A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer

Long noncoding RNA (lncRNA) profiles in ovarian cancer (OC) remain largely unknown. In the present study, we screened {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 as a new candidate lncRNA which promotes development of OC, in two independent datasets ({"type":"entrez-geo","attrs":{"text":"GSE18521","term_id":"18521"}}GSE18521 and {"type":"entrez-geo","attrs":{"text":"GSE38666","term_id":"38666"}}GSE38666) from the Gene Expression Omnibus (GEO). The level of {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 was then detected in 75 paired OC tissues and adjacent normal tissues by qRT-PCR. Results showed that {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 expression was significantly up-regulated in 85.3% (64/75) cancerous tissues compared with normal counterparts (P < 0.01). Further, the 5-year overall survival (OS) in OC patients with high expression of {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 was inferior to that with low expression (17.2 months vs 30.0 months, P = 0.0025). To investigate the functional role of {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614, {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 siRNA was transfected into OC cell lines. Knockdown of {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 expression significantly inhibited cell proliferation and invasion, resulted in cell arrest in G₁ phase of cell cycle and a dramatic increase of apoptosis, both in HO-8910 and OVCAR3 cells. In vivo experiment also revealed that knockdown {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 inhibited OVCAR3 cells proliferation. Finally, western blot assays indicated that lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 may exert its function by targeting ERK1/2 and AKT-mediated signaling pathway. In conclusion, our study suggests that lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AB073614","term_id":"51555790","term_text":"AB073614"}}AB073614 acts as a functional oncogene in OC development.     

Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells

BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-x_L, or MCL-1 (i.e. ABT-199, A-1331852, {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/{"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-x_L, promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/{"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/{"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/{"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/{"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS.     

Hypoxia-Inducible lncRNA-AK058003 Promotes Gastric Cancer Metastasis by Targeting γ-Synuclein

Hypoxia has been implicated as a crucial microenvironmental factor that induces cancer metastasis. We previously reported that hypoxia could promote gastric cancer (GC) metastasis, but the underlying mechanisms are not clear. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of carcinogenesis that act on multiple pathways. However, whether lncRNAs are involved in hypoxia-induced GC metastasis remains unknown. In this study, we investigated the differentially expressed lncRNAs resulting from hypoxia-induced GC and normoxia conditions using microarrays and validated our results through real-time quantitative polymerase chain reaction. We found an lncRNA, {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003, that is upregulated by hypoxia. {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 is frequently upregulated in GC samples and promotes GC migration and invasion in vivo and in vitro. Furthermore, {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 can mediate the metastasis of hypoxia-induced GC cells. Next, we identified γ-synuclein (SNCG), which is a metastasis-related gene regulated by {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003. In addition, we found that the expression of SNCG is positively correlated with that of {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 in the clinical GC samples used in our study. Furthermore, we found that the SNCG gene CpG island methylation was significantly increased in GC cells depleted of {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003. Intriguingly, SNCG expression is also increased by hypoxia, and SNCG upregulation by {"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 mediates hypoxia-induced GC cell metastasis. These results advance our understanding of the role of lncRNA-{"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003 as a regulator of hypoxia signaling, and this newly identified hypoxia/lncRNA-{"type":"entrez-nucleotide","attrs":{"text":"AK058003","term_id":"16554001","term_text":"AK058003"}}AK058003/SNCG pathway may help in the development of new therapeutics.     

Expression characteristics of long non-coding RNA in colon adenocarcinoma and its potential value for judging the survival and prognosis of patients: bioinformatics analysis based on The Cancer Genome Atlas database

BackgroundTo investigate the expression characteristics of long non-coding RNA (lncRNA) in colon adenocarcinoma (COAD) and its potential value in predicting the prognosis of patient survival.MethodsWe downloaded COAD-related RNA sequencing (RNA-seq) data and patient survival data from The Cancer Genome Atlas (TCGA). The data were analyzed for lncRNA expression differences, subjected to Cox regression analysis for survival rate, and Kaplan-Meier (KM) survival curves were plotted to analyze the role of the key genes related to prognostic survival by pathway enrichment analysis.ResultsThe data of 494 COAD clinical samples from TCGA were analyzed; 204 lncRNAs were differentially expressed, 156 were up-regulated, and 48 were down-regulated. The 10 genes with the most significant expression differences were Linc02418, Blacat1, ELFN1-AS1, CRNDE, {"type":"entrez-nucleotide","attrs":{"text":"AC002384.1","term_id":"2275183","term_text":"AC002384.1"}}AC002384.1, {"type":"entrez-nucleotide","attrs":{"text":"AL353801.1","term_id":"7635432","term_text":"AL353801.1"}}AL353801.1, LINC01645, {"type":"entrez-nucleotide","attrs":{"text":"AC073283.2","term_id":"8571848","term_text":"AC073283.2"}}AC073283.2, {"type":"entrez-nucleotide","attrs":{"text":"AC087379.1","term_id":"11994025","term_text":"AC087379.1"}}AC087379.1, and LINC00484. Cox regression analysis of 204 lncRNA genes showed that 23 lncRNA genes with significant effects on the prognosis and survival rate of COAD patients were obtained when P<0.05 was used as the threshold. With P≤0.001 as the threshold, the KM curves of 4 genes (Linc02257, Linc02474, {"type":"entrez-nucleotide","attrs":{"text":"Ac010789.1","term_id":"5917964","term_text":"AC010789.1"}}Ac010789.1, {"type":"entrez-nucleotide","attrs":{"text":"Ac083967.1","term_id":"10717234","term_text":"AC083967.1"}}Ac083967.1) were statistically significant (P<0.05). The gene Linc02257 was selected for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and it was revealed that the inheritance of Linc02257-regulated gene expression was closely related to tumor development, such as collagen-containing extracellular matrix, organogenesis, activity of membrane protein receptors, and ion channel activity. The signaling pathways regulated by Linc02257 were also closely related to tumors, such as neuroactive ligand-receptor interaction, the PI3K-AKT signaling pathway, calcium signaling pathway, and protein digestion and absorption.ConclusionsIn COAD, lncRNA is differentially expressed and plays an important role in the disease regulation. It has potential application value in the diagnosis, targeted therapy, and prognosis of COAD patients.     

A four-long non-coding RNA signature in predicting breast cancer survival

Background

Many long non-coding RNAs(lncRNAs) have been found to be a good marker for several tumors. Using lncRNA-mining approach, we aimed to identify lncRNA expression signature that can predict breast cancer patient survival.

Methods

We performed LncRNA expression profiling in 887 breast cancer patients from Gene Expression Omnibus (GEO) datasets. The association between lncRNA signature and clinical survival was analyzed using the training set(n = 327, from GSE 20685). The validation for the association was performed in another three independent testing sets(252 from {"type":"entrez-geo","attrs":{"text":"GSE21653","term_id":"21653"}}GSE21653, 204 from {"type":"entrez-geo","attrs":{"text":"GSE12276","term_id":"12276"}}GSE12276, and 104 from {"type":"entrez-geo","attrs":{"text":"GSE42568","term_id":"42568"}}GSE42568).

Results

A set of four lncRNA genes ({"type":"entrez-nucleotide","attrs":{"text":"U79277","term_id":"1710245","term_text":"U79277"}}U79277, {"type":"entrez-nucleotide","attrs":{"text":"AK024118","term_id":"10436421","term_text":"AK024118"}}AK024118, {"type":"entrez-nucleotide","attrs":{"text":"BC040204","term_id":"25955567","term_text":"BC040204"}}BC040204, {"type":"entrez-nucleotide","attrs":{"text":"AK000974","term_id":"7021969","term_text":"AK000974"}}AK000974) have been identified by the random survival forest algorithm. Using a risk score based on the expression signature of these lncRNAs, we separated the patients into low-risk and high-risk groups with significantly different survival times in the training set. This signature was validated in the other three cohorts. Further study revealed that the four-lncRNA expression signature was independent of age and subtype. Gene Set Enrichment Analysis (GSEA) suggested that gene sets were involved in several cancer metastasis related pathways.

Conclusions

These findings indicate that lncRNAs may be implicated in breast cancer pathogenesis. The four-lncRNA signature may have clinical implications in the selection of high-risk patients for adjuvant therapy.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-014-0084-7) contains supplementary material, which is available to authorized users.     

Inhibition of CXCR4–CXCL12 chemotaxis in melanoma by AMD11070

Background:

Despite intensive research and novel adjuvant therapies, there is currently no cure for metastatic melanoma. The chemokine receptor CXCR4 controls metastasis to sites such as the liver; however, the therapeutic blockade with the existing agents has proven difficult.

Methods:

{"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070, a novel orally bioavailable inhibitor of CXCR4, was tested for its ability to inhibit the migration of melanoma cells compared with the commonly described antagonist AMD3100.

Results:

{"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070 abrogated melanoma cell migration and was significantly more effective than AMD3100. Importantly for the clinical context, the expression of B-RAF-V600E did not the affect the sensitivity of {"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070.

Conclusion:

Liver-resident myofibroblasts excrete CXCL12, which is able to promote the migration of CXCR4-expressing tumour cells from the blood into the liver. Blockade of this axis by {"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070 thus represents a novel therapeutic strategy for both B-RAF wild-type and mutated melanomas.     

Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells

Background

Chemoresistance is a serious problem in pancreatic cancer, but the mechanism of resistance and strategies against the resistance have not been elucidated. We examined the potential of the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 to enhance the anti-tumor effect of cisplatin and investigated the mechanism of chemoresistance in pancreatic cancer cells using a combination therapy of cisplatin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, both in vitro and in vivo.

Methods

Cisplatin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, individually or in combination, were given to AsPC-1 and PANC-1 cell lines. Tumor growth, DNA fragments, and Akt phosphorylation were examined in vitro. To examine the therapeutic effect of cisplatin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, individually or combination an AsPC-1 tumor xenograft model was prepared for in vivo study.

Results

Cisplatin induced growth inhibition and Akt phosphorylation in pancreatic cancer cells. {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 also inhibited cell proliferation but without showing Akt phosphorylation. However, the combination therapy markedly increased cleavage of caspase-3 and cytoplasmic histone-associated DNA fragments compared to the results with cisplatin alone. In the in vivo study, blocking the PI3K/Akt cascade with {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 increased the efficacy of cisplatin-induced inhibition of tumor growth in nude mice, suppressing half the tumor growth with cisplatin alone. There were no detectable side effects in mice treated with combination therapy.

Conclusion

Our studies suggest that the PI3K/Akt pathway plays an important role in cisplatin resistance of pancreatic cancer cells. The augmentation of cisplatin with PI3K/Akt inhibitor may resolve the chemoresistance problem of cisplatin, and this might be a plausible strategy for achieving tolerance for chemotherapeutic agents in pancreatic cancer therapy.     

Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo

Background

To evaluate whether PI3K/Akt pathway could effect on apoptosis and its mechanism in nasopharyngeal carcinoma cells.

Methods

The activation of the PI3K/Akt and its effect on CNE-2Z cells in vivo and in vitro was investigated by MTT assay, flow cytometry, western blot, ELISA, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays (TUNEL), and immunohistochemical analyses, using PI3K inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002.

Results

The results showed that {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 inhibited the phosphorylating of Akt (S473), cell proliferation, and induced apoptosis in CNE-2Z cells. However, our experiment results also demonstrated that apoptosis-induced {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 was directly regulated by caspase-9 activation pathway.

Conclusion

These data suggested that PI3K inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, induced apoptosis by caspase-9 activation pathway and might be as a potentially useful target for therapeutic intervention in nasopharyngeal carcinoma patients.     

A long non-coding RNA signature to improve prognosis prediction of colorectal cancer

Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including {"type":"entrez-geo","attrs":{"text":"GSE39582","term_id":"39582"}}GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series {"type":"entrez-geo","attrs":{"text":"GSE14333","term_id":"14333"}}GSE14333 (N=197) and {"type":"entrez-geo","attrs":{"text":"GSE17536","term_id":"17536"}}GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, {"type":"entrez-nucleotide","attrs":{"text":"AK123657","term_id":"34529258"}}AK123657, {"type":"entrez-nucleotide","attrs":{"text":"BX648207","term_id":"34367366"}}BX648207 and {"type":"entrez-nucleotide","attrs":{"text":"BX649059","term_id":"34368231"}}BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC.     

Ligand-activated PPARδ modulates the migration and invasion of melanoma cells by regulating Snail expression

Peroxisome proliferator-activated receptor (PPAR) δ is implicated in the carcinogenesis of several types of cancer. However, the therapeutic efficacy of PPARδ ligands against cancer progression is unclear. Here, we showed that PPARδ modulates the migration and invasion of melanoma cells by up-regulating Snail expression. Activation of PPARδ by {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516, a specific ligand for PPARδ, significantly increased the migration and invasion of highly metastatic A375SM cells, but not that of low metastatic A375P cells. The migration- and invasion-promoting effects of PPARδ on A375SM cells was associated with increased Snail expression, which was accompanied by a decrease in E-cadherin expression. Furthermore, a significant concentration- and time-dependent increase in the levels of Snail mRNA and protein was observed in A375SM cells (but not A375P cells) treated with {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516. The effects of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 were almost completely abrogated by a small interfering RNA against PPARδ, suggesting that PPARδ mediates the effects of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516. Activation of PPARδ in SK-MEL-2 and SK-MEL-5 (but not SK-MEL-3) melanoma cell lines also led to significant increases in the expression of Snail mRNA and protein, which mirrored the invasive and migratory potential of these cell lines. These results suggest that PPARδ promotes the aggressive phenotype observed in highly metastatic melanoma cells by up-regulating Snail.     

Low intratumoral genetic neutrophil-to-lymphocyte ratio (NLR) is associated with favorable tumor immune microenvironment and with survival in triple negative breast cancer (TNBC)

Patients with triple negative breast cancer (TNBC) have a poor prognosis. A novel prognostic biomarker may guide management by appropriately selecting patients for particular treatments. Peripheral blood neutrophil-to-lymphocyte ratio (NLR) was reported to associate with cancer progression, thus we hypothesized that intratumor genetic NLR will reflect tumor immune microenvironment (TIME) and breast cancer biology. The intratumoral genetic NLR previously defined as the ratio of CD66b (CEACAM8) and CD8 (CD8A) gene expressions was utilized to analyze total of 2,994 patients from METABRIC, TCGA, {"type":"entrez-geo","attrs":{"text":"GSE21094","term_id":"21094"}}GSE21094, {"type":"entrez-geo","attrs":{"text":"GSE22358","term_id":"22358"}}GSE22358, {"type":"entrez-geo","attrs":{"text":"GSE25088","term_id":"25088"}}GSE25088, {"type":"entrez-geo","attrs":{"text":"GSE32646","term_id":"32646"}}GSE32646, and {"type":"entrez-geo","attrs":{"text":"GSE2603","term_id":"2603"}}GSE2603 cohorts. Intratumoral genetic NLR did not correlate with cancer stage nor clinical parameters of cancer cell proliferation such as Nottingham histological grade or MKI67 expression levels in neither the METABRIC or TCGA cohorts. Intratumoral genetic NLR-high breast cancer was not associated with pathologic complete response (pCR) after neoadjuvant chemotherapy in 5 independent cohorts with different regimens. Despite these results, intratumoral genetic NLR-high TNBC demonstrated worse disease-free, disease-specific, and overall survival. Intratumoral genetic NLR-low TNBC enriched multiple immune-related gene sets, was associated with higher favorable immune-related scores and with a favorable TIME, whereas no gene sets enriched to NLR-high TNBC. In conclusion, intratumoral genetic NLR-low TNBC was associated with favorable TIME and with better survival.     

A novel five-gene score to predict complete pathological response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer

Neoadjuvant Chemotherapy (NAC) is not frequently used in ER-positive/HER2-negative breast cancer (BC) because around 10% patients achieve pathological complete response (pCR). Since NAC can result in cancer downstaging both in the breast and axilla and prevent a morbid surgery, thus a score to predict pCR in this population will be crucial to identify patients who can benefit from this approach. A total of 4038 patients from cohorts; {"type":"entrez-geo","attrs":{"text":"GSE25066","term_id":"25066"}}GSE25066, {"type":"entrez-geo","attrs":{"text":"GSE20194","term_id":"20194"}}GSE20194, Hess, {"type":"entrez-geo","attrs":{"text":"GSE20181","term_id":"20181"}}GSE20181, TCGA-BRCA and METBRIC were analyzed. The score was generated by the 5 most highly expressed genes in the Hallmark E2F targets gene set amongst patients in the {"type":"entrez-geo","attrs":{"text":"GSE25066","term_id":"25066"}}GSE25066 cohort with ER-positive/HER2-negative BC who achieved pCR. The area under the curve was significantly higher in the score than that for the E2F targets score. High score ER-positive/HER2-negative BCs were significantly associated with higher Nottingham pathological grade, AJCC cancer stage, MKI67 expression levels, intratumor heterogeneity, homologous recombination defects, mutation burden, neoantigen load, and infiltration of anti-cancer immune cells (CD4⁺, T helper type1, plasmacytoid dendritic cells, M1 macrophages). They also expressed lower abundance of stromal cells including fibroblasts, lymphatic endothelial cells, pericytes and adipocytes consistently in {"type":"entrez-geo","attrs":{"text":"GSE25066","term_id":"25066"}}GSE25066, TCGA and METABRIC cohorts. All cell proliferation-related gene sets, G2M checkpoint, E2F targets, MYC targets v1 and v2, Mitotic Spindle, were strongly enriched in high score BCs consistently in 3 cohorts. The gene score was significantly associated with high pCR rate consistently in the {"type":"entrez-geo","attrs":{"text":"GSE25066","term_id":"25066"}}GSE25066 (38%, P < 0.001), {"type":"entrez-geo","attrs":{"text":"GSE20194","term_id":"20194"}}GSE20194 (16%, P = 0.006), and Hess cohort (23%, P = 0.037). In conclusion, the 5-gene score reflects cancer cell proliferation and immune cell infiltration, and predicts pCR after NAC in ER-positive/HER2-negative breast cancer.     

Comprehensive bioinformatics analysis of functional molecules in colorectal cancer

BackgroundColorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of cancer-related death. Numerous studies have found that aberrations in cellular molecules play an important role in the development of tumors. Studying and determining the interactions between these molecules can contribute to the diagnosis, treatment, and prognosis of tumors.MethodsThe {"type":"entrez-geo","attrs":{"text":"GSE151021","term_id":"151021"}}GSE151021, {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720, and {"type":"entrez-geo","attrs":{"text":"GSE156719","term_id":"156719"}}GSE156719 data sets were analyzed to screen the differentially expressed messenger RNAs (DEmRNAs), long non-coding RNAs (DElncRNAs), and microRNAs (DEmiRNAs) in CRC. Database for Annotation, Visualization and Integrated Discovery (DAVID) and the Search Tool for the Retrieval of Interacting Genes/Proteins software were used to examine gene enrichment and the hub genes. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN was used to verify the expression of the hub genes. To analyze the overall survival (OS) of the hub genes, Kaplan-Meier plotter (KM plotter) was performed. Finally, the miRCancer database, TargetScan, and {"type":"entrez-geo","attrs":{"text":"GSE156719","term_id":"156719"}}GSE156719 were used to identify the targets of the identified miRNAs. To predict the lncRNA-miRNA interactions, we used DIANA-LncBase v2 and {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720. Finally, the visualization protein‑protein interaction (PPI), competitive endogenous RNA (ceRNA) network was constructed using Cytoscape v3.1.ResultsBy analyzing {"type":"entrez-geo","attrs":{"text":"GSE151021","term_id":"151021"}}GSE151021 and {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720, 23 upregulated mRNAs and 10 downregulated mRNAs were identified as sharing the differentially expressed genes (DEGs) between CRC and adjacent tissues. Furthermore, nucleolar protein 14 (NOP14), the sonic hedgehog (SHH) signaling molecule, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), the BCL2 apoptosis regulator (BCL2), and zinc finger E-box binding homeobox 2 (ZEB2) were considered hub genes. The constructed lncRNA-miRNA-mRNA network revealed 7 intersecting miRNAs (4 upregulated and 3 downregulated), 79 lncRNAs (40 upregulated and 39 downregulated), and 5 mRNAs (3 upregulated and 2 downregulated). Finally, we determined that the dysregulation of lncRNAs, such as HCG16, CASC9, SNHG16, HAND2-AS1, and NR2F1-AS1, secluded altered the expression of several miRNAs, such as hsa-miR-193a-5p, hsa-miR-485-5p, hsa-miR-17-5p, and hsa-miR-92a-3p, and affected the occurrence and development of CRC.ConclusionsWe identified a series of DElncRNAs, DEmRNAs, and DEmiRNAs in CRC that might be considered potential biomarkers in understanding the complex molecular pathways leading to CRC development.     

Analyzing large scale gene expression data in colorectal cancer reveals important clues; CLCA1 and SELENBP1 downregulated in CRC not in normal and not in adenoma

Early detection of colorectal cancer (CRC) increases the chances of survival and reduces the therapeutic problems and costs of treatment. Since molecular biomarkers can help us diagnose colorectal cancer early, we need to identify novel gene for predicting the early stages of tumorigenesis. Here, we integrated five independent CRC gene expression datasets derived from expression profiling by array comparing CRC with normal samples in: {"type":"entrez-geo","attrs":{"text":"GSE21510","term_id":"21510"}}GSE21510, {"type":"entrez-geo","attrs":{"text":"GSE4107","term_id":"4107"}}GSE4107, {"type":"entrez-geo","attrs":{"text":"GSE25071","term_id":"25071"}}GSE25071, {"type":"entrez-geo","attrs":{"text":"GSE15781","term_id":"15781"}}GSE15781 dataset, and {"type":"entrez-geo","attrs":{"text":"GSE8671","term_id":"8671"}}GSE8671 dataset, including 64 samples from 32 patients comparing 32 colonic normal mucosa with 32 colorectal adenoma. To detect genes that expressed differentially in experimental circumstances of these datasets, we used web tool of GEO2R to compare groups of samples in the GEO data series. Furthermore, we constructed the protein-protein interactions network by STRING database for mostly downregulated genes and the expression of their members in PPI network were studied into five datasets separately. Also, the level of expression of selected biomarker genes in different stages of CRC compared to normal was studied. Our data revealed 17 common downregulated genes (average fold change (FC) in five tests ≥6) in CRC in comparison with normal (Test 1 to Test 4) and in adenoma compared with normal (Test 5). Studying of gene expression of PPI network members of these downregulated genes led to identifying of CLCA1, SELENBP1, CWC25, ACOT11, GUCY2C and ALDH1A1 as suppressor genes and PTGS2, PROCR, MOCS3 and NFS1 as oncogenes which respectively downregulated and upregulated in CRC. Since decreasing of gene expression was seen in CRC comparing with normal and due to no different expression seen for these 10 genes in adenoma, they, especially CLCA1 and SELENBP1, could be considered as biomarkers for early detection of CRC. Before using these signature genes in the clinic; however, further validations are required.