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The dynamic interplay between chromatin modification (e.g. DNA methylation) and RNA polymerase II (Pol II) plays a critical role in gene transcription during stem cell development, establishment, and maintenance and in the cellular response to extracellular stimuli such as those that cause DNA damage. Pol II is recruited to the promoter-proximal regions of numerous inactive genes at high conentrations in a process called Pol II stalling. This is a key process prior to gene activation and it involves many interacting factors. Chromatin modification including nucleosome position is dependent on chromatin structure. Stalled genes create a particular structural conformation of chromatin, which acts as a target for chromatin modification. In this way, Pol II stalling may be regarded as a type of signal for chromatin modification in these regions during the dynamic transition between stalled and activated genes. [ABSTRACT FROM AUTHOR]

In the cell nucleus, DNA is wound around histone proteins, which are then packed together to form chromatin. Histones can be chemically tagged by methyl and acetyl groups. Polycomb group (PcG) proteins attach methyl groups to genes, which block their activity. This is similar to the attachment of methyl groups to gene promoters by DNA methyltransferases (DNMTs). This action is directly linked with tumor initiation and metastasis via the promotion of anti-senescence and anti-apoptosis pathways, and by facilitating epithelial mesenchymal transition (EMT). Cell fate transcriptional factors (CFTFs) and long non-coding RNAs (long ncRNAs) recruit PcG proteins to the promoters of tumor suppressor genes, resulting in epigenetic gene silencing by influencing chromatin structure and DNA accessibility. Thus, PcG proteins are potential diagnostic markers and targets for new chemoprevention and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR), a ubiquitously expressed receptor tyrosine kinase, is an important factor in carcinogenesis. Transcriptional intermediary factor 2 (TIF2), a member of the p160 nuclear receptor co-activator gene family, is linked to the proliferation of cancer cells. However, the direct interplay between the EGFR and the nuclear receptors remains unclear. Our previous study demonstrated that nuclear EGFR could directly bind to the cyclin D1 promoter under the regulation of the oncoprotein latent membrane protein 1 (LMP1), but it also indicated that other factors are involved in the activation of target genes. In this study, we found that LMP1 upregulated the expression of TIF2 and promoted the interaction of EGFR with TIF2 in nasopharyngeal carcinoma. Furthermore, we demonstrated that the intact complex was linked with cyclin D1 promoter activity in an LMP1-dependent manner. The physiological functions of the intact complex were associated with cell proliferation and cell cycle progression. These findings suggest that TIF2 is a novel binding partner for nuclear EGFR and is involved in regulating its target gene expression.Abbreviations:ATRSAT-rich region sequenceChIPchromatin immunoprecipitationDNA-PKDNA protein kinaseEBVEpstein–Barr virusEGFepidermal growth factorEGFRepidermal growth factor receptorLMPlatent membrane proteinMAPKmitogen-activated protein kinaseNPCnasopharyngeal carcinomaPBSphosphate-buffered salinePCRpolymerase chain reactionRHARNA helicase ASFKSrc family kinaseSTAT signal transducer and activator of transcriptionTIFtranscriptional intermediary factorTNF-atumor necrosis factor-a [ABSTRACT FROM AUTHOR]

Abstract: Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is considered to be the major oncogenic protein of EBV-encoded proteins and has always been the core of the oncogenic mechanism of EBV. Advanced studies on nuclear translocation of the epidermal growth factor receptor (EGFR) family have greatly improved our knowledge of the biological function of cell surface receptors. In this study, we used the Tet-on LMP1 HNE2 cell line as a cell model, which is a dual-stable LMP1-integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 which could be regulated by the Tet system. We found that LMP1 could regulate the nuclear accumulation of EGFR in a dose-dependent manner quantitatively and qualitatively. We also demonstrated that the nuclear localization sequence of EGFR played some roles in the location of the protein within the nucleus under LMP1 regulation and EGFR in the nucleus could bind to the promoters of cyclinD1 and cyclinE, respectively. We further demonstrated that EGFR is involved in the acceleration of the G1/S phase transition by LMP1 through binding to cyclinD1 and cyclinE directly. These findings provided a novel view that the acceleration of LMP1 on the G1/S transition via the nuclear accumulation of EGFR was critical in the process of nasopharyngeal carcinoma. [Copyright &y& Elsevier]

Purpose: This study aims to identify key genes regulating tumor infiltrating plasma cells (PC) and provide new insights for innovative immunotherapy. Methods: Key genes related to PC were identified using machine learning in lung adenocarcinoma (LUAD) patients. A prognostic model called PC scores was developed using TCGA data and validated with GEO cohorts. We assessed the molecular background, immune features, and drug sensitivity of the high PC scores group. Real-time PCR was utilized to assess the expression of hub genes in both localized LUAD patients and LUAD cell lines. Results: We constructed PC scores based on seventeen PC-related hub genes (ELOVL6, MFI2, FURIN, DOK1, ERO1LB, CLEC7A, ZNF431, KIAA1324, NUCB2, TXNDC11, ICAM3, CR2, CLIC6, CARNS1, P2RY13, KLF15, and SLC24A4). Higher age, TNM stage, and PC scores independently predicted shorter overall survival. The AUC value of PC scores for one year, three years, and five years of overall survival were 0.713, 0.716, and 0.690, separately. The nomogram model that integrated age, stage, and PC scores showed significantly higher predictive value than stage alone (P < 0.01). High PC scores group exhibited an immune suppressing microenvironment with lower B, CD8 + T, CD4 + T, and dendritic cell infiltration. Docetaxel, gefitinib, and erlotinib had lower IC50 in high PC groups (P < 0.001). After validation through the local cohort and in vitro experiments, we ultimately confirmed three key potential targets: MFI2, KLF15, and CLEC7A. Conclusion: We proposed a prediction mode which can effectively identify high-risk LUAD patients and found three novel genes closely correlated with PC tumor infiltration. [ABSTRACT FROM AUTHOR]

Various forms of programmed cell death (PCD) exhibit distinct characteristics depending on their specific molecular mechanisms, and there are interactions among these different forms. Ferroptosis, which is related to autophagy and apoptosis, has an unknown potential interaction with pyroptosis. This study revealed a mutually antagonistic relationship between ferroptosis and pyroptosis, with 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) playing a key role in their interaction. It is found that HMGCR predominantly localized to mitochondria during ferroptosis but shifted to the endoplasmic reticulum following treatment with a pyroptosis inducer. Furthermore, this study demonstrated that BRCC36 (BRCA1/BRCA2‐containing complex subunit 36) deubiquitinated HMGCR in a manner dependent on deubiquitinating enzyme (DUB) activity, and inhibited ferroptosis and promoted pyroptosis. Moreover, as an oncogene in hepatocellular carcinoma (HCC), BRCC36 promoted cancer cell proliferation, migration, invasion, and tumor growth. Thiolutin, an inhibitor of BRCC36, effectively suppressed the interaction between BRCC36 and HMGCR, leading to the inhibition of HCC growth. Therefore, targeting BRCC36 can offer a novel and promising therapeutic strategy for HCC treatment. In conclusion, these findings provide new theoretical evidence for further characterizing tumor heterogeneity and offer new molecular targets for the diagnosis and treatment of HCC. [ABSTRACT FROM AUTHOR]

Background: Disulfidptosis is a type of programmed cell death caused by excessive cysteine-induced disulfide bond denaturation leading to actin collapse. Liver cancer has a poor prognosis and requires more effective intervention strategies. Currently, the prognostic and therapeutic value of disulfidptosis in liver cancer is not clear. Methods: We investigated the features of 16 disulfidptosis-related genes (DRGs) of HCC patients in the TCGA and classified the patients into two disulfidptosis pattern clusters by consensus clustering analysis. Then, we constructed a prognostic model using LASSO Cox regression. Next, the microenvironment and drug sensitivity were evaluated. Finally, we used qPCR and functional analysis to verify the reliability of hub DRGs. Results: Most of the DRGs showed significantly higher expression in cancer tissues than in adjacent tissues. Our prognostic model, the DRG score, can well predict the survival of HCC patients. There were significant differences in survival, features of the microenvironment, effects of immunotherapy, and drug sensitivity between the high- and low-DRG score groups. Ultimately, we demonstrated that a few hub DRGs have differential mRNA expression between liver cancer cells and normal cells and that the protective gene LCAT can inhibit liver cancer metastasis in vitro. Conclusion: We established a novel risk model based on DRG scores to predict HCC patient prognosis, drug sensitivity and immunotherapy efficacy, which provides new insight into the relationship between disulfidptosis and HCC and provides valuable assistance for the personalized treatment of HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti‐tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB‐IN‐3 shows the most effective anti‐cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB‐IN‐3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O‐GlcNAc transferase (OGT) via inhibiting K48‐specific poly‐ubiquitination process on OGT protein at K117 site, and STE20‐like kinase (SLK)‐mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O‐GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment. [ABSTRACT FROM AUTHOR]

Accumulation of vimentin is the core event in epithelial–mesenchymal transition (EMT). Post‐translational modifications have been widely reported to play crucial roles in imparting different properties and functions to vimentin. Here, a novel modification of vimentin, acetylated at Lys104 (vimentin‐K104Ac) is identified, which is stable in lung adenocarcinoma (LUAD) cells. Mechanistically, NACHT, LRR, and PYD domain‐containing protein 11 (NLRP11), a regulator of the inflammatory response, bind to vimentin and promote vimentin‐K104Ac expression, which is highly expressed in the early stages of LUAD and frequently appears in vimentin‐positive LUAD tissues. In addition, it is observed that an acetyltransferase, lysine acetyltransferase 7 (KAT7), which binds to NLRP11 and vimentin, directly mediates the acetylation of vimentin at Lys104 and that the cytoplasmic localization of KAT7 can be induced by NLRP11. Malignant promotion mediated by transfection with vimentin‐K104Q is noticeably greater than that mediated by transfection with vimentin‐WT. Further, suppressing the effects of NLRP11 and KAT7 on vimentin noticeably inhibited the malignant behavior of vimentin‐positive LUAD in vivo and in vitro. In summary, these findings have established a relationship between inflammation and EMT, which is reflected via KAT7‐mediated acetylation of vimentin at Lys104 dependent on NLRP11. [ABSTRACT FROM AUTHOR]

Highlights • Role of chromatin remodeling in immune cell development. • Regulation of inflammatory gene expression by RNA elongation. • RNA transcription-dependent control of inducible genes in lymphocytes. • Dynamic changes of chromatin in immunological memory. Abstract RNA polymerase II (Pol II) binds to promoter-proximal regions of inducible target genes that are controlled and not transcribed by several negative elongation factors, which is known as Pol II stalling. The occurrence of stalling is due to particular modification signatures and structural conformations of chromatin that affect Pol II elongation. The existence and physiological importance of Pol II stalling implies that there is a dynamic balance in chromatin regulation prior to endogenous or exogenous stimulation. In this review, we discuss the effects of ATP-dependent chromatin remodeling complexes and histone modification via transcriptional machinery Pol II C-terminal domain phosphorylated at serine 5 (S5P RNAPII) initiation and S2P RNAPII elongation on the expression or silence of specific genes after the production of activated or differentiated signals or cytokines. The response occurs immediately during immune cell development and function, and it also includes the generation of immunological memories. This summary suggests that the host immune response genes involve a novel mechanism of selectively regulatory chromatin remodeling, a fundamental and crucial aspect of epigenetic regulation. [ABSTRACT FROM AUTHOR]

Background: Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) tumor suppressor genes play crucial roles in DNA repair and regulation of transcription. Mutations in these genes are closely associated with the occurrence of cancers. However, the mutation status of BRCA gene in central south Chinese lung cancer patients remains unclear, and its expression levels in lung cancer also need to be further explored. Methods: In this study, we use next‐generation sequencing (NGS) technology to analyze the BRCA genes mutations in 462 central south Chinese lung cancer patients. Public databases including cBioportal, Catalogue Of Somatic Mutations In Cancer (COSMIC), The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA) and Expression Profiling Interactive Analysis (GEPIA) are also applied to explore the expression level and mutation status of BRCA in lung cancer patients and their relationships with the prognosis. Results: We found that the mutation rate of BRCA1/2 in central south Chinese lung cancer patients is 4.3% and 6.5% respectively, and missense mutations account for the majority in both BRCA1/2, which are similar to the international status of BRCA1/2 from public databases. In addition, 45 novel mutations of BRCA1/2 in lung cancer are reported in this study. Furthermore, we find that the BRCA2 mutations are negatively correlated with overall survival rate in lung cancer using cBioportal. Last, we demonstrate that both of the mRNA and protein levels of BRCA1/2 are upregulated in lung cancer, and the elevated mRNA expression levels are positively linked with poor prognosis. Conclusion: In general, our study better complements knowledge of the BRCA1/2 mutation status in the Chinese lung cancer patients, and firstly reveals the association between BRCA1/2 expression levels and prognosis of lung cancer patients, which may provide great value for the early diagnosis and clinical treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Background: To identify whether RET is a potential target for NSCLC treatment, we examined the status of the RET gene in 631 early and mid stage NSCLC cases from south central China. Methods: RET expression was identified by Western blot. RET‐positive expression samples were verified by immunohistochemistry. RET gene mutation, copy number variation, and rearrangement were analyzed by DNA Sanger sequencing, TaqMan copy number assays, and reverse transcription‐PCR. ALK and ROS1 expression levels were tested by Western blot and EGFR mutation using Sanger sequencing. Results: The RET‐positive rate was 2.5% (16/631). RET‐positive expression was related to poorer tumor differentiation (P < 0.05). In the 16 RET‐positive samples, only two samples of moderately and poorly differentiated lung adenocarcinomas displayed RET rearrangement, both in RET‐KIF5B fusion partners. Neither ALK nor ROS1 translocation was found. The EGFR mutation rate in RET‐positive samples was significantly lower than in RET‐negative samples (P < 0.05). Conclusion: RET‐positive expression in early and mid stage NSCLC cases from south central China is relatively low and is related to poorer tumor differentiation. RET gene alterations (copy number gain and rearrangement) exist in all RET‐positive samples. RET‐positive expression is a relatively independent factor in NSCLC patients, which indicates that the RET gene may be a novel target site for personalized treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Eukaryotic genomes are prevalently transcribed into many types of RNAs that translate into proteins or execute gene regulatory functions. Many RNAs associate with chromatin directly or indirectly and are called chromatin-associated RNAs (caRNAs). To date, caRNAs have been found to be involved in gene and transcriptional regulation through multiple mechanisms and have important roles in different types of cancers. In this review, we first present different categories of caRNAs and the modes of interaction between caRNAs and chromatin. We then detail the mechanisms of chromatin-associated nascent RNAs, chromatin-associated noncoding RNAs and emerging m6A on caRNAs in transcription and gene regulation. Finally, we discuss the roles of caRNAs in cancer as well as epigenetic and epitranscriptomic mechanisms contributing to cancer, which could provide insights into the relationship between different caRNAs and cancer, as well as tumor treatment and intervention. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high prevalence and lethality. Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection are the major risk factors for HCC. Long noncoding RNAs (lncRNAs) are involved in diverse biological processes, and aberrant lncRNA expression is relevant to many human diseases including HCC. Although many researches on HCC have been reported and lncRNAs roles in carcinogenesis have been highlighted recently, reports on roles of lncRNAs in HBV/HCV-induced HCC are limited. In this review, we concentrate on recent progress regarding the functional roles of lncRNAs in HCC and HBV/HCV-related HCC. [ABSTRACT FROM AUTHOR]

Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti‐cancer drugs are severely restricted from reaching the tumour site. Cell‐penetrating peptides (CPPs) are typically made up of 5–30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti‐cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs‐based drug delivery strategy could be improved by clever design or chemical modifications to develop the next‐generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs. [ABSTRACT FROM AUTHOR]

Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies. [ABSTRACT FROM AUTHOR]

Background: Alternative splicing (AS) plays important roles in transcriptome and proteome diversity. Its dysregulation has a close affiliation with oncogenic processes. This study aimed to evaluate AS-based biomarkers by machine learning algorithms for lung squamous cell carcinoma (LUSC) patients. Method: The Cancer Genome Atlas (TCGA) database and TCGA SpliceSeq database were utilized. After data composition balancing, Boruta feature selection and Spearman correlation analysis were used for differentially expressed AS events. Random forests and a nested fivefold cross-validation were applied for lymph node metastasis (LNM) classifier building. Random survival forest combined with Cox regression model was performed for a prognostic model, based on which a nomogram was developed. Functional enrichment analysis and Spearman correlation analysis were also conducted to explore underlying mechanisms. The expression of some switch-involved AS events along with parent genes was verified by qRT-PCR with 20 pairs of normal and LUSC tissues. Results: We found 16 pairs of splicing events from same parent genes which were strongly related to the splicing switch (intrapair correlation coefficient = − 1). Next, we built a reliable LNM classifier based on 13 AS events as well as a nice prognostic model, in which switched AS events behaved prominently. The qRT-PCR presented consistent results with previous bioinformatics analysis, and some AS events like ITIH5-10715-AT and QKI-78404-AT showed remarkable detection efficiency for LUSC. Conclusion: AS events, especially switched ones from the same parent genes, could provide new insights into the molecular diagnosis and therapeutic drug design of LUSC. [ABSTRACT FROM AUTHOR]

In this research, we firstly explored the role of the microbiome combined with transcriptomics and proteomics in pure ground-glass opacity (pGGO) (<1 cm) development by 16S rRNA gene sequencing technology (Figure S1), and demonstrated the pGGO microbiome features in lung adenocarcinoma (LUAD) patients. And from our study, it suggested that Oxalobacteraceae may display the ability to modulate the tumour microenvironment by influencing the core immune/inflammation-related genes, thus having an impact on pGGO development. And Oxalobacteraceae may display the ability to modulate the tumour microenvironment by influencing the core immune/inflammation-related genes. [Extracted from the article]

L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH. [ABSTRACT FROM AUTHOR]

Many human tumor cells are characterized by overexpression or mutation of epidermal growth factor receptor (EGFR). Emerging evidence indicates that EGFR, as well as some of its downstream components, can translocate to the nucleus and play roles in transcriptional regulation, signaling conduction and repair of DNA double strands breaks (DSBs). EGFR in its nuclear manifestation promotes DSB repair by interacting with proteins including DNA-PK, ATM, Rad51 and BRCA1, involved in DSB repair, via the PI3K-Akt and Ras-Raf-MAPK pathways. DNA damage repair in tumor cells is emerging as an attractive target in radiotherapy and chemotherapy. Interruption of EGFR functions, or those of its downstream components, presents a promising strategy for confounding DNA damage repair in tumor cells. [ABSTRACT FROM AUTHOR]

Abstract: The Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1), an oncogenic protein, plays an important role in the carcinogenesis of nasopharyngeal carcinoma (NPC). Phosphorylation of p53 protein is likely to play the key role in regulating its activity. p53 protein accumulates but mutation of p53 gene is not common in NPC. The molecular mechanisms of p53 augmentation have not been completely elucidated. Here, the role of MAP kinases in the phosphorylation of p53 modulated by LMP1 was determined. p53 could be activated and phosphorylated clearly at Ser15, Ser20, Ser392, and Thr81 modulated by LMP1. Furthermore, LMP1-induced phosphorylation of p53 at Ser15 was directly by ERKs; at Ser20 and Thr81 by JNK, at Ser 15 and Ser392 by p38 kinase. The phosphorylation of p53 was associated with its transcriptional activity and stability modulated by LMP1. These results strongly suggest that MAP kinases have a direct role in LMP1-induced phosphorylation of p53 at multiple sites, which provide a novel view for us to understand the mechanism of the activation of p53 in the carcinogenesis of nasopharyngeal carcinoma. [Copyright &y& Elsevier]

Abstract: Apoptosis is a highly conserved procedure of cell death and occurs under various stimuli, including oxidative stress. A small heat shock protein, αB-crystallin, is found to process resistance to apoptosis in some cells and tissues. But the mechanisms under this protective role are not fully understood. In the present study, we reported the early protective role of αB-crystallin against hydrogen peroxide-induced apoptosis in mice myogenic C2C12 cells. αB-Crystallin interacted with p53, a proapoptotic protein, during cell apoptosis and such protein interaction mainly occurred in the cytoplasm of the cells, suggesting that the interaction of αB-crystallin with p53 might prevent the translocation of p53 from cytoplasm to mitochondria. Hence, this study provides a hint that αB-crystallin affects on p53 mitochondrial translocation during oxidative stress-induced apoptosis. [Copyright &y& Elsevier]

GTPase-activating protein (GAP) is a negative regulator of GTPase protein that is thought to promote the conversion of the active GTPase-GTP form to the GTPase-GDP form. Based on its ability to regulate GTPase proteins and other domains, GAPs are directly or indirectly involved in various cell requirement processes. We reviewed the existing evidence of GAPs regulating regulated cell death (RCD), mainly apoptosis and autophagy, as well as some novel RCDs, with particular attention to their association in diseases, especially cancer. We also considered that GAPs could affect tumor immunity and attempted to link GAPs, RCD and tumor immunity. A deeper understanding of the GAPs for regulating these processes could lead to the discovery of new therapeutic targets to avoid pathologic cell loss or to mediate cancer cell death. [ABSTRACT FROM AUTHOR]

Purpose: Gastric adenocarcinoma is one of the most important causes of cancer death and lacks effective treatment. Eighty-four gastric adenocarcinoma tissue samples along with the clinical information were collected. After analyzing the expression of HOXC11 and LSH in the gastric adenocarcinoma tissues, we explored the prognosis of patients and its correlation with clinical characteristics. Both HOXC11 and LSH were over-expressed in MKN-45 cell lines to verify the effect of high expression of HOXC11 and LSH on GAC. Methods: The expression of HOXC11 and LSH in 84 cases with gastric adenocarcinoma (GAC) was detected via immunohistochemistry, including 17 cases in stage I, 7 cases in stage II, 27 cases in stage III and 33 cases in stage IV. The expression levels of HOXC11 and LSH, and the clinicopathological characteristics of the samples, were also studied. Cell proliferation, migration, cell cycle and apoptosis assays were utilized for demonstrating malignancy of HOXC11 and LSH over-expressed cells. Results: Among 84 GAC pathological samples, 12 high HOXC11 expression, and 72 showed low expression; 54.8% (46/84) high LSH expression, and 45.2% (38/84) exhibited low expression. Survival analysis of the Kaplan-Meier plotter gastric cancer datasets showed that subjects with low expression of HOXC11 and LSH had a longer survival time, with a median survival time of 40.2 and 36.4 months, while the subjects with high HOXC11 and LSH expression were only 20.5 and 10 months, respectively. Meanwhile, HOXC11 and LSH over-expressed cells showed a stronger proliferous and migratory ability, and a sped up cell cycle. Conclusion: The high expression level of HOXC11 and LSH both manifested the poor survival prognosis of GAC patients, and more pronounced malignant phenotype in GAC cells indicated that HOXC11 and LSH can be a strong predictive factor of inferior disease-free survival. From this, we can consider that HOXC11 and LSH both have significant status in GAC stage and survival prediction. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) regulate gene expression or activities. This study investigated the role of lncRNA LINC00551 in ESCC development and progression. Three paired ESCC and normal tissues were subjected to next‐generation sequencing and we identified 82 upregulated and 60 downregulated lncRNAs, including LINC00551, which was confirmed to markedly downregulated in 78 ESCC tissues and in the Gene Expression Profiling Interactive Analysis data set. Downregulated LINC00551 expression was associated with lymph node metastasis, advanced TNM stage, and tumor size. Moreover, downregulated LINC00551 expression was also associated with poor progression‐free survival and overall survival of ESCC patients. In vitro and in vivo, LINC00551 overexpression inhibited ESCC cell proliferation and invasion, whereas knockdown of LINC00551 expression promoted ESCC cell proliferation and invasion. RNA pull‐down and mass spectrometry assays identified the potential LINC00551 binding proteins, and HSP27 was a promising LINC00551 targeting proteins after RNA immunoprecipitation assay. At the protein level, LINC00551 bound to and decreased HSP27 phosphorylation, and in turn, downregulated ESCC cell proliferation and invasion. The current study demonstrated the functional significance of LINC00551 in ESCC development, progression, and prognosis. Further study will assess LINC00551 as a novel prognostic marker or therapeutic target for ESCC. [ABSTRACT FROM AUTHOR]

Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors. [ABSTRACT FROM AUTHOR]

As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment. [ABSTRACT FROM AUTHOR]

Ferroptosis, a novel form of regulated cell death, is different from other types of cell death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on cell death linked to cardiomyopathy, tumorigenesis, and cerebral hemorrhage to name a few. Here we summarize current literature on ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming and epigenetic regulators in cancer progression. With regard to organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction and golgi stress-related lipid peroxidation all contribute to induction of ferroptosis. Understanding the underlying mechanism in ferroptosis could provide insight into the treatment of various intractable diseases including cancers. [ABSTRACT FROM AUTHOR]

There is emerging evidence of bioactive material transport by exosomes in melanoma. However, the functions of exosome content underlying such cancer progression remain largely unknown. We aimed at determining whether exosome secretion contributes to cellular microRNA‐494 (miR‐494) loss and investigated the roles of miR‐494 in melanoma progression. The exosomes from blood serum and cell culture conditioned media were separated by ultracentrifugation. A short hairpin RNA was used to silence rab27a for inhibiting exosome release. To address the functional role of exosomal miR‐494, we assessed cell proliferation, migration, invasion capabilities, and cell apoptosis. Finally, subcutaneous xenograft and lung‐metastasis models were constructed to determine the effect of exosomal miR‐494 in vivo. Based on long noncoding RNA microarray analysis of melanocyte and melanoma‐derived exosomes from the Gene Expression Omnibus database, we discovered that miR‐494 was enriched in melanoma‐derived exosomes. And miR‐494 was increased in exosomes secreted from melanoma patients' serum and A375 cells. Rab27a depletion reduced exosome secretion and rescued the abundance of cellular miR‐494. Functional studies revealed that knockdown of rab27a and subsequent accumulation of miR‐494 significantly suppressed the malignant phenotypes of melanoma cells via inducing cell apoptosis. Nude mice experiments confirmed that tumor growth and metastasis were suppressed by increasing miR‐494 accumulation after rab27a depletion. In conclusion, blocking transferred exosome‐shuttled miR‐494 is a potential therapeutic option for melanoma. [ABSTRACT FROM AUTHOR]

BACKGROUND: It remains controversial if Mohs surgery is superior to surgical excision in treating localized sebaceous carcinoma. OBJECTIVE: To compare Mohs surgery and surgical excision for treating patients with localized sebaceous carcinoma. MATERIALS AND METHODS: The US National Cancer Database was used to identify patients with histologically confirmed Stage 0 to 2 sebaceous carcinoma from 2004 to 2014. Clinicopathologic and socioeconomic factors were compared between treatment groups using the chi-square test. Overall survival (OS) was evaluated by log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses compared with age- and sex-matched US population were performed. RESULTS : Of 1,265 patients, 234 received Mohs surgery and 1,031 received surgical excision. Mohs surgery had a higher rate of negative margin (p =.004). On multivariate Cox regression analysis, Mohs surgery was associated with longer OS than surgical excision (HR: 0.703, 95% CI: 0.496-0.995, p =.047). The survival benefit of Mohs surgery persisted on relative survival analysis and propensity score-matched analysis (p =.0385), after matching the 2 groups on patient and disease characteristics. CONCLUSION : Patients who received Mohs surgery had significantly longer OS when compared with those who received surgical excision. Prospective clinical trials comparing these treatment paradigms are warranted. [ABSTRACT FROM AUTHOR]

Background: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome.Methods: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization.Results: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers.Conclusions: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to elucidate the regulation of the DPC4 gene by miR-190 in colorectal cancer (CRC) cells. The present study was undertaken to determine whether the DPC4 gene is a target gene of miRNA-190, identify target motifs and to elucidate the mechanism of regulation of DPC4 by miRNA-190.Materials and Methods: MiR-190 and DPC4 expression were measured in five different CRC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The regulation of DPC4 by miR-190 was evaluated by qRT-PCR, Western blotting, and luciferase reporter assays in the human CRC cell line HT-29 after treatment with miR-190 mimics and inhibitors.Results: The DPC4 mRNA, miR-, and DPC4 protein expression levels were highest in LS174T cells while lowest in SW480 and SW620 cells. The DPC4/miR-190 ratio in the HT-29 cancer cell line was the largest. MiR-190 expression increased dramatically after treatment with miR-190 mimics and decreased significantly after treatment with miR-190 inhibitors. DPC4 protein expression decreased in the miR-190 mimics transfection group when compared to the negative control (N.C.) group and increased in the miR-190 inhibitor groups when compared to the inhibitor plus N.C. group. MiR-190 inhibits the relative luciferase activity of psiCHECK-2™ vector-3'UTR compared to the N.C. group, while miR-190 had no obvious effect on the relative luciferase activity of the psiCHECK-2™ vector-3'UTRmut and psiCHECK-2™ vector transfected cells.Conclusions: The DPC4 gene might be the target gene of miR-190, which may negatively regulate the DPC4 gene in human CRC cells by translational suppression rather than mRNA degradation. [ABSTRACT FROM AUTHOR]

Primary cutaneous peripheral T-cell lymphoma, unspecified (PCPTL) accounts for <6% of cutaneous T-cell lymphoma cases. Due to its rarity, no large study exists in the literature on PCPTL. Among 4057 patients with PCPTL diagnosed from 2004 to 2014 in the National Cancer Database, 428, 913, 517, 754, and 1435 had lesions localized primarily to the upper extremity, head and neck, lower extremity, trunk, and overlapping lesion or unspecified site, respectively. PCPTL that primarily involved the head and neck had the longest overall survival (OS), followed by PCPTL that primarily involved the trunk, upper extremity, and lower extremity. Patients with lesions localized to the lower extremity had significantly shorter OS when compared to those with disease localized to other primary sites after adjusting for confounding factors. The difference in OS among disease sites was only significant in stage I disease, but not higher stages, and persisted in younger patients. [ABSTRACT FROM AUTHOR]

Radiation therapy has become an important tool in the treatment of cancer patients, but most patients relapse within 5 years. Relapse is due to the presence of cancer stem cells (CSCs), but the molecular mechanism of radioresistance in CSCs remains largely elusive. Here, we found that irradiation-resistant (IR) cells exhibited increased stem cell-like properties together with elevated anchorage-independent growth and metastasis ability. EGFR not only leads to increased acquisition of endometrial cancer stem cell markers in radioresistant sublines but is critical for the cancer stem-cell phenotype and tumorigenicity. Moreover, PKM2 functions as an interacting partner of EGFR, which induces the EMT phenotype and stem cell-like properties in IR cells. Finally, we found that the regulatory function of the EGFR-PKM2 axis is dependent on nuclear EGFR. In sum, our study indicated that EGFR and PKM2 directly interact and bind with each other to regulate the transcription of stemness-related genes and promote the stem-like phenotype, thus promoting invasion and metastasis. [ABSTRACT FROM AUTHOR]

Background: For many years, lung cancer has been the most common and deadly cancer worldwide. Early diagnosis of non‐small cell lung cancer (NSCLC) in particular is very difficult because the symptoms are often ignored. The five‐year survival rate is very low despite great improvements to therapy. Thus, there is an urgent need to identify prognostic biomarkers and target molecules for the clinical diagnosis and individualized treatment of NSCLC. Methods: We performed quantitative real‐time PCR to determine the expression levels of the long non‐coding RNA (lncRNA) linc01433 in NSCLC and normal matched lung tissue. Subsequently, we established cell lines with overexpression or knockdown of linc01433 to evaluate the effects on proliferation and metastasis in vitro. Epithelial‐to‐mesenchymal transition was examined using Western blot. Results: Linc01433 was significantly overexpressed in NSCLC tissues compared to normal lung tissues. In addition, linc01433 levels were associated with smoking history. Linc01433 overexpression in lung cancer cells increased proliferation, migration, and invasion abilities, as well as epithelial‐to‐mesenchymal transition. Conclusions: Linc01433 is a cancer‐related lncRNA that may have an oncogene‐like effect in NSCLC. [ABSTRACT FROM AUTHOR]

Metabolism is essential to all living organisms that provide cells with energy, regulators, building blocks, enzyme cofactors and signaling molecules, and is in tune with nutritional conditions and the function of cells to make the appropriate developmental decisions or maintain homeostasis. As a fundamental biological process, metabolism state affects the production of multiple metabolites and the activation of various enzymes that participate in regulating gene expression, cell apoptosis, cancer progression and immunoreactions. Previous studies generally focus on the function played by the metabolic enzymes in the cytoplasm and mitochondrion. In this review, we conclude the role of them in the nucleus and their implications for cancer progression, immunity and metastasis. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to investigate the histogenesis of lymphoepithelial carcinoma (LEC) and its relationship with Epstein-Barr virus (EBV).Materials and Methods: The expression of EBV was detected using in situ hybridization, and the CK5/6, p63, and p40 expression levels were detected using immunohistochemistry in 45 paraffin-embedded tissues from LEC.Results: In 45 paraffin-embedded LEC tissues from 10 different samples, the positive CK5/6 signals were located in the cell membrane. The positive signals for p63 and p40 were located in the cell nucleus. In all LEC cases, the positive rates of CK5/6, p63, and p40 were 93.3% (42/45), 95.6% (43/45), and 93.3% (42/45), respectively. The positive EBV-encoded RNA (EBER) signals were located in the cell nucleus. In the 45 LEC cases, the expression of EBER was strongly positive with a positive rate of 100% (45/45).Conclusions: LEC is closely related to EBV, and EBV plays an important role in the development of LEC. LEC showed positive squamous cell markers, indicating that the samples contain squamous cell carcinoma (SQCC). LEC is EBV (+) with nonkeratinizing SQCC, and this name better reflects the nature of this disease. [ABSTRACT FROM AUTHOR]

Background Myeloid sarcoma is a tumor mass that consists of myeloblasts or immature myeloid cells at an extramedullary site. Pathological diagnosis is very difficult based on morphology if systemic signs of disease are absent. The subtype of myeloid sarcoma is also minimally identifiable in the histological picture. Findings We investigated 18 paraffin-embedded myeloid sarcoma samples, and our immunohistochemical data confirmed the relevance of some key markers for the diagnosis and subclassification of myeloid sarcoma. CD34 was found as a marker in 67% of the myeloid sarcoma cases, and CD34 was positive in all immature types of myeloid sarcoma. CD68 was found in 83% of the myeloid sarcoma cases, but CD68 was most identified in the differentiated type of myeloid sarcoma. Myeloperoxidase (MPO) was positive in all myeloid sarcomas. Notably, the reactivity of MPO in the blastic subtype was much lower in myeloid sarcomas. CD117 reactivity was found in 67% of myeloid sarcomas. Ten-eleven translocation 2 (TET2) protein exhibited significant negative reactivity in 88% of the cases, and 5-methylcytosine (5-hmC) was significantly positive in the nucleus in 100% of the cases. Conclusions Our findings indicated that an immunohistochemical panel that included MPO, CD68 and CD34 could be used for the detection of blastic, differentiated and immature types of myeloid sarcoma. Changes in novel epigenetic regulators, including the loss of TET2 and gain of 5-hmC, as characteristics of myeloid malignancies may be useful novel markers of myeloid sarcoma. [ABSTRACT FROM AUTHOR]

Abstract: DNA methylation plays an important role in the regulation of gene expression, as it is the first epigenetic modification to take place on a given DNA strand. Several factors may directly or indirectly regulate the dynamic distribution of DNA methylation and demethylation between intergenic and intragenic gene regions, thereby controlling gene expression. CpG islands have direct implications for the understanding of DNA methylation patterns in normal conditions and in some common disease states, including cancer. Here, we summarize several recent studies on the genome-wide distribution of DNA methylation and demethylation and their related factors, and we discuss the potential of DNA methylation and demethylation patterns to contribute to gene transcription patterns in tumorigenesis. [Copyright &y& Elsevier]

The latent membrane protein 1 (LMP1), which is encoded by the Epstein-Barr virus (EBV), is an important oncogenic protein that is closely related to carcinogenesis and metastasis of nasopharyngeal carcinoma (NPC), a prevalent cancer in China. We previously reported that the expression of the functional chemokine receptor CXCR4 is associated with human NPC metastasis. In this study, we show that LMP1 induces tyrosine sulfation of CXCR4 through tyrosylprotein sulfotransferase-1 (TPST-1), an enzyme that is responsible for catalysis of tyrosine sulfation in vivo, which is likely to contribute to the highly metastatic character of NPC. LMP1 could induce tyrosine sulfation of CXCR4 and its associated cell motility and invasiveness in a NPC cell culture model. In contrast, the expression of TPST-1 small interfering RNA reversed LMP1-induced tyrosine sulfation of CXCR4. LMP1 conveys signals through the epidermal growth factor receptor (EGFR) pathway, and EGFR-targeted siRNA inhibited the induction of TPST-1 by LMP1. We used a ChIP assay to show that EGFR could bind to the TPST-1 promoter in vivo under the control of LMP1. A reporter gene assay indicated that the activity of the TPST-1 promoter could be suppressed by deleting the binding site between EGFR and TPST-1. Finally, in human NPC tissues, the expression of TPST-1 and LMP1 was directly correlated and clinically, the expression of TPST-1 was associated with metastasis. These results suggest the up-regulation of TPST-1 and tyrosine sulfation of CXCR4 by LMP1 might be a potential mechanism contributing to NPC metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Epstein-Barr virus encoded latent membrane protein 1 (LMP1), an oncogenic protein, plays an important role in the carcinogenesis of nasopharyngeal carcinoma. The MDM2 gene is a cellular pro-oncogene that is abnormally up-regulated in human tumors. MDM2 is overexpressed in nasopharyngeal carcinoma, which is associated with the presence of EBV and cervical lymph node metastasis. Because MDM2 is capable of self-ubiquitination, and the ubiquitin proteasome pathway-dependent degradation is an important mechanism for regulating MDM2 levels in cells. Here we show that LMP1 augment MDM2 protein expression in dose-dependent level, and also lead to a drastic accumulation of ubiquitinated MDM2 species, this effect is associated with the stability of MDM2 modulated by LMP1. This is the first time to explain LMP1-regulated MDM2 through a post-ubiquitination mechanism. [Copyright &y& Elsevier]

Background: The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown. Results: Here, we present data suggesting that LSH regulates p53 in cis through two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH–PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivation in cis in lipid metabolism, especially lipid catabolism. Conclusion: These findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer. [ABSTRACT FROM AUTHOR]

Background & aim: Gastric cancer (GC) is the third-leading cause of cancer-related deaths. We established a prospective database of patients with GC who underwent surgical treatment. In this study, we explored the prognostic significance of the expression of CFP1 and 14-3-3 in gastric cancer, by studying the specimens collected from clinical subjects. Materials & methods: Immunohistochemistry was used to detect the expression of CFP1 and 14-3-3 in 84 GC subjects, including 73 patients who have undergone radical gastrectomy and 11 patients who have not undergone radical surgery. Survival analysis was performed by km-plot data. Results: According to the survival analysis, we can see that the survival time of patients with high expression of CFP1 is lower than the patients with low expression in gastric cancer, while the effect of 14-3-3 is just the opposite. The survival time of patients with higher expression of 14-3-3 is also longer. Conclusion: The CFP1 and 14-3-3 genes can be used as prognostic markers in patients with GC, but the study is still needed to confirm. [ABSTRACT FROM AUTHOR]

Background: Metastasis is responsible for the majority of deaths in a variety of cancer types, including breast cancer. Although several factors or biomarkers have been identified to predict the outcome of patients with breast cancer, few studies have been conducted to identify metastasis-associated biomarkers.Methods: Quantitative iTRAQ proteomics analysis was used to detect differentially expressed proteins between lymph node metastases and their paired primary tumor tissues from 23 patients with metastatic breast cancer. Immunohistochemistry was performed to validate the expression of two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins in 190 paraffin-embedded tissue samples. These four proteins were further analyzed for their correlation with clinicopathological features in 190 breast cancer patients.Results: We identified 637 differentially regulated proteins (397 upregulated and 240 downregulated) in lymph node metastases compared with their paired primary tumor tissues. Data are available via ProteomeXchange with identifier PXD013931. Furthermore, bioinformatics analysis using GEO profiling confirmed the difference in the expression of EpCAM between metastases and primary tumors tissues. Two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins were associated with the progression of breast cancer. Obviously, EpCAM plays a role in the metastasis of breast cancer cells to the lymph node. We further identified αB-crystallin as an independent biomarker to predict lymph node metastasis and the outcome of breast cancer patients.Conclusion: We have identified that EpCAM plays a role in the metastasis of breast cancer cells to the lymph node. αB-crystallin, a stress-related protein that has recently been shown to be important for cell invasion and survival, was identified as a potential prognostic biomarker to predict the outcome of breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Elucidating mechanisms in oncogenes and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, regulation of oncogene by chromatin modifiers at post-transcriptional level is critical and remains unclear. We have investigated the role of GINS4 in NSCLC. Methods: The expression of chromatin modifier lymphoid-specific helicase (LSH) and GINS4 was assessed in tumor and normal tissue from 79 patients with NSCLC with clinical characteristics. HBE, A549, H358, and H522, PC9, 95C and 95D were cultured after overexpression or silencing of GIAT4RA. Cell proliferation assay, cell migration and invasion assays, plate colony formation assay, immunofluorescence assay, Operetta® high-content screening and analysis, Western blot analysis and Co-Immunoprecipitation (Co-IP) assay, RNA immunoprecipitation assay and tumor growth assay was used to address the potential interplay of between GINS4 and LSH, and the functional of GINS4. Results: GINS4 is highly expressed in lung cancer cells and tissues, and GINS4 expression is not association with clinical risk factors, but linked with clinical stage and lymphatic metastasis status. Higher expression of GINS4 poorly linked with overall survival in lung adenocarcinomas. Furthermore, GINS4 promoted many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial–mesenchymal transition, tumor sphere and tumor growth in vivo. Interestingly, our results demonstrated that LSH increases GINS4 expression through binding to 3'UTR region of GINS4 and stabilizing its mRNA levels. Finally, LSH overexpression rescues GINS4 knockdown-induced features. Conclusions: GINS4 facilitates lung cancer progression by promoting key characteristics of tumor potential, and LSH epigenetically interacts with and stabilizes GINS4 transcripts. [ABSTRACT FROM AUTHOR]

Peripheral circulating free DNA (cfDNA) is DNA that is detected in plasma or serum fluid with a cell-free status. For cancer patients, cfDNA not only originates from apoptotic cells but also from necrotic tumor cells and disseminated tumor cells that have escaped into the blood during epithelial-mesenchymal transition. Additionally, cfDNA derived from tumors, also known as circulating tumor DNA (ctDNA), carries tumor-associated genetic and epigenetic changes in cancer patients, which makes ctDNA a potential biomarker for the early diagnosis of tumors, monitory and therapeutic evaluations, and prognostic assessments, among others, for various kinds of cancer. Moreover, analyses of cfDNA chromatin modifications can reflect the heterogeneity of tumors and have potential for predicting tumor drug resistance. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are endogenous non-coding RNAs that contain approximately 22 nucleotides. They serve as key regulators in various biological processes and their dysregulation is implicated in many diseases including cancer and autoimmune disorders. It has been well established that the maturation of miRNAs occurs in the cytoplasm and miRNAs exert post-transcriptional gene silencing (PTGS) via RNA-induced silencing complex (RISC) pathway in the cytoplasm. However, numerous studies reaffirm the existence of mature miRNA in the nucleus, and nucleus-cytoplasm transport mechanism has also been illustrated. Moreover, active regulatory functions of nuclear miRNAs were found including PTGS, transcriptional gene silencing (TGS), and transcriptional gene activation (TGA), in which miRNAs bind nascent RNA transcripts, gene promoter regions or enhancer regions and exert further effects via epigenetic pathways. Based on existing interaction rules, some miRNA binding sites prediction software tools are developed, which are evaluated in this article. In addition, we attempt to explore and review the nuclear functions of miRNA in immunity, tumorigenesis and invasiveness of tumor. As a non-canonical aspect of miRNA action, nuclear miRNAs supplement miRNA regulatory networks and could be applied in miRNA based therapies. [ABSTRACT FROM AUTHOR]