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To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.

Lung cancer ranks among the most lethal types of cancer globally, with a high occurrence and fatality rate. The spread of cancer to other parts of the body, known as metastasis, is the primary cause of treatment failure and death in lung cancer cases. Current approaches for treating advanced lung cancer typically involve a combination of chemotherapy and targeted therapy. However, the majority of patients ultimately develop resistance to these treatments, leading to a worsened prognosis. In recent years, cancer biology research has predominantly focused on the role of protein-encoding genes in cancer development. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that do not encode proteins but are crucial RNA molecules involved in numerous biological functions. While many functions of lncRNAs remain unknown, some have been linked to human diseases, including cancer. Studies have demonstrated that lncRNAs interact with other large molecules in the cell, such as proteins, DNA, and RNA, influencing various critical aspects of cancer. LncRNAs play a significant role in regulating gene expression and have a crucial function in the transcriptional regulation of cancer cells. They mediate various biological and clinical processes such as invasion, metastasis, apoptosis, and cell proliferation. Dysregulation of lncRNAs has been found to impact the process of carcinogenesis through advanced technologies like RNA sequencing and microarrays. Collectively, these long non-coding RNAs hold promise as potential biomarkers and therapeutic targets for human cancers. In this segment, we provide a comprehensive summary of the literature on the characteristics and formation of lncRNAs, along with an overview of their current known roles in lung cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Propofol has become a microtubule-stabilizing drug for prostate cancer (PC) therapy, but propofol resistance impairs the therapeutic effect. This study aimed to explore the regulatory mechanism of propofol in the pathogenesis of PC through mechanisms involving N6-methyladenosine (m6A) modification. The changes in PC cell malignancy were evaluated by means of transwell, cell counting kit 8 (CCK-8), western blotting and tumour xenograft model assays. Long noncoding RNA TRHDE-AS1 and m6A methyltransferase METTL14 expression levels were determined via reverse transcription quantitative polymerase chain reaction (RT-qPCR). The m6A modification of TRHDE-AS1 which was mediated by METTL14 was confirmed by conducting methylated RNA immunoprecipitation (MeRIP) assay. We observed that propofol (200 μM) inhibited PC cell malignancy in vivo and in vitro, elucidating that it impaired cell proliferation, migration and tumour growth but induced apoptosis. TRHDE-AS1 expression was observed to be lower in PC cells and tissues, and propofol induced TRHDE-AS1 upregulation in PC cells. Propofol was capable of reversing the tumour-promoting effect of TRHDE-AS1 knockdown in PC cells. Additionally, METTL14 was upstream of TRHDE-AS1 to induce m6A modification of TRHDE-AS1 in PC cells. Collectively, our results show that propofol prevents PC progression by upregulating TRHDE-AS1 expression and METTL14 is involved in the m6A modification of TRHDE-AS1. These findings suggest that TRHDE-AS1 may be a potential therapeutic target for the improvement of propofol's therapeutic effect., (© 2024 John Wiley & Sons Australia, Ltd.)

An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease., (© 2021. The Author(s).)

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The study aims to search and identify differentially expressed genes (DEGs) in cervical cancer tissues as novel biomarkers to predict cervical cancer prognosis. The Cancer Genome Atlas (TCGA) data on gene expression profiles in cervical cancer were downloaded and analyzed using R software to identify DEGs in cervical cancer tissues. miRNAs targeted by differentially expressed long non-coding RNAs (DElncRNAs) and mRNAs targeted by microRNAs (miRNAs) were identified using the online miRcode, miRTarBase, TargetScan, and miRDB tools. The ceRNA network and lncRNA expression modules in cervical cancer tissues were constructed using weighted gene co-expression network analysis (WGCNA) and analyzed bioinformatically. The Kaplan-Meier analysis was performed to confirm these DEGs as prognostic markers. Immunohistochemical (IHC) analysis was used to verify expression of the hub genes in 10 paired cervical cancer and normal tissues. A total of 1914 DEmRNAs, 210 DElncRNAs, and 67 DEmiRNAs were identified in cervical cancer samples. There were 39 lncRNAs, 19 miRNAs, and 87 mRNAs involved in the ceRNA network and 25 DElncRNAs, three DEmiRNAs, and four mRNAs involved in the ceRNA sub-network. CACNA1C-AS1 was associated with the yellow and blue modules in the ceRNA sub-network, and LIFR-AS1 was associated with the blue module. The DEmRNAs were involved in cancer-related pathways, and three hub genes (i.e., E2F1, CCNB1, and CCNE1) were highly expressed in cervical squamous cell carcinoma and adenocarcinoma tissues and associated with the prognosis of patients. The ceRNA network and WGCNA analyses are useful to identify novel DEGs that can serve as prognostic markers in cervical cancer. The DEGs will be validated in future studies., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background: Long noncoding RNAs (lncRNAs) have been shown to be related to the occurrence and development of a variety of cancers including hepatocellular carcinoma (HCC). However, a large number of potential HCC-related lncRNAs remain undiscovered and are yet to be fully understood., Methods: Differentially expressed lncRNAs were first obtained from the tumor tissues and adjacent normal tissues of five HCC patients using high-throughput microarray chips. Then the expression levels of 10 differentially expressed lncRNAs were verified in 50 pairs of tissue samples from patients with HCC by quantitative real-time PCR (qRT-PCR). The oncogenic effects of lncRNA-4045 (ENST00000524045.6) in HCC cell lines were verified through a series of in vitro experiments including CCK-8 assay, plate clone formation assay, transwell assay, scratch assay, and flow cytometry. Subsequently, the potential target genes of lncRNA-4045 were predicted by bioinformatics analysis, fluorescence in situ hybridization assay, and RNA sequencing. The mechanism of lncRNA-4045 in HCC was explored by WB assay as well as rescue and enhancement experiments., Results: The results from microarray chips showed 1,708 lncRNAs to have been significantly upregulated and 2725 lncRNAs to have been significantly downregulated in HCC tissues. Via validation in 50 HCC patients, a novel lncRNA lncRNA-4045 was found significantly upregulated in HCC tissues. Additionally, a series of in vitro experiments showed that lncRNA-4045 promoted the proliferation, invasion, and migration of HCC cell lines, and inhibited the apoptosis of HCC cell lines. The results of qRT-PCR in HCC tissues showed that the expression levels of AKR1B10 were significantly positively correlated with lncRNA-4045. LncRNA-4045 knockdown significantly down-regulated AKR1B10 protein expression, and overexpression of lncRNA-4045 led to significant up-regulation of AKR1B10 protein in HCC cell lines. Lastly, down-regulation of AKR1B10 could partially eliminate the enhancement of cell proliferation induced by lncRNA-4045 overexpression, while up-regulation of AKR1B10 was shown to enhance those effects., Conclusion: LncRNA-4045 may promote HCC via enhancement of the expression of AKR1B10 protein., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets., Competing Interests: Declaration Of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Breast cancer (BC) is the most abundant and aggressive cancer that impacts millions of women with poorly understood mechanisms. Here, we aimed to investigate the function of LINC01806 in BC development. Human BC tissues and nearby normal specimens were taken from diagnosed BC patients. The expression levels of LINC01806, miR-1286, ZEB1, and EMT-related markers were evaluated by qRT-PCR and western blotting. FISH was used to visualize the subcellular localization of LINC01806. The viability, proliferation, migration and invasion capacities of BC cells were assessed by MTT, colony formation, and transwell assays. Interactions among LINC01806, miR-1286 and ZEB1 were validated by dual luciferase assay. The unpaired Student t-test (for two groups) or one-way ANOVA following with Tukey post-hoc test (for more than three groups) was employed for statistical analysis. LINC01806 level was elevated in BC tissues. Knockdown of LINC01806 suppressed EMT process and BC cell proliferation, migration, and invasion. LINC01806 co-localized and directly bound with miR-1286 in the cytoplasm. MiR-1286 inhibitor blocked the effects of LINC01806 knockdown on BC cell EMT, proliferation and migration. MiR-1286 targeted ZEB1 and overexpression of ZEB1 blocked the regulatory functions of miR-1286 mimics in BC. LINC01806 facilitates EMT and accelerates BC cell proliferation, migration, and invasion via acting as miR-1286 sponge to disinhibit ZEB1 expression., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer 1,2 , but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Endometrial cancer (EC), a widely occurring cancer in the uterus, is among the top four most frequent malignancies in women. To improve approaches for combating this disease, it is essential to gain a more comprehensive comprehension of the intricate causes of EC. Accumulating evidence highlight the essential role of long non-coding RNA (LncRNA) in EC progression, while its biological and mechanical function has not been fully revealed. In this study, a LncRNA microarray analysis was performed using four pairs of paclitaxel (PTX) resistant EC cells, FGD5-AS1 was identified as a significantly upregulated gene. Biologically, it was found that FGD5-AS1 enhances chemoresistance of EC cells to PTX treatment and blocking immune escape via PD-1/PD-L1 checkpoint. Furthermore, FGD5-AS1 exerted an oncogene role in EC cells via promoting cell proliferation and migration. Mechanically, METTL3 could upregulate FGD5-AS1 expression via N6-methyladenosine (m6A) modification. The biological roles of METTL3 were exerted via modulating FGD5-AS1 expression in EC. Collectively, our research has shed light on the involvement of the METTL3/FGD5-AS1 axis in the development of PTX resistance in EC. This finding offers a new avenue for further exploration of the underlying mechanisms of chemoresistance in EC and provides valuable insights for the development of potential therapeutic targets in the treatment of EC., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide with increasing incidence and mortality in developed countries. Oncogenes and microRNAs regulate key signaling pathways in CRC and are known to be deregulated. Oncogenic transcriptional regulator high-mobility group AT-hook 2 (HMGA2) participates in the transformation of several cancers including CRC and exhibits strong correlation with poor prognosis and distal metastasis. Evidence of HMGA2 and its co-regulated miRs contributing to tumor progression remains to be clarified., Methods: We performed gene-set enrichment analysis on the expression profiles of 70 CRC patients and revealed HMGA2 correlated genes that are targeted by several miRs including miR-194. To eliminate the oncogenic effects in HMGA2-driven CRC, we re-expressed miR-194 and found that miR-194 functions as a tumor suppressor by reducing cell proliferation and tumor growth in vitro and in vivo ., Results: As a direct upstream inhibitory regulator of miR-194, overexpression of HMGA2 reduced miR-194 expression and biological activity, whereas re-expressing miR-194 in cells with high levels of HMGA2 impaired the effects of HMGA2, compromising cell survival, the epithelial-mesenchymal transition process, and drug resistance., Conclusion: Our findings demonstrate that novel molecular correlations can be discovered by revisiting transcriptome profiles. We uncover that miR-194 is as important as HMGA2, and both coordinately regulate the oncogenesis of CRC with inverted behaviors, revealing alternative molecular therapeutics for CRC patients with high HMGA2 expression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4 + T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4 + T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Competing Interests: The authors have declared that no competing interests exist.

MYCN, an oncogenic transcription factor of the Myc family, is a major driver of neuroblastoma tumorigenesis. Due to the difficulty in drugging MYCN directly, revealing the molecules in MYCN regulatory networks will help to identify effective therapeutic targets for neuroblastoma therapy. Here we perform ChIP-sequencing and small RNA-sequencing of neuroblastoma cells to determine the MYCN-binding sites and MYCN-associated microRNAs, and integrate various types of genomic data to construct MYCN regulatory networks. The overall analysis indicated that MYCN-regulated genes were involved in a wide range of biological processes and could be used as signatures to identify poor-prognosis MYCN-non-amplified patients. Analysis of the MYCN binding sites showed that MYCN principally served as an activator. Using a computational approach, we identified 32 MYCN co-regulators, and some of these findings are supported by previous studies. Moreover, we investigated the interplay between MYCN transcriptional and microRNA post-transcriptional regulations and identified several microRNAs, such as miR-124-3p and miR-93-5p, which may significantly contribute to neuroblastoma pathogenesis. We also found MYCN and its regulated microRNAs acted together to repress the tumor suppressor genes. This work provides a comprehensive view of MYCN regulations for exploring therapeutic targets in neuroblastoma, as well as insights into the mechanism of neuroblastoma tumorigenesis., Competing Interests: The authors declare no competing financial interests.

Genome-wide cancer mutation analyses are revealing an extensive landscape of functional mutations within the noncoding genome, with profound effects on the expression of long noncoding RNAs (lncRNAs). While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, we now understand that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA. Recent advancements in surveying lncRNA molecular mechanisms are now providing the tools to functionally annotate these cancer-associated transcripts, making these molecules attractive targets for therapeutic intervention in the fight against cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: ArfGAP with GTPase domain, Ankyrin repeat and PH domain 2 Antisense 1 (AGAP2-AS1) is a promising long noncoding RNA that may possess prognostic value for different types of tumors. The objective of this meta-analysis is to evaluate the prognostic value of long noncoding RNA AGAP2-AS1 in cancer patients., Methods: A systematic literature search of the PubMed, Cochrane Library, EMBASE, Medline, Web of Science, CNKI, Weipu, and Wanfang electronic databases were carried out in this meta-analysis. Synthetic hazard ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were obtained to determine the prognostic and clinicopathological significance of AGAP2-AS1 expression in tumors., Results: The final meta-analysis included 10 studies that contained 948 patients. The pooled results provided evidence that AGAP2-AS1 overexpression predicted reduced overall survival (OS) (HR = 1.77, 95% CI: 1.49-2.09, P < .00001), disease-free survival (HR = 1.84, 95% CI: 1.40-2.41, P < .0001), and progression-free survival (HR = 1.84, 95% CI: 1.01-3.33, P = .04) and for various cancers. Additionally, the AGAP2-AS1 overexpression was concerned with lymph node metastasis (positive vs negative, OR = 2.95, 95% CI: 1.96-4.45, P < .00001), advanced tumor node metastasis stage (III/IV vs I/II, OR = 3.73, 95% CI: 2.71-5.13, P < .00001), and tumor size (larger vs smaller, OR = 2.28, 95% CI: 1.24-4.18, P = .008). Besides, data from gene expression profiling interactive analysis dataset verified the results in our meta-analysis. The results showed that the expression level of AGAP2-AS1 was higher in most tumor tissues than in the corresponding normal tissues and was linked to poor OS and disease-free survival., Conclusions: Our results indicated that AGAP2-AS1 overexpression was closely correlated with shorter OS in multiple cancer types, suggesting that AGAP2-AS1 might function as a promising predictor for clinical outcomes in cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Persistent abnormal proliferation and long distant metastasis of tumors contribute to high mortality rate in non-small cell lung cancer (NSCLC) patients. Strategies that prevent NSCLC proliferation and/or metastasis have been studied but still need to be further explored. Numerous studies have proved the diversity functions of long noncoding RNAs (lncRNAs) exerted in cancer, including NSCLC. In this study, we aim to identify and investigate the role of novel lncRNAs in NSCLC progression., Methods: RNA sequence data were retrieved from the Cancer Genome Atlas (TCGA), differentially expressed lncRNAs (DElncRNAs) were screened out based on the R language, then real-time PCR experiment was introduced to detect the DElncRNA expression levels. A series of experiments including MTT, cell cycle, transwell, and wound healing assays were employed to explore the effect of DElncRNA MGC27382 on cell proliferation and invasion ability., Results: We detected that DElncRNA MGC27382 is down-regulated in NSCLC tissues and cells. Overexpression of MGC27382 prevented NSCLC cell proliferation via down-regulating cyclin D1 and cyclin E. Moreover, wound healing and transwell assays indicated that the ability of cell invasion and migration could be impaired when cells were treated with MGC27382 overexpression. Further studies demonstrated that MGC27382-mediated inhibition on NSCLC progression can be impaired by LY294002, which is a frequently used inhibitor of AKT/GSK3β pathway., Conclusion: MGC27382 is down-regulated in NSCLC. It exerts an inhibitory role in NSCLC development through suppressing the AKT/GSK3β pathway. Our results indicate that the lncRNA MGC27382 might be a tumor-suppressor gene in NSCLC. Overexpression of MGC27382 is thought to be a potential strategy for overcoming NSCLC progression., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Non-coding RNAs are involved with maintenance and regulation of physiological mechanisms and are involved in pathological processes, such as cancer. Among the small ncRNAs, miRNAs are the most explored in tumorigenesis, metastasis development, and resistance to chemotherapy. These small molecules of ~ 22 nucleotides are modulated during early renal development, involved in the regulation of gene expression and Wilms' tumor progression. Wilms' tumors are embryonic tumors with few mutations and complex epigenetic dysregulation. In recent years, the small ncRNAs have been explored as potentially related both in physiological development and in the tumorigenesis of several types of cancer. Besides, genes regulated by miRNAs are related to biological pathways as PI3K, Wnt, TGF-β, and Hippo signaling pathways, among others, which may be involved with the underlying mechanisms of resistance to chemotherapy, and in this way, it has emerged as potential targets for cancer therapies, including for Wilms' tumors., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epigenetic alteration is one of the hallmarks of colorectal cancer (CRC). Many driver genes are regulated by DNA methylation in CRC. However, the role of DNA methylation regulating lncRNAs remain elusive. Here, we identify that SNHG11 (small nucleolar RNA host gene 11) is upregulated by promotor hypomethylation in CRC and is associated with poor prognosis in CRC patients. SNHG11 can promote CRC cell migration and metastasis under hypoxia. Interestingly, the DNA-binding motif of SNHG11 is similar to that of HIF-1α. In addition, SNHG11-associated genes are enriched with members of the HIF-1 signaling pathway in CRC. Mechanistically, SNHG11 binds to the pVHLrecognition sites on HIF-1α, thus blocking the interaction of pVHL with HIF-1α and preventing its ubiquitination and degradation. Moreover, SNHG11 upregulates the expression of HIF-1α target genes, i.e., AK4, ENO1, HK2, and Twist1. Notably, SNHG11 can bind to the HRE sites in the promoter of these genes and increase their transcription. In summary, these results identify a SNHG11/ HIF-1α axis that plays a pivotal role in tumor invasion and metastasis.

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.

Long noncoding RNAs (LncRNAs) have emerged as important players in cancer biology. Increasing evidence suggests that LncRNAs are frequently dysregulated in cancer and may function as oncogenes or tumor suppressors. Urothelial carcinoma associated 1 (UCA1), a LncRNA, firstly identified in bladder transitional cell carcinoma, seems to act as an oncogene in many different types of human cancers by promoting cell proliferation and migration. In this study, we revealed a novel biological function of UCA1, which was different from that reported by previous studies, was responsible for maintaining the low-tumorigenic, nonmetastatic phenotypes in primary prostate epithelial cells. UCA1 could stabilize E-cadherin protein by preventing the interaction between E-cadherin and its E3 ligase MDM2, which suppressed MDM2-mediated ubiquitination and degradation of E-cadherin. In addition, we also found that UCA1 acted as a sponge of miR-296-3p, which targeted E-cadherin gene CDH1 messenger RNA at the posttranscription level. Taken together, these findings demonstrated that UCA1 had a new important role in effectively keeping E-cadherin at a high level through a dual mechanism, which maintained primary prostate cancer cells at the low-tumorigenic and nonmetastatic status., (© 2020 Wiley Periodicals LLC.)

A growing number of studies have revealed the critical roles of long noncoding RNAs (lncRNAs) in the tumorigenesis and cancer progression. Recently, next-generation sequencing technologies combined with bioinformatic have demonstrated that a great number of dysregulated lncRNAs are associated with diverse cancers. However, lots of lncRNAs' function and their underlying molecular mechanisms in oral carcinoma (OC) cancer remain unclear. In this study, we performed integrative lncRNA profiling analysis using the TCGA RNA sequencing data and gene microarray data from Gene Expression Omnibus to identify more OC associated lncRNAs. A total of 619 differentially expressed lncRNAs were identified between the five data sets, and only the double homeobox A pseudogene 8 (DUXAP8) was screened among the up-regulated lncRNAs in all the five groups. Meanwhile, univariate Cox regression analyses disclosed that some lncRNAs are associated with the outcome of OC patients, such as DUXAP8, LINC00152, MIR4435-2HG and LINC00582. Furthermore, we uncovered that silenced DUXAP8 expression exerted suppressive impact on the proliferation of OC cells through interacting with histone-lysine N-methyltransferase enzyme Enhancer of zeste homolog 2 (EZH2) and repressing KLF2 expression. In a word, we identified a lot of unreported OC associated lncRNAs, which may provide a useful resource of lncRNAs for other studies.

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.

Long noncoding RNAs (lncRNAs) were demonstrated to play important roles in gene regulation and cancer progression. However, the functional roles of lncRNAs and the detailed mechanisms underlying gastric cancer (GC) progression remain largely unclear. Here, we identified a novel cancer-related lncRNA, termed lncRNA GCMA (Gastric Cancer metastasis-associated lncRNA), which was upregulated in GC tissues with lymph node metastasis (LNM) compared with tissues without LNM. High expression of GCMA was significantly associated with poor prognosis of patients with GC. Luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that SP1 transcription factor directly bound to the GCMA promoter region and activated its transcription. Functionally, upregulation of GCMA dramatically promoted GC cells proliferation, migration and invasion in vitro, whereas knockdown of GCMA elicited the opposite function. Consistently, stable knockdown of GCMA inhibited tumor proliferation, invasion and metastasis in vivo. Mechanistically, by using bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, luciferase assays and western-blot assays, GCMA was demonstrated to function as a competing endogenous RNA (ceRNA) via competitively absorbing miR-124 and miR-34a to upregulate slug and snail, thereby induced epithelial-mesenchymal transition (EMT) and GC cell metastasis in vitro and in vivo. Collectively, these results demonstrate that GCMA functions as an oncogenic lncRNA that may serve as a potential prognostic biomarker for GC and shed new lights on targeted therapy of GC in the future.

Long noncoding RNA HOX antisense intergenic RNA (HOTAIR) is overexpressed in many types of cancers, and substantial evidence has suggested a link between cancers and HOTAIR. In the present study, we reviewed the structure and the corresponding biologic function of HOTAIR to clarify its molecular mechanism in cancer progression. HOTAIR promotes proliferation, invasion, and migration, and inhibits apoptosis in cancer cells. HOTAIR also participates in the pathogenesis and progression of cancer by regulating inflammation and immune signaling. These findings suggested that HOTAIR is a novel biomarker in human cancers., (© 2020 Wiley Periodicals, Inc.)

Long noncoding RNAs (lncRNAs) are a group of non-protein-coding transcripts exceeding 200 nucleotides in length, which are emerging as key players in various fundamental biological processes. Furthermore, it is increasingly recognized that mutation and dysregulation of lncRNAs contribute importantly to a variety of human diseases, particularly human cancers. Previous studies have revealed that altered lncRNAs have a close association with tumorigenesis, metastasis, prognosis and diagnosis of cancers. The present review aims to exhibit a brief overview of the associated reports of lncRNAs in cancers, including colorectal cancer, gastric cancer, lung adenocarcinoma, nasopharyngeal carcinoma, cervical cancer and esophageal cancer. Altogether, we argue that lncRNAs have potential as new biomarkers in cancer prognosis and diagnosis, and as promising therapeutic targets for the prevention and treatment of human cancers.

The long noncoding RNAs (lncRNAs) are associated with tumorigenesis and progression of cancer. While DNA methylation is a common epigenetic regulator of gene expression, the methylation of lncRNAs was rarely studied. To address this gap, we integrated DNA methylation and RNA-seq data to characterize the landscape of lncRNA methylation in colon adenocarcinoma (COAD). We collected and analyzed the lncRNA expression and methylation data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia to identify the epigenetically regulated lncRNAs. We further investigated the biological and clinical relevance of the identified lncRNAs via bioinformatics analysis. We identified 20 epigenetically upregulated lncRNAs in COAD, including several well-studied lncRNAs whose methylation regulation were poorly investigated, such as PVT1 and UCA1. We also revealed several novel tumor-associated lncRNAs in COAD, including GATA2-As1 and CYTOR. Next, we explored their biology function using gene set enrichment analysis and competitive endogenous RNA analysis. We characterized the methylation landscape of lncRNA in COAD and identified 20 epigenetically upregulated lncRNAs. Our findings will shed new light on the epigenetic regulation of lncRNA expression by DNA methylation., (© 2019 Wiley Periodicals, Inc.)

Background: The activation of NF-κB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB signaling pathway. However, the underlying mechanisms have not yet been elucidated., Methods: The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IκBα promoter., Results: We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB signaling pathway, leading to reduced tumorigenesis in vivo., Conclusions: Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-κB signaling pathway and may represent a new therapeutic target of PDAC.

Hypoxia is a salient feature of the tumor microenvironment. HIF-1α is a master regulator of hypoxic adaption. The polycomb repressor complex 2 (PRC2) molecule Ezh2 is known to play roles in essential cellular processes of cell fate decisions. However, how PRC2-mediated epigenetic dynamic changes take part in hypoxic adaption is not completely understood. Recently, we identified a long non-coding RNA (lncRNA) named HITT (HIF-1α inhibitor at translation levels) that plays roles in modulating hypoxia-mediated angiogenesis and tumor growth in vivo. In this study, we reveal an important activity of HITT in evading hypoxia-induced apoptosis by coordinating with PRC2 activity to regulate HIF-1α transcription. Genetic or chemical inhibition of PRC2 significantly elevates HIF-1α mRNA levels. The occupancy of Ezh2 and its substrate H3K27me3 on the HIF-1α promoter is detected under normoxia, and is reduced by hypoxia. Restoring hypoxia-inhibited HITT expression rescues the association between Ezh2/H3K27me3 and the HIF-1α promoter, which also simultaneously abrogates hypoxia-induced HIF-1α mRNA transcription. Further mechanistic studies revealed that HITT inhibits HIF-1α transcription by guiding Ezh2 through the formation of an RNA-DNA triplex with the HIF-1α promoter. Importantly, HITT/Ezh2-regulated HIF-1α transcription leads to alerted HIF-1α protein output and elicits a significant effect to evade hypoxia-induced apoptosis. Importantly, a close association between HIF-1α mRNA and HITT was further verified in human colon cancer tissues in vivo. Collectively, these findings suggest a model for the epigenetic regulation of hypoxia-induced HIF-1α transcription modulated by lncRNA HITT, which provides important insights into how tumor cells sense and adapt to hypoxic stress.

Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence., (©2013 AACR.)

Unlabelled: The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers., Significance: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.

A major function of long non-coding RNAs (lncRNAs) is regulating gene expression through changes in chromatin state. Experimental evidence suggests that in cancer, they can influence Polycomb Repressive Complexes (PRC) to retarget to an occupancy pattern resembling that of the embryonic state. We have previously demonstrated that the expression level of lncRNA in the HOX locus, including HOTAIR, is a predictor of breast cancer metastasis. In this current project, RNA in situ hybridization of probes to three different lncRNAs (HOTAIR, ncHoxA1, and ncHoxD4), as well a immunohistochemical staining of EZH2, is undertaken in formalin-fixed paraffin-embedded breast cancer tissues in a high throughput tissue microarray format to correlate expression with clinicopathologic features. Though overall EZH2 and HOTAIR expression levels were highly correlated, the subset of cases with strong HOTAIR expression correlated with ER and PR positivity, while the subset of cases with strong EZH2 expression correlated with an increased proliferation rate, ER and PR negativity, HER2 underexpression, and triple negativity. Co-expression of HOTAIR and EZH2 trended with a worse outcome. In matched primary and metastatic cancers, both HOTAIR and EZH2 had increased expression in the metastatic carcinomas. This is the first study to show that RNA in situ hybridization of formalin fixed paraffin-embedded clinical material can be used to measure levels of long non-coding RNAs. This approach offers a method to make observations on lncRNAs that may influence the cancer epigenome in a tissue-based technique.

To elucidate mechanisms of cancer progression, we generated inducible human neoplasia in three-dimensionally intact epithelial tissue. Gene expression profiling of both epithelia and stroma at specific time points during tumor progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. A core cancer progression signature was distilled using the increased signaling specificity of downstream oncogene effectors and subjected to network modeling. Network topology predicted that tumor development depends on specific extracellular matrix-interacting network hubs. Blockade of one such hub, the beta1 integrin subunit, disrupted network gene expression and attenuated tumorigenesis in vivo. Thus, integrating network modeling and temporal gene expression analysis of inducible human neoplasia provides an approach to prioritize and characterize genes functioning in cancer progression.

The balance of quiescence and cell division is critical for tissue homeostasis and organismal health. Serum stimulation of fibroblasts is well studied as a classic model of entry into the cell division cycle, but the induction of cellular quiescence, such as by serum deprivation (SD), is much less understood. Here we show that SS and SD activate distinct early transcriptional responses genome-wide that converge on a late symmetric transcriptional program. Several serum deprivation early response genes (SDERGs), including the putative tumor suppressor genes SALL2 and MXI1, are required for cessation of DNA synthesis in response to SD and induction of additional SD genes. SDERGs are coordinately repressed in many types of human cancers compared to their normal counterparts, and repression of SDERGs predicts increased risk of cancer progression and death in human breast cancers. These results identify a gene expression program uniquely responsive to loss of growth factor signaling; members of SDERGs may constitute novel growth inhibitors that prevent cancer., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3beta and beta-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3beta, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3beta/beta-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.

Cancer invasion and metastasis have been likened to wound healing gone awry. Despite parallels in cellular behavior between cancer progression and wound healing, the molecular relationships between these two processes and their prognostic implications are unclear. In this study, based on gene expression profiles of fibroblasts from ten anatomic sites, we identify a stereotyped gene expression program in response to serum exposure that appears to reflect the multifaceted role of fibroblasts in wound healing. The genes comprising this fibroblast common serum response are coordinately regulated in many human tumors, allowing us to identify tumors with gene expression signatures suggestive of active wounds. Genes induced in the fibroblast serum-response program are expressed in tumors by the tumor cells themselves, by tumor-associated fibroblasts, or both. The molecular features that define this wound-like phenotype are evident at an early clinical stage, persist during treatment, and predict increased risk of metastasis and death in breast, lung, and gastric carcinomas. Thus, the transcriptional signature of the response of fibroblasts to serum provides a possible link between cancer progression and wound healing, as well as a powerful predictor of the clinical course in several common carcinomas., Competing Interests: The authors have declared that no conflicts of interest exist.

Backgrounds: Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC., Methods: The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p., Results: We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue., Conclusions: Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

Long non-coding RNA (LncRNA) LINC00160 was reported to be associated with cancer progression and mediates drug resistance. However, the role of LINC00160 in prostate cancer remains unclear. The study sought to study the function of LINC00160 in prostate cancer. Moreover, the potential mechanism was investigated. Silence of LINC00160 inhibited proliferation and promoted the apoptosis of prostate cancer cells, retarded the glycolysis of prostate cancer cells. By acting as a transcription activator, STAT3 induced LINC00160 expression, which regulated RCAN1 transcription epigenetically via binding to EZH2. Mechanically, LINC00160 mediated prostate cell proliferation and metabolism by repressing RCAN1 expression. In summary, LINC00160 may function as the novel marker for prostate cancer diagnosis and therapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metastasis of bladder cancer is a complex process and has been associated with poor clinical outcomes. However, the mechanisms of bladder cancer metastasis remain largely unknown. The present study found that the long noncoding RNA lnc00892 was significantly downregulated in bladder cancer tissues, with low lnc00892 expression associated with poor prognosis of bladder cancer patients. Lnc00892 significantly inhibited the migration, invasion, and metastasis of bladder cancer cells in vitro and in vivo. In-depth analysis showed that RhoA/C acted downstream of lnc00892 to inhibit bladder cancer metastasis. Mechanistically, lnc00892 reduces nucleolin gene transcription by competitively binding the promoter of nucleolin with c-Jun, thereby inhibiting nucleolin-mediated stabilization of RhoA/RhoC mRNA. Taken together, these findings provide novel insights into understanding the mechanisms of bladder cancer metastasis and suggest that lnc00892 can serve as a potential therapeutic target in patients with invasive bladder cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Linc-ROR have been well-demonstrated to play important roles in cancer progression and angiogenesis. However, the underlying oncogenic mechanism of Linc-ROR in hepatocellular carcinoma is poorly understood. In this study, we demonstrate that Linc-ROR plays an oncogenic role in part through its positive regulation of DEPDC1 expression. Mechanistically, Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and regulates DEPDC1 mRNA stability by binding HNRNPK. Thus, these findings suggest that function of Linc-ROR-mediated DEPDC1 could predispose hepatocellular carcinoma patients to progression and angiogenesis, and may serve as a potential target for anticancer therapies., (© 2021. The Author(s).)

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children's Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory networks impact ALL biology and contribute to transcriptomic differences among ALL subtypes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Long non-coding RNAs (LncRNAs) have recently emerged as vital regulators in the development and progression of hepatocellular carcinoma (HCC), providing new opportunities as novel therapeutic targets. Here we identified the lncRNA NIFK-AS1 as being highly expressed in HCC tissues and cells and showed this up-regulation resulted from METTL3-dependent m 6 A methylation. Functionally, knockdown of NIFK-AS1 inhibited the proliferation, colony formation, migration, and invasion of HCC cells. Moreover, these effects were elicited though AKT1 and we uncovered a ceRNA network involving an NIFK-AS1/miR-637/AKT1 axis with downstream effects on HCC progression involving regulation of MMP-7 and MMP-9 expression. From the clinical perspective, we showed that knockdown of NIFK-AS1 sensitized HCC cells to sorafenib through the up-regulation of the drug transporters OATP1B1 and OATP1B3. Clinical investigations showed HCC patients with low NIFK-AS1 expression benefited from sorafenib therapy and this phenomenon was reproduced in patient-derived tumor xenograft models (PDX) comparing HCC with low and high expression of NIFK-AS1. Taken together, these results suggest an essential role for NIFK-AS1 in HCC progression and promote NIFK-AS1 as a new therapeutic target and predictor of sorafenib benefit in HCC patients., (© 2021. Japan Human Cell Society.)

Long noncoding RNA (lncRNA) FOXC2-AS1 has been reported to act as an oncogene in multiple human cancers. However, the clinical significance, functional role and underlying mechanism of FOXC2-AS1 in gastric cancer (GC) remains largely unknown. Here, we found that FOXC2-AS1 expression was significantly elevated in GC tissues and cells, and overexpression of FOXC2-AS1 indicated advanced TNM stage and shorter overall survival in GC patients. Functionally, knockdown of FOXC2-AS1 attenuated the proliferation, migration and invasion of GC cells, whereas overexpression of FOXC2-AS1 showed the opposite effects. Further investigation revealed that FOXC2-AS1 interacted with FOXC2 mRNA and repressed its degradation. FOXC2-AS1 recruited RNA methyltransferase NSUN2 to FOXC2 mRNA, increasing its m 5 C level and association with YBX1. Taken together, our findings suggested that FOXC2-AS1 acted as an oncogenic lncRNA by stabilizing FOXC2 mRNA in an m 5 C-dependent manner, which may provide a novel therapeutic target for GC., (© 2021. Japan Human Cell Society.)

Some lncRNA-associated competing endogenous RNAs (ceRNAs) are considered as potential biomarkers for targeted therapies and prognosis in human cancer. In our present study, we aimed to construct a ceRNA network and establish a genomic-clinicopathologic nomogram to provide insights into the molecular mechanisms and predict survival for HBV-related HCC. The Cancer Genome Atlas (TCGA) database was applied to collect the data of LIHC RNA-seq dataset and miRNA-seq dataset as well as the clinicopathological information. Identification of differentially expressed RNAs (mRNAs, lncRNAs, and miRNAs) between HBV-related HCC samples and normal samples was conducted using Limma package in R. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for performing the functional enrichment analysis of differentially expressed mRNAs. The ceRNA network was carried out using Cytoscape. The LASSO-penalized Cox regression analysis was implemented to identify HCC-related lncRNAs, and the multivariate Cox regression analysis was conducted for the establishment of a genomic-clinicopathology nomogram. A total of 1859 DEmRNAs, 113 DElncRNAs, and 89 DEmiRNAs were screened out etween HBV-related HCC samples and normal samples. A ceRNA network including 44 DEmRNAs, 7 DElncRNAs, and 20 DEmiRNAs was constructed. 7 DElncRNAs (PVT1, LINC01138, LINC02499, AL355488.2, FGF14-AS2, MAFG-AS1 and LINC00261) were finally identified as prognostic indicators. The area under the curve reached 0.8169 for the 7-lncRNA signature. The predictive accuracy and clinical application value were remarkably high for the genomic-clinicopathologic nomogram integrating the histological grade and the 7-gene-based prognostic index. Taken together, we have established a ceRNA network with HBV-related HCC-specific DElncRNAs, DEmiRNAs, and DEmRNAs. Furthermore, the genome-wide data of lncRNA expression were analyzed using the TCGA database, and a 7-lncRNA signature was identified as a potential prognostic predictor for HBV-related HCC patients. Novel functional studies were provided by our current findings for elucidating the molecular mechanism of lncRNA in HBV-related HCC., (© 2021. Japan Human Cell Society.)