observed. Stable miR-660 expression inhibited the capacity of H460 metastatic lung cancer cells to form lung nodules when injected intravenously into SCID mice suggesting a potential role of miR-660 in metastatic dissemination.