Integrative, genome-wide association study identifies chemicals associated with common women's malignancies.

BACKGROUND: Breast cancer, cervical cancer, and ovarian cancer are three of the most commonly diagnosed malignancies in women, and more cancer prevention research is urgently needed. METHODS: Summary data of a large genome-wide association study of female cancers were derived from the UK biobank. We performed a transcriptome-wide association study and a gene set enrichment analysis to identify correlations between chemical exposure and aberrant expression, repression, or mutation of genes related to cancer using the Comparative Toxicogenomics Database. RESULTS: We identified five chemicals (NSC668394, glafenine, methylnitronitrosoguanidine, fenofibrate, and methylparaben) that were associated with the incidence of both breast cancer and cervical cancer. CONCLUSION: Using a transcriptome-wide association study and gene set enrichment analysis we identified environmental chemicals that are associated with an increased risk of breast cancer, cervical cancer, and ovarian cancer.

Tamoxifen induces fatty liver disease in breast cancer through the MAPK8/FoxO pathway.

BACKGROUND: Prevention of metabolic complications of long-term adjuvant endocrine therapy in breast cancers remained a challenge. We aimed to investigate the molecular mechanism in the development of tamoxifen (TAM)-induced fatty liver in both estrogen receptor (ER)-positive and ER-negative breast cancer. METHODS AND RESULTS: First, the direct protein targets (DPTs) of TAM were identified using DrugBank5.1.7. We found that mitogen-activated protein kinase 8 (MAPK8) was one DPT of TAM. We identified significant genes in breast cancer and fatty liver disease (FLD) using the MalaCards human disease database. Next, we analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of those significant genes in breast cancer and FLD using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). We found that overlapping KEGG pathways in these two diseases were MAPK signaling pathway, Forkhead box O (FoxO) signaling pathway, HIF-1 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and PI3K-Akt signaling pathway. Furthermore, the KEGG Mapper showed that the MAPK signaling pathway was related to the FoxO signaling pathway. Finally, the functional relevance of breast cancer and TAM-induced FLD was validated by Western blot analysis. We verified that TAM may induce fatty liver in breast cancer through the MAPK8/FoxO signaling pathway. CONCLUSION: Bioinformatics analysis combined with conventional experiments may improve our understanding of the molecular mechanisms underlying side effects of cancer drugs, thereby making this method a new paradigm for guiding future studies on this issue.

Long Non-coding RNA SNHG17 Promotes Cell Proliferation and Invasion in Castration-Resistant Prostate Cancer by Targeting the miR-144/CD51 Axis.

Previously, we found that the expression of long non-coding RNA (lncRNA) small nucleolar RNA host gene 17 (SNHG17) was up-regulated in castration-resistant prostate cancer (CRPC) cells compared to that in hormone sensitive prostate cancer (HSPC) cells. Moreover, we found that CD51 was up-regulated in prostate cancer cells and promoted the carcinogenesis and progression of prostate cancer. However, the regulatory mechanism of SNHG17 and CD51 in the development of CRPC remains unclear. In the current study, we aimed to elucidate the expressions, functions, and underlying mechanism of SNHG17 and CD51 in CRPC. Our results further confirmed that both SNHG17 and CD51 were up-regulated in CRPC tissues and cells. In addition, we found that SNHG17 expression was positively correlated with CD51 expression in prostate cancer. Mechanically, SNHG17 functioned as a competing endogenous RNA (ceRNA) to up-regulate CD51 expression through competitively sponging microRNA-144 (miR-144), and CD51 was identified as a direct downstream target of miR-144 in CRPC. Functionally, down-regulation of SNHG17 or up-regulation of miR-144 inhibited the proliferation, migration, and invasion of CRPC cells, whereas up-regulation of SNHG17 and down-regulation of miR-144 promoted the proliferation, migration and invasion of CRPC cells in vitro and in vivo. Using gain and loss-of function assay and rescue assay, we showed that miR-144 inhibited cell proliferation, migration and invasion by directly inhibiting CD51 expression, and SNHG17 promoted cell proliferation, migration and invasion by directly enhancing CD51 expression in CRPC cells. Taken together, our study reveals the role of the SNHG17/miR-144/CD51 axis in accelerating CRPC cell proliferation and invasion, and suggests that SNHG17 may serve as a novel therapeutic target for CRPC.

Integrating Genome-Wide Association Studies and Gene Expression Profiles With Chemical-Genes Interaction Networks to Identify Chemicals Associated With Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate in global cancer. Exploring the associations between chemicals and CRC has great significance in prophylaxis and therapy of tumor diseases. This study aims to explore the relationships between CRC and environmental chemicals on genetic basis by bioinformatics analysis. The genome-wide association study (GWAS) datasets for CRC were obtained from the UK Biobank. The GWAS data for colon cancer (category C18) includes 2,581 individuals and 449,683 controls, while that of rectal cancer (category C20) includes 1,244 individuals and 451,020 controls. In addition, we derived CRC gene expression datasets from the NCBI-GEO (GSE106582). The chemicals related gene sets were acquired from the comparative toxicogenomics database (CTD). Transcriptome-wide association study (TWAS) analysis was applied to CRC GWAS summary data and calculated the expression association testing statistics by FUSION software. We performed chemicals related gene set enrichment analysis (GSEA) by integrating GWAS summary data, mRNA expression profiles of CRC and the CTD chemical-gene interaction networks to identify relationships between chemicals and genes of CRC. We observed several significant correlations between chemicals and CRC. Meanwhile, we also detected 5 common chemicals between colon and rectal cancer, including methylnitronitrosoguanidine, isoniazid, PD 0325901, sulindac sulfide, and importazole. Our study performed TWAS and GSEA analysis, linked prior knowledge to newly generated data and thereby helped identifying chemicals related to tumor genes, which provides new clues for revealing the associations between environmental chemicals and cancer.

SPOP regulates the DNA damage response and lung adenocarcinoma cell response to radiation.

Speckle-type POZ protein (SPOP) plays an important role in maintaining genome stability. Disability or mutation of the SPOP gene has been reported to contribute to prostate cancer incidence and prognosis. However, the functions of SPOP in lung cancer remain poorly understood, especially in lung adenocarcinoma (LUAD). Here, we found that SPOP affects the LUAD cell response to radiation by regulating the DNA damage response (DDR) pathway. SPOP is widely expressed in lung cancer cell lines, and SPOP protein levels are upregulated when cells experience DNA damage. SPOP knockdown affects DDR repair kinetics, apoptosis and cell cycle checkpoints that are induced by IR (ionizing radiation). Furthermore, we found that SPOP positively regulates the expression of DDR factors Rad51 and Ku80. Taken together, these data indicate the essential roles of SPOP in the DDR signaling pathways and LUAD cell response to radiation.

Identification of a Five-CpG Signature with Diagnostic Value in Thyroid Cancer.

Thyroid cancer (TC) ranks as the most common endocrine malignancy, and its incidence and mortality rates continue to rise annually. Increasing evidence have shown that DNA methylation, a kind of stable epigenetic modification, is associated with carcinogenesis, suggesting its potential as biomarkers for the early detection of tumors. With the aim of exploring likely DNA methylation biomarkers for TC diagnosis, we conducted a synthetic analysis of DNA methylation profiles based on 789 samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In the discovery phase, we identified five CpG probes (cg11228682, cg01291854, cg06778183, cg01668008, and cg01702055) on the condition of DNA methylation data from GSE86961 (n = 82) and constructed a five-CpG signature-based diagnostic model for TC. In addition, we validated the diagnostic score formula in two independent training cohorts, GSE97466 (n = 141) and TCGA (n = 566), as well as the previous developing cohort GSE86961. Receiver operating characteristic analysis revealed that the five-CpG signature had a good diagnostic performance to distinguish TC samples from benign samples. In conclusion, our findings suggest that the five-CpG signature could provide a novel biomarker with useful applications in TC diagnosis.

Tetrandrine induces apoptosis in human neuroblastoma through regulating the Hippo/YAP signaling pathway.

Tetrandrine (TET), a bis-benzylisoquinoline alkaloid, shows cytotoxicity against several different types of tumors. However, the mechanism by which TET exerts its anti-cancer capabilities remains unclear. In this study, we confirmed that TET inhibits proliferation and induces apoptosis in neuroblastoma (NB) in vitro and in vivo. Moreover, we revealed that the anti-cancer ability of TET is associated with a decreased expression of anti-apoptotic Bcl-2. Importantly, we demonstrated that the Hippo/YAP pathway is involved in down-regulating of Bcl-2. Notably, YAP overexpression promoted proliferation and suppressed apoptosis, even partially reversed TET-induced effects in NB cells. Our findings support the prospect that TET could be a potential therapeutic agent for NB, and suggest that targeting the Hippo/YAP pathway may represent a valuable approach to NB treatment.

Propranolol selectively inhibits cervical cancer cell growth by suppressing the cGMP/PKG pathway.

AIM: To observe the effect of propranolol in cervical cancer and investigate the mechanism of the effect． METHODS AND RESULTS: We found 5 direct protein targets (DPTs) of propranolol (PRO) by DrugBank5.0 firstly. Next, we analyzed protein-protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of PRO DPTs and the result showed that PRO was linked with cGMP/PKG pathway. Then, we recognized the top 38 upexpressed genes of cervical cancer (CC) based original microarray datasets (GSE7803, GSE9750, GSE39001 and GSE63514). Further, we analyzed the biological process with the 38 overexpressed genes by STRING. We found some of overexpressed genes of CC participated in GMP biosynthetic process. Lastly, the function of PRO in CC was validated by MTT assay, Western blotting, flow cytometry and colony formation assay methods. We verified PRO can suppress cGMP/PKG pathway then inhibits CC cell growth. CONCLUSION: The bioinformatical analysis combine with traditional experiment can help us understanding potential molecular mechanism about how PRO acting in CC. This method is a new paradigm which can guide future researches about mechanism in existing diseases and drugs.

Integrated Bioinformatics Analysis for Identificating the Therapeutic Targets of Aspirin in Small Cell Lung Cancer.

PURPOSE: We explored the mechanism of aspirin in SCLC by dissecting many publicly available databases. METHODS AND RESULTS: Firstly, 11 direct protein targets (DPTs) of aspirin were identified by DrugBank 5.0. Then protein-protein interaction (PPI) network and signaling pathways of aspirin DPTs were analyzed. We found that aspirin was linked with many kinds of cancer, and the most significant one is SCLC. Next, we classified the mutation of 4 aspirin DPTs in SCLC (IKBKB, NFKBIA, PTGS2 and TP53) using cBio Portal. Further, we identified top 50 overexpressed genes of SCLC by Oncomine, and the interconnected genes with the 4 aspirin DPTs in SCLC (IKBKB, NFKBIA, PTGS2 and TP53) by STRING. Lastly, we figured out 5 consistently genes as potential therapeutic targets of aspirin in SCLC. CONCLUSION: The integrated bioinformatical analysis could improve our understanding of the underlying molecular mechanism about how aspirin working in SCLC. Integrated bioinformatical analysis may be considered as a new paradigm for guiding future studies about interaction in drugs and diseases.

Transcriptome-wide association study identifies multiple genes and pathways associated with pancreatic cancer.

AIM: To identify novel candidate genes for pancreatic cancer. METHODS: We performed a transcriptome-wide association study (TWAS) analysis of pancreatic cancer (PC). GWAS summary data were driven from the published studies of PC, totally involving 558 542 SNPs in 1896 individuals with pancreatic cancer and 1939 healthy controls. FUSION software was applied to the PC GWAS summary data for tissue-related TWAS analysis, including whole blood, peripheral blood, adipose, and pancreas. The functional relevance of identified genes with PC was further validated by Oncomine, STRING, and CluePedia tool. RESULTS: Transcriptome-wide association study analysis identified 19 genes significantly associated with PC, such as LRP5L (P value = 5.21 × 10-5 ), SOX4 (P value = 3.2 × 10-4 ), and EGLN3 (P value = 6.2 × 10-3 ). KEGG pathway enrichment analysis detected several PC-associated pathways, such as One carbon pool by folate (P value = 1.60 × 10-16 ), Cell cycle (P value = 1.27 × 10-7 ), TGF-beta signaling pathway (P value = 4.64 × 10-6 ). Further comparing the 19 genes with previously identified overexpressed genes in PC patients found one overlapped gene SOX4. CONCLUSION: We identified some novel candidate genes and pathways associated with PC. Our results provide novel clues for the genetic mechanism studies of pancreatic cancer.