Temporal expression and functional analysis of long non‐coding RNAs in colorectal cancer initiation

Long non‐coding RNAs (lncRNAs) have potential applications in clinical diagnosis and targeted cancer therapies. However, the expression profile of lncRNAs in colorectal cancer (CRC) initiation is still unclear. In this study, the expression profiles of lncRNAs and mRNAs were determined by microarray at specific tumour stages in an AOM/DSS‐induced primary colon cancer model. The temporal expression of lncRNAs was analysed by K‐means clustering. Additionally, weighted correlation network analysis (WGCNA) and gene ontology analysis were performed to construct co‐expression networks and establish functions of the identified lncRNAs and mRNAs. Our results suggested that 4307 lncRNAs and 5798 mRNAs are deregulated during CRC initiation. These differential expression genes (DEGs) exhibited a clear correlation with the differential stage of tumour initiation. WGCNA results suggested that a series of hub lncRNAs are involved in regulating cell stemness, colon inflammation, oxidative stress response and cell death at each stage. Among them, lncRNA H19 was up‐regulated in colon tumours and correlated with poor patient prognosis. Collectively, we have been the first to demonstrate the temporal expression and function of lncRNAs in CRC initiation. These results provide novel diagnosis and therapy targets for CRC.     

Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG,and hypomethylation of TRPM2-AS1 promoter in colorectal cancer

Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.     

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

LncRNAs play a pivotal role in the regulation of epigenetic modification, cell cycle, differentiation, proliferation, migration and other physiological activities. In particular, considerable studies have shown that the aberrant expression and dysregulation of lncRNAs are widely implicated in cancer initiation and progression by acting as tumour promoters or suppressors. Hippo signalling pathway has attracted researchers’ attention as one of the critical cancer‐related pathways in recent years. Increasing evidences have demonstrated that lncRNAs could interact with Hippo cascade and thereby contribute to acquisition of multiple malignant hallmarks, including proliferation, metastasis, relapse and resistance to anti‐cancer treatment. Specifically, Hippo signalling pathway is reported to modulate or be regulated by widespread lncRNAs. Intriguingly, certain lncRNAs could form a reciprocal feedback loop with Hippo signalling. More speculatively, lncRNAs related to Hippo pathway have been poised to become important putative biomarkers and therapeutic targets in human cancers. Herein, this review focuses on the crosstalk between lncRNAs and Hippo pathway in carcinogenesis, summarizes the comprehensive role of Hippo‐related lncRNAs in tumour progression and depicts their clinical diagnostic, prognostic or therapeutic potentials in tumours.     

长链非编码RNA相关表观遗传修饰在癌症中的进展*

长链非编码RNA(lncRNA)是一类转录本长度大于200 nt的RNA分子,编码蛋白质的功能有限,但其功能多样且复杂。已有研究报道lncRNA与肿瘤的发展进程密切相关,lncRNA可以通过不同方式参与细胞内生物学进程的调控,是潜在的癌症调节因子,其中,调节表观遗传修饰水平是其影响癌症进程的主要手段;癌症发病过程中细胞内存在着不同程度的表观遗传修饰,其主要为包括甲基化、乙酰化、磷酸化、糖基化、泛素化等修饰方式在内的DNA修饰、RNA修饰以及蛋白质的翻译后修饰,在癌症的不同阶段其修饰的异常程度不同,从而影响肿瘤发生的生物学进程。研究表明,lncRNA可以通过自身修饰或参与其他生物大分子的表观遗传修饰进程参与癌症的发生发展。因此,回顾了lncRNA所参与的表观遗传修饰形式和lncRNA在表观遗传修饰方面所起到的作用,并概述了lncRNA通过影响表观遗传修饰水平从而调控癌症进程的方法。旨在总结癌症细胞内表观遗传修饰方面所涉及lncRNA的研究进展,为癌症诊断和治疗提供潜在的靶标和生物学标志物。     

Long non-coding RNAs and their implications in cancer epigenetics

LncRNAs (long non-coding RNAs) have emerged as key molecular players in the regulation of gene expression in different biological processes. Their involvement in epigenetic processes includes the recruitment of histone-modifying enzymes and DNA methyltransferases, leading to the establishment of chromatin conformation patterns that ultimately result in the fine control of genes. Some of these genes are related to tumorigenesis and it is well documented that the misregulation of epigenetic marks leads to cancer. In this review, we highlight how some of the lncRNAs implicated in cancer are involved in the epigenetic control of gene expression. While very few lncRNAs have already been identified as players in determining the cancer-survival outcome in a number of different cancer types, for most of the lncRNAs associated with epigenetic regulation only their altered pattern of expression in cancer is demonstrated. Thanks to their tissue-specificity features, lncRNAs have already been proposed as diagnostic markers in specific cancer types. We envision the discovery of a wealth of novel spliced and unspliced intronic lncRNAs involved in epigenetic networks or in highly location-specific epigenetic control, which might be predominantly altered in specific cancer subtypes. We expect that the characterization of new lncRNA (long non-coding RNA)–protein and lncRNA–DNA interactions will contribute to the discovery of potential lncRNA targets for use in therapies against cancer.     

The prognostic and therapeutic values of long noncoding RNA PANDAR in colorectal cancer

Long noncoding RNAs (lncRNAs) consist of 200 nucleotide sequences that play essential roles in different processes, including cell proliferation, and differentiation. There is evidence showing that the dysregulation of lncRNAs promoter of CDKN1A antisense DNA damage-activated RNA (PANDAR) leads to the development and progression in several cancers including colorectal cancer, via p53-dependent manner. This suggests that these lncRNAs may be of value as prognostic indices and a therapeutic target, as a high expression of lncRNAs PANDAR is associated with poor prognosis. Furthermore, modulating lncRNAs PANDAR has been reported to induce apoptosis and inhibit the tumor growth through modulation of cell cycle and epithelial-mesenchymal transition (EMT) pathway. The aim of the current review was to provide an overview of the prognostic and therapeutic values of lncRNAs PANDAR in colorectal cancer     

Long non‐coding RNAs in non‐small cell lung cancer as biomarkers and therapeutic targets

Lung cancer‐associated mortality is the most common cause of cancer death worldwide. Non‐coding RNAs (ncRNAs), with no protein‐coding ability, have multiple biological roles. Long non‐coding RNAs (lncRNAs) are a recently characterized class of ncRNAs that are over 200 nucleotides in length. Many lncRNAs have the ability of facilitating or inhibiting the development and progression of tumours, including non‐small cell lung cancer (NSCLC). Because of their fundamental roles in regulating gene expression, along with their involvement in the biological mechanisms underlying tumourigenesis, they are a promising class of tissue‐ and/or blood‐based cancer biomarkers. In this review, we highlight the emerging roles of lncRNAs in NSCLC, and discuss their potential clinical applications as diagnostic and prognostic markers and as therapeutic targets.     

Rise of the RNA Machines: Exploring the Structure of Long Non-Coding RNAs

Novel, profound and unexpected roles of long non-coding RNAs (lncRNAs) are emerging in critical aspects of gene regulation. Thousands of lncRNAs have been recently discovered in a wide range of mammalian systems, related to development, epigenetics, cancer, brain function and hereditary disease. The structural biology of these lncRNAs presents a brave new RNA world, which may contain a diverse zoo of new architectures and mechanisms. While structural studies of lncRNAs are in their infancy, we describe existing structural data for lncRNAs, as well as crystallographic studies of other RNA machines and their implications for lncRNAs. We also discuss the importance of dynamics in RNA machine mechanism. Determining commonalities between lncRNA systems will help elucidate the evolution and mechanistic role of lncRNAs in disease, creating a structural framework necessary to pursue lncRNA-based therapeutics.     

Expression profile of lncRNAs and miRNAs in esophageal cancer: Implications in diagnosis,prognosis, and therapeutic response

Esophageal cancer is the seventh most common cancer worldwide. Although a number of environmental and lifestyle-related risk factors have been identified for this kind of cancer, the exact molecular mechanisms of tumor evolution have not been clarified yet. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) as important regulators of gene expression and chromatin configuration have essential roles in the pathogenesis of esophageal cancer. They have been shown to alter the function of cancer-related signaling pathways such as phosphoinositide 3-kinase/protein kinase B and Wnt pathway, thus they might modulate the response of patients to pathway-targeted therapies. Moreover, a number of lncRNAs, such as AFAP1-AS1, UCA1, HOTAIR, LOC285194, and TUSC7, are involved in conferring chemoresistant/radioresistant in esophageal cancer cells. A complex network of interaction exists between lncRNAs and miRNAs in the context of esophageal cancer. Finally, various panels of lncRNAs and miRNAs have been introduced that can predict the survival of esophageal cancer patients. In this review article, we summarize the recent findings regarding the role of miRNAs and lncRNAs in the pathogenesis of esophageal cancer with the special focus on their regulatory roles on signaling pathways, their potential as diagnostic/prognostic markers, and their relevance with therapeutic response.     

Systematic identification of dysregulated lncRNAs associated with platinum-based chemotherapy response across 11 cancer types

Aberrant expression of long non-coding RNAs (lncRNAs) leads to the development of chemoresistance by regulating a series of biological processes, which is one of the major obstacles in the cancer treatment. This study aimed to identify some key lncRNAs that are associated with platinum-based chemoresistance in multiple cancers. Regulating the expression levels of these lncRNAs can enhance the sensitivity of patients to chemotherapy drugs and improve the therapeutic effect of cancer. By systematically analyzing 648 samples regarding platinum drug response from the Cancer Genome Atlas (TCGA), we have identified 32 dysregulated lncRNAs across 11 cancer types that could affect platinum-based chemotherapy response, of which 78.125% (25/32) were significantly down-regulated in drug-resistant samples. Drug response prediction model that had been constructed based on the expression pattern of these dysregulated lncRNAs could accurately predict the chemotherapy response of tumor patients, and the area under the curve (AUC) was between 0.8034 and 0.9984. In particular, all of these dysregulated lncRNAs that we identified were cancer-specific. They were significantly associated with the survival of tumor patients and could serve as cancer-specific biomarkers for prognosis. In conclusion, this study will contribute to improving the drug resistance of tumor patients during chemotherapy, and it is of real significance for selecting effective chemotherapy drugs and achieving precision medicine.     

An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells

Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non-small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing. Selected candidate lncRNAs were further characterized by PCR, gene-ontology analysis, and targeted bisulfite sequencing. Differential expression in response to therapy was observed more frequently in cis-acting than in overlapping lncRNAs (78% vs. 22%, fold change ≥1.5), while significantly altered methylation profiles were more commonly associated with overlapping lncRNAs (29% vs. 8%; P value <0.001). Moreover, overlapping lncRNAs contain more CpG islands (CGIs) (25% vs. 17%) and the majority of CGI-containing overlapping lncRNAs share these CGIs with their associated coding genes (84%). The differences in expression between sensitive and resistant cell lines were replicated in 87% of the selected candidates (P<0.05), while our bioinformatics approach identifying differential methylation was confirmed in all of the selected lncRNAs (100%). Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444). These novel findings provide new insights into epigenetic mechanisms and acquired resistance to cisplatin that highlight specific lncRNAs, some with unknown function, that may signal strategies in epigenetic therapies.