Factor In Human Cancer Research Articles

Chem-CRISPR/dCas9FCPF: a platform for chemically induced epigenome editing.

Epigenetic aberration is one of the major driving factors in human cancer, often leading to acquired resistance to chemotherapies. Various small molecule epigenetic modulators have been reported. Nonetheless, outcomes from animal models and clinical trials have underscored the substantial setbacks attributed to pronounced on- and off-target toxicities. To address these challenges, CRISPR/dCas9 technology is emerging as a potent tool for precise modulation of epigenetic mechanism. However, this technology involves co-expressing exogenous epigenetic modulator proteins, which presents technical challenges in preparation and delivery with potential undesirable side effects. Recently, our research demonstrated that Cas9 tagged with the Phe-Cys-Pro-Phe (FCPF)-peptide motif can be specifically targeted by perfluorobiphenyl (PFB) derivatives. Here, we integrated the FCPF-tag into dCas9 and established a chemically inducible platform for epigenome editing, called Chem-CRISPR/dCas9FCPF. We designed a series of chemical inhibitor-PFB conjugates targeting various epigenetic modulator proteins. Focusing on JQ1, a panBET inhibitor, we demonstrate that c-MYC-sgRNA-guided JQ1-PFB specifically inhibits BRD4 in close proximity to the c-MYC promoter/enhancer, thereby effectively repressing the intricate transcription networks orchestrated by c-MYC as compared with JQ1 alone. In conclusion, our Chem-CRISPR/dCas9FCPF platform significantly increased target specificity of chemical epigenetic inhibitors, offering a viable alternative to conventional fusion protein systems for epigenome editing.

RUNX2 as a Prognostic Factor in Human Cancers.

The RUNX2 transcription factor was discovered as an essential transcriptional regulator for commitment to osteoblast lineage cells and bone formation. Expression of RUNX2 in other tissues, such as breast, prostate, and lung, has been linked to oncogenesis, cancer progression, and metastasis. In this study, we sought to determine the extent of RUNX2 involvement in other tumors using a pan-cancer analysis strategy. We correlated RUNX2 expression and clinical-pathological parameters in human cancers by interrogating publicly available multiparameter clinical data. Our analysis demonstrated that altered RUNX2 expression or function is associated with several cancer types from different tissues. We identified three tumor types associated with increased RUNX2 expression and four other tumor types associated with decreased RUNX2 expression. Our pan-cancer analysis for RUNX2 revealed numerous other discoveries for RUNX2 regulation of different cancers identified in each of the pan-cancer databases. Both up and down regulation of RUNX2 was observed during progression of specific types of cancers in promoting the distinct types of cancers.

Molecular characteristics and clinical implications of serine/arginine-rich splicing factors in human cancer.

As critical splicing regulators, serine/arginine-rich splicing factors (SRSFs) play pivotal roles in carcinogenesis. As dysregulation of SRSFs may confer potential cancer risks, targeting SRSFs could provide important insights into cancer therapy. However, a global and comprehensive pattern to elaborate the molecular characteristics, mechanisms, and clinical links of SRSFs in a wide variety of human cancer is still lacking. In this study, a systematic analysis was conducted to reveal the molecular characteristics and clinical implications of SRSFs covering more than 10000 tumour samples of 33 human cancer types. We found that SRSFs experienced prevalent genomic alterations and expression perturbations in multiple cancer types. The DNA methylation, m6A modification, and miRNA regulation of SRSFs were all cancer context-dependent. Importantly, we found that SRSFs were strongly associated with cancer immunity, and were capable of predicting response to immunotherapy. And SRSFs had colossal potential for predicting survival in multiple cancer types, including those that have received immunotherapy. Moreover, we also found that SRSFs could indicate the drug sensitivity of targeted therapy and chemotherapy. Our research highlights the significance of SRSFs in cancer occurrence and development, and provides sufficient resources for understanding the biological characteristics of SRSFs, offering a new and unique perspective for developing cancer therapeutic strategies.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.

Identification of the cell cycle characteristics of non-small cell lung cancer and its relationship with tumor immune microenvironment, cell death pathways, and metabolic reprogramming.

The genes related to the cell cycle progression could be considered the key factors in human cancers. However, the genes involved in cell cycle regulation in non-small cell lung cancer (NSCLC) have not yet been reported. Therefore, it is necessary to evaluate the genes related to the cell cycle in all types of cancers, especially NSCLC. This study constituted the first pan-cancer landscape of cell cycle signaling. Cluster analysis based on cell cycle signaling was conducted to identify the potential molecular heterogeneity of NSCLC. Further, the discrepancies in the tumor immune microenvironment, metabolic remodeling, and cell death among the three clusters were investigated. Immunohistochemistry was performed to validate the protein levels of the ZWINT gene and examine its relationship with the clinical characteristics. Bioinformatics analyses and experimental validation of the ZWINT gene were also conducted. First, pan-cancer analysis provided an overview of cell cycle signaling and highlighted its crucial role in cancer. A majority of cell cycle regulators play risk roles in lung adenocarcinoma (LUAD); however, some cell cycle genes play protective roles in lung squamous cell carcinoma (LUSC). Cluster analysis revealed three potential subtypes for patients with NSCLC. LUAD patients with high cell cycle activities were associated with worse prognosis; while, LUSC patients with high cell cycle activities were associated with a longer survival time. Moreover, the above three subtypes of NSCLC exhibited distinct immune microenvironments, metabolic remodeling, and cell death pathways. ZWINT, a member of the cell signaling pathway, was observed to be significantly associated with the prognosis of LUAD patients. A series of experiments verified the higher expression levels of ZWINT in NSCLC compared to those in paracancerous tissues. The activation of epithelial-mesenchymal transition (EMT) induced by ZWINT might be responsible for tumor progression. This study revealed the regulatory function of the cell cycle genes in NSCLC, and the molecular classification based on cell cycle-associated genes could evaluate the different prognoses of patients with NSCLC. ZWINT expression was found to be significantly upregulated in NSCLC tissues, which might promote tumor progression via activation of the EMT pathway.

Abstract 3623: Targetable cofactor landscape of transcription factors in human cancers

Abstract Transcription factors (TF) are proteins that bind to DNA to regulate target gene expression and play a crucial role in maintaining tumor initiating and maintenance programs. However, except for a small fraction, it is difficult to directly target TF proteins due to lack of defined pockets and inherent protein-DNA, protein-protein interactions. In many cases, TF activity is tuned via cofactors, which e.g. dimerize to bind DNA (MYC/MAX) or maintain active TF protein turnover (HIF1A/EGLN1, MYC/HDAC2). Identifying such targetable cofactors of TFs will open new opportunities to target oncogenic TFs in cancers. Genome-scale CRISPR knock-out screens have been proven to be a valuable resource for identifying targets and biomarkers in cancers. In this work, we developed a framework called CONTEXT (COfactor depeNdencies in high Transcription factor EXpression phenoType) utilizing functional genomic screens and matched TF expression data. In CONTEXT, we aim to identify cofactor dependencies associated with TF activities using 859 cell lines spanning 28 cancer types. We further utilized patient cancer gene expression data from the TCGA project, to prioritize clinically relevant TF-cofactor associations. In total, we identified 1,003 TF-cofactor associations which involve 196 and 503 unique TFs and cofactors, respectively. Our approach reliably identified previously known TF-cofactor associations e.g. HIF1A/EGLN1, HIF1A/VHL, TEAD1/JUN but also previously unknown associations such as TEAD1/RAC1 or TEAD1/PTK2. Our analysis and validations provide a framework for the identification of potential cofactors of TFs which are crucial for the development and progression of cancer. We anticipate the cofactor dependencies from this resource to guide early stage drug development and inform on potential combination therapies in resistant phenotypes. Citation Format: Venu Thatikonda, Jesse Lipp, Andreas Schlattl, Daniel Gerlach, Alexandra Popa. Targetable cofactor landscape of transcription factors in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3623.

Plasmacytoma variant translocation 1 stabilized by EIF4A3 promoted malignant biological behaviors of lung adenocarcinoma by generating circular RNA LMNB2

ABSTRACT Increasing evidence suggests that plasmacytoma variant translocation 1 (PVT1) plays a vital role in the development of multiple tumors including lung adenocarcinoma (LUAD). Eukaryotic initiation factor 4A-3 (EIF4A3) is considered a key factor in human cancers. However, the role and potential mechanism of PVT1 combined with EIF4A3 in LUAD remain unclear. This study investigated the effects and regulatory mechanisms of PVT1, EIF4A3, and circLMNB2 on the growth, migration, invasion, and epithelial-mesenchymal transition (EMT) of LUAD cells (H1299 and HCC827 cells) The expression level, diagnostic value and prognostic significance of PVT1, EIF4A3, and circLMNB2 were assessed, and enrichment analysis was performed using R package. Rescue experiments and a xenograft model were used to validate the PVT1/EIF4A3/circLMNB2 axis in LUAD. PVT1 and EIF4A3 were upregulated and indicated poor prognosis in LUAD. Knockdown of PVT1 and EIF4A3 suppressed LUAD cell proliferation, migration, invasion, and EMT. Mechanistically, PVT1 was stabilized by EIF4A3. PVT1 could recruit EIF4A3 to promote circLMNB2 expression. Rescue experiments indicated that circLMNB2 overexpression could reverse the reduced behavior caused by PVT1 or EIF4A3 knockdown. Enrichment analysis showed that PVT1/EIF4A3/circLMNB2 may regulate LUAD development by participating in ribosome biogenesis and spliceosome formation. Our findings demonstrate that PVT1/EIF4A3/circLMNB2 enhances the malignant behaviors of LUAD cells, providing a novel perspective for the clinical treatment of LUAD.

The Effectiveness of the Nimali Variety of Sri Lankan Punica granatum L. Fruit Extracts on Rhabdomyosarcoma (RD) Cells Concerning the Apoptotic Signaling Pathway.

Objective: Pomegranate ,a polyphenol-rich fruit, has been considered as one of the ancient fruits with anticancer effect. Cell cycle arrest is considered as an ordinary factor in human cancer, and apoptosis is the frequent drug target. This study aimed to evaluate the effectiveness of the Nimali variety of Sri Lankan Punica granatum L. fruit extracts on rhabdomyosarcoma (RD) cells concerning the apoptotic signaling pathway. Methods: Antiproliferative activity of aqueous extracts of pomegranate peel, pericarp, was assessed using multiple extraction methods (sonication, microwaving, sonication followed by microwaving, keeping in a waterbath, and boiling at 100ºC). Total protein content, nitric oxide production, LDH, and caspase-8 and caspase-3 activities were analyzed in peel extracts prepared by sonicated or microwave methods. RT-qPCR was performed with intact RNA to explore the apoptotic pathway and gene expression. Results:Peel extracts expressed minimum cell viability in a dose-dependent manner, induced cell death on RD cells. However, sonicated peel extract (SPL) indicated the lowest IC50 of 14.8±2.2 μg/mL comparative to healthy VERO cells (>1,000 μg/mL). A decrease of nitrite content in the supernatant was visualized in the graph plotted against concentration. Furthermore, SPL upregulated caspase-8 and caspase-3 signaling pathways and expression of p21 and p53 genes. Conclusion:The findings highlighted the promising therapeutic potential of SPL to inhibit RD growth and progression and to modulate the caspase-8 and caspase-3, p53, and p21 dependent pathway.

Systematic Pan-Cancer Analysis Reveals Molecular Characteristics and Clinical Relevance of Serine/Arginine-Rich Splicing Factors in Human Cancers

Systematic Pan-Cancer Analysis Reveals Molecular Characteristics and Clinical Relevance of Serine/Arginine-Rich Splicing Factors in Human Cancers

Aging Predisposes B cells to Malignancy by Activating c-Myc and Perturbing the Genome and Epigenome

Age is the single major risk factor for human cancer, but naturally occurring cancers are rarely studied in aging models. Like humans, mice spontaneously develop cancer with age, and standard laboratory strains are predisposed for B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells acquire somatic mutations in tumor suppressors and oncogenes (e.g. Trp53, Pim1, and Myh11) and undergo monoclonal expansions, with some clones representing 86% of splenic B cells. Clonal B cells had hypermethylated promoters and globally silenced expression, suggesting a role of DNA methylation in clonal selection of premalignant B cells. B-cell size, spleen weight, and a novel population of B cells, which we named Myc+ cells, emerged as convenient markers of malignancy. High-throughput analyses of clonal B cells and the use of genetic mouse models revealed that c-Myc drives B-cell size increase and clonal expansion with age. Phoshoproteome and co-culture experiments revealed that c-Myc is activated by signals from the aging microenvironment. Moreover, single-cell RNA-seq suggested that clonal B cells originate from age-associated B cells, further underlying the importance of aging environment in cancer transformation. Longitudinal analyses demonstrated a negative impact of premalignant B cells on mouse lifespan and linked it to age-related myeloid bias. Together, our study revealed cell-autonomous changes that cooperate with the aging microenvironment to give rise to preneoplastic B cells. This stidy established a novel model to study how aging predisposes cells to cancer transformation.

Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors.

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti‐tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein‐1 (VAP‐1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP‐1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP‐1‐specific inhibitor U‐V296 inhibited murine tumor growth by enhancing IFN‐γ‐producing tumor antigen‐specific CD8+ T cells. U‐V296 exhibited significant synergistic anti‐tumor effects with ICIs. In the TME of mice treated with U‐V296, the expression of genes associated with M2‐like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2O2, an enzymatic product of VAP‐1, which promoted the production of IL‐4 by mouse Th2 and inhibited IFN‐γ by mouse Th1 and human tumor‐infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP‐1 inhibitor. TCGA database analysis showed that VAP‐1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL‐4, IL4R, and IL‐13 expression and a negative correlation with IFN‐γ expression. These results indicated that VAP‐1 is involved in the immunosuppressive TMEs through H2O2‐associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.

Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression.

Enhancer of zeste homolog 2 (EZH2), an oncogene, is a commonly up‐regulated epigenetic factor in human cancer. Hepatocellular carcinoma deletion gene 1 (DLC1) is an antioncogene that is either expressed at low levels or not expressed in many malignant tumours. Curcumin is a promising anticancer drug that has antitumour effects in many tumours, but its mechanism of action is unclear. Our research demonstrated that EZH2 was up‐regulated in breast cancer (BC) tissues and cells, whereas DLC1 was down‐regulated, and the expression of EZH2 and DLC1 was negatively correlated in BC. By analysing the characteristics of clinical cases, we found that positive expression of EZH2 and negative expression of DLC1 may be predictors of poor prognosis in patients with triple‐negative breast cancer (TNBC). Moreover, knockdown of EZH2 expression restored the expression of DLC1 and inhibited the migration, invasion and proliferation, promoted the apoptosis, and blocked the cell cycle of MDA‐MB‐231 cells. Furthermore, we found that curcumin restored the expression of DLC1 by inhibiting EZH2; it also inhibited the migration, invasion and proliferation of MDA‐MB‐231 cells, promoted their apoptosis and blocked the cell cycle. Finally, xenograft tumour models were used to demonstrate that curcumin restored DLC1 expression by inhibiting EZH2 and also inhibited the growth and promoted the apoptosis of TNBC cells. In conclusion, our results suggest that curcumin can inhibit the migration, invasion and proliferation, promote the apoptosis, block the cycle of TNBC cells and restore the expression of DLC1 by inhibiting the expression of EZH2.

The expression landscape of cachexia-inducing factors in human cancers.

BackgroundCachexia is a multifactorial syndrome highly associated with specific tumour types, but the causes of variation in cachexia prevalence and severity are unknown. While circulating plasma mediators (soluble cachectic factors) derived from tumours have been implicated with the pathogenesis of the syndrome, these associations were generally based on plasma concentration rather than tissue‐specific gene expression levels. Here, we hypothesized that tumour gene expression profiling of cachexia‐inducing factors (CIFs) in human cancers with different prevalence of cachexia could reveal potential cancer‐specific cachexia mediators and biomarkers of clinical outcome.MethodsFirst, we combined uniformly processed RNA sequencing data from The Cancer Genome Atlas and Genotype‐Tissue Expression databases to characterize the expression profile of secretome genes in 12 cancer types (4651 samples) compared with their matched normal tissues (2737 samples). We systematically investigated the transcriptomic data to assess the tumour expression profile of 25 known CIFs and their predictive values for patient survival. We used the Xena Functional Genomics tool to analyse the gene expression of CIFs according to neoplastic cellularity in pancreatic adenocarcinoma, which is known to present the highest prevalence of cachexia.ResultsA comprehensive characterization of the expression profiling of secreted genes in different human cancers revealed pathways and mediators with a potential role in cachexia within the tumour microenvironment. Cytokine‐related and chemokine‐related pathways were enriched in tumour types frequently associated with the syndrome. CIFs presented a tumour‐specific expression profile, in which the number of upregulated genes was correlated with the cachexia prevalence (r 2: 0.80; P value: 0.002) and weight loss (r 2: 0.81; P value: 0.002). The distinct gene expression profile, according to tumour type, was significantly associated with prognosis (P value ≤ 1.96 E‐06). In pancreatic adenocarcinoma, the upregulated CIF genes were associated with tumours presenting low neoplastic cellularity and high leucocyte fraction and not with tumour grade.ConclusionsOur results present a biological dimension of tumour‐secreted elements that are potentially useful to explain why specific cancer types are more likely to develop cachexia. The tumour‐specific profile of CIFs may help the future development of better targeted therapies to treat cancer types highly associated with the syndrome.

Ubiquitin-conjugating enzyme E2T knockdown suppresses hepatocellular tumorigenesis via inducing cell cycle arrest and apoptosis.

BACKGROUNDHepatocellular carcinoma (HCC) is now the most common primary liver malignancy worldwide, and multiple risk factors attribute to the occurrence and development of HCC. Recently, increasing studies suggest that ubiquitin-conjugating enzyme E2T (UBE2T) serves as a promising prognostic factor in human cancers, although the molecular mechanism of UBE2T in HCC remains unclear.AIMTo investigate the clinical relevance and role of UBE2T in HCC development.METHODSUBE2T expression in HCC tissues from the TCGA database and its association with patient survival were analyzed. A lentivirus-mediated strategy was used to knock down UBE2T in HCC cells. qRT-PCR and Western blot assays were performed to check the effect of UBE2T silencing in HCC cells. Cell growth in vitro and in vivo was analyzed by multiparametric high-content screening and the xenograft tumorigenicity assay, respectively. Cell cycle distribution and apoptosis were determined by flow cytometry. The genes regulated by UBE2T were profiled by microarray assay.RESULTSUBE2T was overexpressed in HCC tissues compared with paired and non-paired normal tissues. High expression of UBE2T predicted a poor overall survival in HCC patients. In vitro, lentivirus-mediated UBE2T knockdown significantly reduced the viability of both SMMC-7721 and BEL-7404 cells. In vivo, the xenograft tumorigenesis of SMMC-7721 cells was largely attenuated by UBE2T silencing. The cell cycle was arrested at G1/S phase in SMMC-7721 and BEL-7404 cells with UBE2T knockdown. Furthermore, apoptosis was increased by UBE2T knockdown. At the molecular level, numerous genes were dysregulated after UBE2T silencing, including IL-1B, FOSL1, PTGS2, and BMP6.CONCLUSIONUBE2T plays an important role in cell cycle progression, apoptosis, and HCC development.

Long non-coding RNA XIST expression as a prognostic factor in human cancers: A meta-analysis.

A large number of literature has shown that high expression of X inactive-specific transcript (XIST) is associated with poor prognosis and metastasis of cancer in patients. However, most of this literature is limited by the small sample sizes and discrete outcomes. Therefore, a meta-analysis was performed to investigate the relation between XIST expression and tumor node metastasis (TNM) stage, lymph node metastasis, distant metastasis, and overall survival of cancer patients. We searched for literature in PubMed, Embase, and Web of Science. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association of XIST expression with prognosis and clinicopathological characteristics of cancer patients. Finally, a total of 14 articles involving 1123 patients were included in this meta-analysis. The results suggested that high expression of XIST has a significant relationship with a relatively poor overall survival for patients with malignant tumors (HR 1.82; 95% CI 1.32, 2.52; P = 0.0003). Moreover, high expression of XIST was significantly associated with poor TNM stage (OR 3.64; 95% CI 2.62, 5.07; P < 0.0001), lymph node metastasis (OR 2.39; 95% CI 1.65, 3.46; P < 0.0001) and distant metastasis (OR 2.84; 95% CI 1.90, 4.23; P < 0.0001). In conclusion, high expression of lncRNA XIST may be a predictive factor of poor prognosis in human cancers.

C-FLIP, a Novel Biomarker for Cancer Prognosis, Immunosuppression, Alzheimer's Disease, Chronic Obstructive Pulmonary Disease (COPD), and a Rationale Therapeutic Target.

Dysregulation of c-FLIP (cellular FADD-like IL-1β-converting enzyme inhibitory protein) has been shown in several diseases including cancer, Alzheimer’s disease, and chronic obstructive pulmonary disease (COPD). c-FLIP is a critical anti-cell death protein often overexpressed in tumors and hematological malignancies and its increased expression is often associated with a poor prognosis. c-FLIP frequently exists as long (c-FLIPL) and short (c-FLIPS) isoforms, regulates its anti-cell death functions through binding to FADD (FAS associated death domain protein), an adaptor protein known to activate caspases-8 and -10 and links c-FLIP to several cell death regulating complexes including the death-inducing signaling complex (DISC) formed by various death receptors. c-FLIP also plays a critical role in necroptosis and autophagy. Furthermore, c-FLIP is able to activate several pathways involved in cytoprotection, proliferation, and survival of cancer cells through various critical signaling proteins. Additionally, c-FLIP can inhibit cell death induced by several chemotherapeutics, anti-cancer small molecule inhibitors, and ionizing radiation. Moreover, c-FLIP plays major roles in aiding the survival of immunosuppressive tumor-promoting immune cells and functions in inflammation, Alzheimer’s disease (AD), and chronic obstructive pulmonary disease (COPD). Therefore, c-FLIP can serve as a versatile biomarker for cancer prognosis, a diagnostic marker for several diseases, and an effective therapeutic target. In this article, we review the functions of c-FLIP as an anti-apoptotic protein and negative prognostic factor in human cancers, and its roles in resistance to anticancer drugs, necroptosis and autophagy, immunosuppression, Alzheimer’s disease, and COPD.

Prognostic Role of Tenascin-C for Cancer Outcome: A Meta-Analysis.

Background:The prognostic value of tenascin-C in different types of cancers remains controversial. To clarify its prognostic value on overall survival rates, we have conducted a meta-analysis to quantitatively assess the prognostic roles of tenascin-C for patients with cancer.Methods:We systematically searched all published studies about the role of tenascin-C in cancers on PubMed, Web of Science, Cochrane Library, and Embase. The pooled hazard ratio with 95% confidence intervals was used to analyze the association between tenascin-C expression level and overall survival of patients with cancer. The pooled odds ratio with 95% confidence intervals was used to investigate the association between tenascin-C expression level and clinicopathologic features of patients with cancer. Trial sequential analysis was performed to obtain the required information size.Results:In this meta-analysis, 18 studies including 2732 patients were incorporated. The pooled hazard ratio of 18 trials was 1.73 (95% confidence interval: 1.29-2.32, P < .001) for overall survival, suggesting that elevated tenascin-C expression strongly predicted poor prognosis among patients with various cancers. Simultaneously, elevated tenascin-C expression was also significantly associated with lymph node metastasis (odds ratio = 2.42, 95% confidence interval: 1.79-3.26, P < .001). However, no significant correlation was observed between the tenascin-C expression and distant metastasis (odds ratio = 1.72, 95% confidence interval: 0.86-3.44, P = .127).Conclusions:Tenascin-C is considered as a promising unfavorable prognostic factor in human cancers. Likewise, tenascin-C can be used as a monitoring indicator for poor prognosis in a wide range of cancers.

RETRACTED ARTICLE: p300 promotes proliferation, migration, and invasion via inducing epithelial-mesenchymal transition in non-small cell lung cancer cells

BackgroundHistone acetyltransferase p300 is a crucial transcriptional coactivator and has been implicated as a poor prognostic factor in human cancers. However, little is known about the substantial functions and mechanisms of p300 in NSCLC proliferation and distant metastasis.MethodsWe constructed p300 down-regulated and up-regulated cell lines through RNAi and recombinant plasmid transfection. Cell Counting Kit-8 assays were used to test the cell proliferation and confirmed by colony formation assays. Wound healing assays and transwell chamber assays were used to test the migration and invasion ability. Based upon these results, we measured the epithelial markers and mesenchymal markers after regulating p300 expression to explore epithelial-mesenchymal transition as a potential mechanism of p300 promoting NSCLC metastasis.ResultsIn NSCLC cells NCI-H1975 and NCI-H1993, down-regulation of p300 leads to inhibition of cell proliferation and colony formation. Cells with reduced p300 expression also demonstrate inhibited migration and invasion ability. Contrarily, up-regulation of p300 significantly enhanced the proliferation, colony formation, migration and invasion ability of NCI-H460. Importantly, further investigation shows that decreased p300 expression is associated with reduced expression of mesenchymal markers and increased expression of epithelial markers, while up-regulated p300 expression correlated with decreased expression of epithelial markers and increased expression of mesenchymal markers.ConclusionsAs a crucial tumor promoter, p300 promotes cell proliferation, migration, and invasion in NSCLC cells. Epithelial-mesenchymal transition is a potential mechanism of p300 promoting NSCLC metastasis.

Systematic analysis reveals long noncoding RNAs regulating neighboring transcription factors in human cancers

Long noncoding RNAs (lncRNAs) are proposed to play essential roles in regulating gene transcription. Moreover, a subset has been implicated in modulating the expression of the nearby loci. Here we systematically evaluated the relationship between lncRNAs and their neighboring genes based on transcriptome expression profiles from 4900 samples across 12 cancer types. Our findings reveal that lncRNAs, especially those of high syntenic conservation across species, are spatially correlated with transcription factors across the genome. Combining the methods of conservation, co-expression, and causal inference test, we identified a list of 28 lncRNA/TF regulatory pairs across 12 TCGA cancer types, and 19 of which were further confirmed in additional cancer cell lines. Several of these pairs, including PTV1/MYC and GATA6-AS1/GATA6, show prior evidence of regulatory relationships. Other candidates such as LINC00261/FOXA2 and PITRM1-AS1/KLF6 were novel. Our study highlights the significant roles of lncRNAs in tumorigenesis and provides a comprehensive overview of lncRNA regulation on its neighboring TF genes in human cancers.

The regulatory network analysis of long noncoding RNAs in human colorectal cancer.

Colorectal cancer (CRC) is among one of the most prevalent and lethiferous diseases worldwide. Long noncoding RNAs (lncRNAs) are commonly accepted to function as a key regulatory factor in human cancer, but the potential regulatory mechanisms of CRC-associated lncRNA are largely obscure. Here, we integrated several expression profiles to obtain 55 differentially expressed (DE) lncRNAs. We first detected lncRNA interactions with transcription factors, microRNAs, mRNAs, and RNA-binding proteins to construct a regulatory network and then create functional enrichment analyses for them using bioinformatics approaches. We found the upregulated genes in the regulatory network are enriched in cell cycle and DNA damage response, while the downregulated genes are enriched in cell differentiation, cellular response, and cell signaling. We then employed module-based methods to mine several intriguing modules from the overall network, which helps to classify the functions of genes more specifically. Next, we confirmed the validity of our network by comparisons with a randomized network using computational method. Finally, we attempted to annotate lncRNA functions based on the regulatory network, which indicated its potential application. Our study of the lncRNA regulatory network provided significant clues to unveil lncRNAs potential regulatory mechanisms in CRC and laid a foundation for further experimental investigation.