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.     

Molecular characterization of lung cancer: A two-miRNA prognostic signature based on cancer stem-like cells related genes

Lung cancer is one of the deadliest cancers worldwide. To increase the survival rate of lung cancer, it is necessary to explore specific prognosis markers. More and more evidence finds that noncoding RNA is closely associated with the survival of lung cancer, and cancer stem cells (CSCs) also play a significant role in the progress of lung cancer. The objective of this study is to find CSLCs genes that affect the prognosis of lung cancer. The differential expression of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs) in the Cancer Genome Atlas (TCGA) database and differential expression data from microarray of CD326⁺ and CD326⁻ A549 cell are intersected to identify stable and consistent expression genes (2 lncRNAs, 15 miRNAs, and 134 mRNAs). The intersection of lncRNAs and miRNAs is analyzed by univariate and multivariate Cox regression to obtained prognostic genes. Two miRNAs (miR-30b-5p and miR-29c-3p) are significantly correlated with the overall survival rate. Then using these two miRNAs to construct a risk score model as a prognosis signature of lung cancer. Subsequently, we analyzed the association between two miRNAs and clinical information of lung cancer patients, of which T stage, Neoplasm cancer and risk score (P < .05) can be used as independent prognostic indicators of lung cancer. Finally, target genes of 2 miRNAs and 134 mRNAs were annotated with Gene Ontology and analyzed with Kyoto Encyclopedia of Genes and Genomes pathway, and verified with the GEO database. In summary, this study illustrates the role of miRNAs in the promotion of lung cancer by CSCs, which is important to find molecular biomarkers of lung cancer.     

ZEB1‐AS1: A crucial cancer‐related long non‐coding RNA

Long non‐coding RNAs (lncRNAs) recently emerge as a novel class of non‐coding RNAs (ncRNAs) with larger than 200 nucleotides in length. Due to lack an obvious open reading frame, lncRNAs have no or limited protein‐coding potential. To date, accumulating evidence indicates the vital regulatory function of lncRNAs in pathological processes of human diseases, especially in carcinogenesis and development. Deregulation of lncRNAs not only alters cellular biological behavior, such as proliferation, migration and invasion, but also represents the poor clinical outcomes. Zinc finger E‐box binding homeobox 1 antisense 1 (ZEB1‐AS1), an outstanding cancer‐related lncRNA, is identified as an oncogenic regulator in diverse malignancies. Dysregulation of ZEB1‐AS1 has been demonstrated to exhibit a pivotal role in tumorigenesis and progression, suggesting its potential clinical value as a promising biomarker or therapeutic target for cancers. In this review, we make a summary on the current findings regarding the biological functions, underlying mechanisms and clinical significance of ZEB1‐AS1 in cancer progression.     

The lncRNA ZEB1-AS1 sponges miR-181a-5p to promote colorectal cancer cell proliferation by regulating Wnt/β-catenin signaling

Long noncoding RNAs (lncRNAs) are important regulators of the biological functions and underlying molecular mechanisms of colorectal cancer (CRC). However, the role of the lncRNA ZEB1-AS1 in CRC is not thoroughly understood. In this study, we found that ZEB1-AS1 was markedly upregulated in CRC. ZEB1-AS1 knockdown significantly suppressed CRC cell proliferation and induced apoptosis, whereas enhanced expression of ZEB1-AS1 had the opposite effect. Bioinformatics analysis identified miR-181a-5p as a candidate target of ZEB1-AS1. Moreover, we found an inverse correlation between ZEB1-AS1 and miR-181a-5p expression in CRC tissue. Inhibition of miR-181a-5p significantly upregulated ZEB1-AS1, whereas overexpression of miR-181a-5p had the opposite effect, suggesting that ZEB1-AS1 is negatively regulated by miR-181a-5p. Using luciferase reporter and RIP assays, we found that miR-181a-5p directly targets ZEB1-AS1. Importantly, ZEB1-AS1 may act as an endogenous ‘sponge’ to regulate miRNA targets by competing for miR-181a-5p binding. In summary, our findings provide the evidence supporting the role of ZEB1-AS1 as an oncogene in CRC. Our study also demonstrates that miR-181a-5p targets not only protein-coding genes but also the lncRNA ZEB1-AS1.     

The miRNA hsa-miR-6515-3p potentially contributes to lncRNA H19-mediated-lung cancer metastasis

Aberrant expression of long noncoding RNAs (lncRNAs) contributes to all phenotypes of cancer including metastasis, which is a major cause of death in many advanced malignancies. One particular lncRNA, H19, is found to be a crucial player in cancer progression by modulating multiple microRNAs (miRNAs). In this study, we screened miRNAs possibly associated with H19 using lung carcinoma cell lines and patient with lung cancer tissues, and selected one possible hit, hsa-miR-6515-3p, to perform in vitro functional assays. Its inhibition leads to decreased proliferation and migration of SPC-A1 lung cancer cells and is in good correlation with H19-knockdown groups. These results indicate that H19 may be an epigenetic regulator of miR-6515-3p, and its dysregulation may contribute to lung cancer progression and metastasis.     

Cancer Specific Long Noncoding RNAs Show Differential Expression Patterns and Competing Endogenous RNA Potential in Hepatocellular Carcinoma

Long noncoding RNAs (lncRNAs) regulate gene expression by acting with microRNAs (miRNAs). However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in hepatocellular cell carcinoma (HCC) are not fully understood. The lncRNA profiles in 372 HCC patients, including 372 tumor and 48 adjacent non-tumor liver tissues, from The Cancer Genome Atlas (TCGA) and NCBI GEO omnibus (GSE65485) were analyzed. Cancer specific lncRNAs (or HCC related lncRNAs) were identified and correlated with clinical features. Based on bioinformatics generated from miRcode, starBase, and miRTarBase, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in HCC. We found 177 cancer specific lncRNAs in HCC (fold change ≥ 1.5, P < 0.01), 41 of them were also discriminatively expressed with gender, race, tumor grade, AJCC tumor stage, and AJCC TNM staging system. Six lncRNAs (CECR7, LINC00346, MAPKAPK5-AS1, LOC338651, FLJ90757, and LOC283663) were found to be significantly associated with overall survival (OS, log-rank P < 0.05). Collectively, our results showed the lncRNA expression patterns and a complex ceRNA network in HCC, and identified a complex cancer specific ceRNA network, which includes 14 lncRNAs and 17 miRNAs in HCC.     

Close interactions between lncRNAs,lipid metabolism and ferroptosis in cancer

Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.     

Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition

Recent studies reveal that long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and lncRNA MALAT-1 expression is upregulated in some tumors. However, the contributions of MALAT-1 to bladder cancer metastasis remain largely unknown. In the present study we evaluated MALAT-1 expression in bladder cancer tissues by real-time PCR, and defined its biological functions. We verified that MALAT-1 levels were upregulated in bladder cancer tissues compared with adjacent normal tissues, and MALAT-1 expression was remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. SiRNA-mediated MALAT-1 silencing impaired in vitro bladder cancer cell migration. Downregulation of MALAT-1 resulted in a decrease of the epithelial-mesenchymal transition (EMT)-associated ZEB1, ZEB2 and Slug levels, and an increase of E-cadherin levels. We further demonstrated that MALAT-1 promoted EMT by activating Wnt signaling in vitro. These data suggest an important role for MALAT-1 in regulating metastasis of bladder cancer and the potential application of MALAT-1 in bladder cancer therapy.     

LINC00657 expedites neuropathic pain development by modulating miR-136/ZEB1 axis in a rat model

Long non-coding RNAs (lncRNAs) are involved in the progression of several diseases. The interactions among lncRNAs, microRNA (miRNAs) or their targeting genes are reported to play crucial roles in the development of diseases. LINC00657 is observed to be upregulated in several cancers. However, the biological role of LINC00657 in neuropathic pain progress is unclear. Hence, in our study, we aimed to investigate the function of LINC00657 in neuropathic pain development. A chronic constriction injury (CCI) rat model was established, and we found that LINC00657 was greatly increased in CCI rats associated with a decrease of miR-136. Inhibition of LINC00657 suppressed neuropathic pain via alleviating mechanical and thermal hyperalgesia. In addition, miR-136 overexpression can also inhibit the neuropathic pain development. MiR-136 was predicted to serve as a miRNA target of LINC00657, and dual-luciferase reporter assay confirmed the correlation between LINC00657 and miR-136. Moreover, we observed that the decrease of LINC00657 was able to inhibit the neuroinflammation of CCI rats by targeting expression of cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β while miR-136 inhibitors reversed this phenomenon. Next, by using bioinformatics analysis, ZEB1 was predicted as a direct target of miR-136, and miR-136 could negatively modulate ZEB1 expression. Besides these, ZEB1 was remarkably increased in the CCI rats. Knockdown of ZEB1 can inhibit neuropathic pain development, while miR-136 inhibitors can reverse it. In conclusion, it was implied that LINC00657 can induce the neuropathic pain development via regulating miR-136/ZEB1 axis.     

Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension

The incidence of hypoxic pulmonary hypertension (HPH) is increasing. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play an important role in HPH, but the functions and mechanism have yet to be fully elucidated. In the present study, we established a HPH rat model with 8 h of hypoxia exposure (10% O₂) per day for 21 days. High-throughput sequencing identified 60 differentially expressed (DE) lncRNAs, 20 DE miRNAs and 695 DE mRNAs in rat lung tissue. qRT-PCR verified the accuracy of the results. The DE mRNAs were significantly enriched in immune response, inflammatory response, leukocyte migration, cell cycle, cellular response to interleukin-1, IL-17 signalling pathway, cytokine–cytokine receptor interaction and Toll-like receptor signalling pathway. According to the theory of competing endogenous RNA (ceRNA) networks, lncRNA–miRNA–mRNA network was constructed by Cytoscape software, 16 miRNAs and 144 mRNAs. The results suggested that seven DE lncRNAs (Ly6l, AABR07038849.2, AABR07069008.2, AABR07064873.1, AABR07001382.1, AABR07068161.1 and AABR07060341.2) may serve as molecular sponges of the corresponding miRNAs and play a major role in HPH.     

New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diversity of neurological disorders characterized by the progressive degeneration of the structure and function of the central nervous system (CNS). The most common NDs are Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, many studies have investigated associations between common NDs with noncoding RNAs (ncRNAs) molecules. ncRNAs are regulatory molecules in the normal functioning of the CNS. Two of the most important ncRNAs are microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). These types of ncRNAs are involved in different biological processes including brain development, maturation, differentiation, neuronal cell specification, neurogenesis, and neurotransmission. Increasing data has demonstrated that miRNAs and lncRNAs have strong correlations with the development of NDs, particularly gene expression. Besides, ncRNAs can be introduced as new biomarkers for diagnosis and prognosis of NDs. Hence, in this review, we summarized the involvement of various miRNAs and lncRNAs in most common NDs followed by a correlation of ncRNAs dysregulation with the AD, PD, and HD.     

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.     

Long noncoding RNA MEG3 play an important role in osteosarcoma development through sponging microRNAs

More and more evidence indicate long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) to indirectly regulate messenger RNAs (mRNAs) by acting as microRNA (miRNA) sponges, which represents a novel layer of gene regulation that plays a critical role in the development of cancers. However, functional roles and regulatory mechanisms of lncRNA-mediated ceRNAs network in osteosarcoma are still largely unknown. Here, we comprehensively compared the expression profiles of mRNAs, lncRNAs, and miRNAs between osteosarcoma and normal samples from the Gene Expression Omnibus (GEO) to elaborate related latent mechanisms. Two lncRNAs, ie, LINC01560 and MEG3, were identified to be aberrantly expressed. Importantly, MEG3 was considered as a promising diagnostic biomarker and therapeutic target for patients with osteosarcoma according to the Kaplan-Meier analysis of another independent osteosarcoma data set from the Cancer Genome Atlas (P = 0.05). Eventually, we successfully established a dysregulated lncRNA-related ceRNA network, including one osteosarcoma-specific lncRNA, three miRNAs and four mRNAs. In conclusion, this study should be beneficial for improving our understanding of the lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of osteosarcoma and providing it with novel candidate diagnostic and therapeutic biomarkers.