Breast cancer is the second most common types of cancer worldwide. Molecular strategies have developed rapidly; however, novel treatments strategies with high efficacy and lower toxicity are still urgently demanded. Notably, biological networks estimated from microarray data and functional activity network analysis could be utilized to identify and validate potential targets. In this study, two microarray data (GSE13477, GSE31192) were firstly selected, and analyzed by multi-functional activity network analysis to generate the core protein-protein-interaction (PPI) network. Several potential targets were subsequently identified and c-Met and poly (ADP-ribose) polymerase-1 (PARP-1) were manually chosen as the key targets in breast cancer. Furthermore, virtual screening and molecular dynamics (MD) simulations were utilized to recognize novel c-Met/PARP-1 inhibitors in Specs products database. Three small molecules, namely, ZINC19909930, ZINC20032678 and ZINC13562414 were selected. Additionally, these compounds were synthesized, and two breast cancer cell lines, MDA-MB-231 and MCF-7 cells were used to validate our bioinformatic findings in vitro. MTT assay and Hoechst staining showed that ZINC20032678 significantly induced breast cancer cell death, which was mediated through apoptosis by flow cytometry. Furthermore, ZINC20032678 was shown to target the active sites of the both targets and recruitment of downstream apoptotic signaling pathways, eventually inducing breast cancer cell apoptosis. Collectively, our findings not only offer systems biology approaches based drug target identification, but also provide the new clues for developing novel inhibitors for future breast cancer research.

Silibinin (SB), a flavonoid extracted from milk thistle seeds, has been found to exert antitumor effects in numerous tumor types. Our previous study reported that SB had anti-metastatic effects in prostate cancer (PCa). However, the exact underlying molecular mechanisms remain to be determined. The present study aimed to investigate the effects of SB on the migration, invasion and epithelial-mesenchymal transition (EMT) of castration-resistant PCa (CRPC) cells using wound healing, Transwell assays, and western blotting. The results revealed that SB treatment significantly inhibited the migration and invasion of CRPC cell lines. Moreover, SB was confirmed to activate autophagy, as determined using LC3 conversion, LC3 turnover and LC3 puncta assays. Further mechanistic studies indicated that the expression levels of Yes-associated protein (YAP) were downregulated in an autophagy-dependent manner after SB treatment. In addition, the SB-induced autophagic degradation of YAP was associated with the anti-metastatic effects of SB in CRPC. In conclusion, the findings of the present study suggested that SB might inhibit the migration, invasion and EMT of PCa cells by regulating the autophagic degradation of YAP, thus representing a potential novel treatment strategy for metastatic CRPC.

Long non-coding RNAs (lncRNAs) have been considered as biomarkers for the carcinogenesis and development of various cancers. However, the prognostic significance of lncRNAs in renal cell carcinoma (RCC) remains unclear. This study aimed to determine the predictive ability of lncRNAs in clear cell RCC (ccRCC). Among the cohort of kidney renal clear cell carcinoma (KIRC) of the The Cancer Genome Atlas (TCGA), 525 patients were enrolled in our study. Expression of lncRNAs based on RNAseq was obtained from TCGA. Kaplan-Meier prognostic analysis and a Cox proportional hazards regression model were used to assess related factors. The lncRNA signature was then validated in an independent cohort of an additional 60 ccRCC patients. Hierarchical clustering of the KIRC TCGA dataset identified 26 differentially expressed lncRNAs (11 down-regulated and 15 up-regulated) using average linkage clustering. Kaplan-Meier survival analysis identified 30 statistically significant lncRNAs that strongly predicted prognosis, with 4 ccRCC-specific lncRNAs (TCL6, PVT1, MIR155HG, and HAR1B) being differentially expressed and correlating significantly with OS. Patients assigned to the high-risk group were associated with poor OS compared with patients in the low-risk group (HR = 2.57; 95%CI, 1.89-3.50; p < 0.001). This finding was validated in the Tongji Hospital cohort, and the four-lncRNA signature was shown to be significantly predictive of ccRCC prognosis (p < 0.001). In this study, we constructed an applicable four-lncRNA-based classifier as a reliable prognostic and predictive tool for OS in patients with ccRCC.

Background: Nasopharyngeal carcinoma (NPC) is the most common head and neck squamous cell carcinoma in south China. Radiation technology improves the local control rates in early NPC. However, the distant metastases are still the main cause of treatment failure. Thus, to find biomarkers for prognosis will help to enhance the survival of NPC. ATRX is a chromatin remodeling protein localized in the nucleus. Deletion or mutation of ATRX gene has been demonstrated in a variety of malignancies. However, the significance of ATRX expression in the prognosis of NPC remains unclear. Methods: Tumor tissues from 227 NPC patients diagnosed in the Second Xiangya Hospital of Central South University from 2011 to 2016 were selected. Immunohistochemistry was used to detect the ATRX expression level of the tumor tissue. Chi-square test was used to analyze the relationship between ATRX expression and clinical characteristics such as age, sex, T stage, N stage and clinical stage. Kaplan-Meier method was used for survival analysis, and log-rank was used to compare the difference in survival rate. Results: There were 53 patients with negative ATRX expression, accounting for 24.2% of the total group. ATRX expression was not significantly associated with age, sex, N stage, clinical stage, and progression-free survival (PFS) (P>0.05). However, patients with negative ATRX expression had earlier T staging (P=0.045) and a higher 5-year overall survival (84.9% vs 66.9%, P=0.022). Conclusions: Loss of ATRX expression may contribute to better prognosis in patients with NPC.

Background: Long noncoding RNAs (LncRNAs) possess crucial roles in carcinogenesis. The current study aims to evaluate the effects of interleukin-1β (IL-1β)-mediated lncRNA cardiac hypertrophy-related factor (CHRF)/microRNA-489 (miR-489)/myeloid differentiation factor 88 (Myd88) on non-small-cell lung cancer (NSCLC). Methods: Initially, the expression of IL-1β and lncRNA CHRF in NSCLC cells and tissues was determined, respectively. H460 cell line with highest lncRNA CHRF expression was selected for in vitro experimentations. Afterward, the interaction among lncRNA CHRF, miR-489, and Myd88 was verified with their significance in cell functions and tumorigenicity and lung metastasis analyzed following. Results: IL-1β and lncRNA CHRF was remarkably upregulated in NSCLC. IL-1β was able to elevate lncRNA CHRF expression. Additionally, lncRNA CHRF targeted miR-489 and miR-489 targeted Myd88. Moreover, functional assay results suggested that under IL-1β treatment, lncRNA CHRF induced NSCLC cell malignant properties and tumorigenicity and lung metastasis through modulation of miR-489/Myd88 axis. Conclusion: Taken together, our findings revealed that IL-1β-induced elevation of lncRNA CHRF aggravated NSCLC through modulation of miR-489/Myd88 axis, which provides a novel direction for NSCLC therapy development.

Hsp70 (heat shock protein 70) plays critical roles in cancer cell proliferation and apoptosis. Recently, accumulating evidences have demonstrated the cancer promoting effects of Hsp70 in bladder cancer. The development of novel therapeutic approaches targeting Hsp70 thus received great attention from researchers. In this study, we demonstrated that silibinin, a natural polyphenolic flavonoid isolated from the milk thistle, targeted Hsp70 by inhibiting its transcription in bladder cancer cells. We also demonstrated that knockdown of endogenous Hsp70 enhanced silibinin-induced apoptosis, while overexpression of exogenous Hsp70 could partially reverse the effects of silibinin-induced cell apoptosis. Furthermore, we found that silibinin could activate HSF1/Hsp70-regulated mitochondrial apoptotic pathway. Mechanically, silibinin inhibited the interaction between Apaf-1 and Hsp70, thus increasing the recruitment of pro caspase-9. Results from in vivo study demonstrated that silibinin suppressed the growth of bladder cancer xenografts, which was accompanied with the activation of caspase-3 and downregulation of HSF1 and Hsp70. Taken together, our data indicates that silibinin induces mitochondrial apoptosis via inhibiting HSF1/Hsp70 pathway and also suggests the therapeutic potential of silibinin in the treatment of bladder cancer.