HOTAIR: an oncogenic long non-coding RNA in different cancers

Long non-coding RNAs (lncRNAs) refer to a group of RNAs that are usually more than 200 nucleotides and are not involved in protein generation. Instead, lncRNAs are involved in different regulatory processes, such as regulation of gene expression. Different lncRNAs exist throughout the genome. LncRNAs are also known for their roles in different human diseases such as cancer. HOTAIR is an lncRNA that plays a role as an oncogenic molecule in different cancer cells, such as breast, gastric, colorectal, and cervical cancer cells. Therefore, HOTAIR expression level is a potential biomarker for diagnostic and therapeutic purposes in several cancers. This RNA takes part in epigenetic regulation of genes and plays an important role in different cellular pathways by interacting with Polycomb Repressive Complex 2 (PRC2). In this review, we describe the molecular function and regulation of HOTAIR and its role in different types of cancers.KEYWORDS : HOTAIR, long non-coding RNA (lncRNA), epigenetic, cancer     

Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes

Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.     

High expression of long non‐coding RNA AFAP1‐AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy

To evaluate the clinical significance of lncRNAs in the resistance to cisplatin‐based chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). We focused on lncRNAs which were frequently reported in ESCC or were involved in chemoradiotherapy resistance. LncRNA expressions were examined in paired cisplatin‐resistant and parental ESCC cell lines. Dysregulated lncRNAs were further measured in 162 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (dCRT). Then the correlations between lncRNA expression and response to dCRT and prognosis were analyzed. Three lncRNAs (AFAP1‐AS1, UCA1, HOTAIR) were found to be deregulated in cisplatin‐resistant cells compared with their parent cells. AFAP1‐AS1 was significantly up‐regulated in tumor tissues compared with adjacent normal tissues (P = 0.006). Furthermore, overexpression of AFAP1‐AS1 was closely associated with lymph node metastasis (P < 0.001), distant metastasis (P = 0.016), advanced clinical stage (P = 0.002), and response to dCRT (P < 0.001). Kaplan–Meier survival analysis revealed that high expression of AFAP1‐AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001). In the multivariate analysis, high expression of AFAP1‐AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004). Thus, high expression of AFAP1‐AS1 could serve as a potential biomarker to predict tumor response and survival. Determination of this lncRNA expression might be useful for selection ESCC patients for dCRT. © 2016 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.     

长链非编码RNA在非小细胞肺癌中的研究进展

肺癌是全球发病率最高，也是死亡率最高的恶性肿瘤之一,非小细胞肺癌占肺癌的绝大部分。目前发现大量的非编码RNA(long non-coding RNA，lncRNAs)极大地改变了人们对肿瘤的理解。lncRNAs是一组非编码的RNA(ncRNAs)超过200个核苷酸，不具有蛋白质编码能力。越来越多的证据表明，特定的lncRNAs可能参与肿瘤发生的过程。它们参与了多重分子调控以及基因表达变化相关的途径，重要的是据报道，lncRNAs与肺癌的治疗有关，包括化疗、分子靶向治疗等，它们可以作为潜在肺癌的诊断生物学指标或目标。本文将对长链非编码RNA在非小细胞肺癌中的研究进展作一综述。     

Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR

Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.     

Long Noncoding RNA in Digestive Tract Cancers: Function,Mechanism, and Potential Biomarker

Digestive tract cancers (DTCs) are a leading cause of cancer-related death worldwide. Current therapeutic tools for advanced stage DTCs have limitations, and patients with early stage DTCs frequently have a missed diagnosis due to shortage of efficient biomarkers. Consequently, it is necessary to develop novel biomarkers for early diagnosis and novel therapeutic targets for treatment of DTCs. In recent years, long noncoding RNAs (lncRNAs), a class of noncoding RNAs with >200 nucleotides, have been shown to be aberrantly expressed in DTCs and to have an important role in DTC development: the expression profiles of lncRNAs strongly correlated with poor survival of patients with DTCs, and lncRNAs acted as oncogenes or tumor suppressor genes in DTC progression. In this review, we summarized the functional lncRNAs and expounded on their regulatory mechanisms in DTCs.

Implications for Practice:

Digestive tract cancers (DTCs) are a leading cause of cancer-related death worldwide. It is necessary to exploit novel biomarkers for early diagnosis and novel therapeutic targets for treatment of DTCs. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs with approximately 200 nucleotides to 100,000 bases, participate in the progression of a variety of diseases. This review summarizes functional lncRNAs, which were shown to serve as novel biomarkers for diagnosis and prognosis of DTCs and to act as oncogenes or tumor suppressor genes in DTC development. In addition, the potential mechanism of functional lncRNAs in DTCs is highlighted.     

A functional variant in HOXA11-AS,a novel long non-coding RNA,inhibits the oncogenic phenotype of epithelial ovarian cancer

The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants.     

Six mutator-derived lncRNA signature of genome instability for predicting the clinical outcome of colon cancer

BackgroundColon adenocarcinoma (COAD) is one of the most common malignancies worldwide. Genomic instability is one of the hallmarks of colon cancer and is associated with prognosis. Nevertheless, the impact of genome instability-associated long non-coding RNAs (lncRNAs) along with their clinical significance in cancers has remained mostly unexplored.MethodsIn this study, a mutator hypothesis-derived computational frame integrating the somatic mutation profiles and lncRNA expression profiles in a tumor genome was developed, which enabled the identification of 137 novel genomic instability-associated lncRNAs in colon cancer. Subsequently, a genome instability-derived lncRNA signature (GILncSig) segregated the patients into low- and high-risk groups with prominent differences in outcomes.ResultsCombined with the overall survival data, we established 6 six lncRNA-based signature to predict prognosis, which were LINC00896, AC007996.1, NKILA, {"type":"entrez-nucleotide","attrs":{"text":"AP003555.2","term_id":"17426126"}}AP003555.2, MIRLET7BHG, and AC009237.14. We found that the expression level of PD-L1 (CD274) and somatic mutations in the high-risk group were higher than those in the low-risk group. This suggests that high-risk patients may be sensitive to immunotherapy. We further found that the prognosis of patients in the high-risk group was significantly lower than that of patients in the low-risk group, and that patients’ prognosis was likely to be worse as the patient’s risk score increased.ConclusionsIn conclusion, this study explores the role of lncRNAs in genomic instability and cancer prognosis and provides a new idea for the prognostic prediction of colon cancer.     

Non-coding RNAs: emerging regulators of glucose metabolism in hepatocellular carcinoma

Reprogramming of metabolism is one of the hallmarks of cancer, among which glucose metabolism dysfunction is the most prominent feature. The glucose metabolism of tumor cells is significantly different from that of normal cells. Glucose metabolism reprogramming of hepatocellular carcinoma (HCC) has become an important research hotspot in the field of HCC, a variety of tumor metabolic interventions have been applied clinically. Moreover, various Non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding (lncRNAs) as well as circular RNAs (circRNAs), have recently been proved to play potential roles in glucose metabolism. This review summarizes the effects of ncRNAs on HCC that participate in glucose metabolism and discuss the related mechanisms to find potential and effective targeted treatments for HCC.     

Expression of long noncoding RNAs in cancer‐associated fibroblasts linked to patient survival in ovarian cancer

Cancer‐associated fibroblasts (CAFs) are the most abundant cell type in the tumor microenvironment and are responsible for producing the desmoplastic reaction that is a poor prognostic factor in ovarian cancer. Long non‐coding RNAs (lncRNAs) have been shown to play important roles in cancer. However, very little is known about the role of lncRNAs in the tumor microenvironment. We aimed to identify lncRNAs expressed in ovarian CAFs that were associated with patient survival and used computational approaches to predict their function. Increased expression of 9 lncRNAs and decreased expression of 1 lncRNA in ovarian CAFs were found to be associated with poorer overall survival. A “guilt‐by‐association” approach was used to predict the function of these lncRNAs. In particular, MIR155HG was predicted to play a role in immune response. Further investigation revealed high MIR155HG expression to be associated with higher infiltrates of immune cell subsets. In conclusion, these data indicate expression on several lncRNAs in CAFs are associated with patient survival and are likely to play an important role in regulating CAF function.     

lncRNAs在淋巴造血系统肿瘤中的研究进展

长链非编码RNAs（long noncoding RNAs,lncRNAs）是长度≥200个核苷酸的非蛋白编码转录子。多数lncRNAs在肿瘤组织中显示致癌基因的作用,通过影响肿瘤细胞的增生、迁移、浸润和转移促进肿瘤的发生发展;部分lncRNAs已成为特定肿瘤的诊断及预后标志物。对其表达、功能及机制的研究成为当前肿瘤研究的热点,但多集中于上皮源性肿瘤。本文旨在对lncRNAs在淋巴造血系统肿瘤中的研究进展进行综述。      

The treatment of mouse colorectal cancer by oral delivery tumor-targeting Salmonella

Systemic administration of Salmonella to tumor-bearing mice leads to its preferential accumulation in tumor sites, the enhancement of host immunity, and the inhibition of tumor growth. However, the underlying mechanism for Salmonella-induced antitumor immune response via oral delivery remained uncertain. Herein, we used mouse colorectal cancer (CT26) as tumor model to study the therapeutic effects after oral delivery of Salmonella. When orally administered into tumor-bearing mice, Salmonella significantly accumulated in the tumor sites, inhibited tumor growth and extended the survival of mice. No obvious toxicity was observed during orally administered Salmonella by examining body weight and inflammatory cytokines. As indoleamine 2, 3-dioxygenase 1 (IDO) is a crucial mediator for tumor-mediated immune tolerance, we examined the expression of IDO. We demonstrated that Salmonella inhibited IDO expression in mouse cancer cells. Furthermore, immunohistochemical studies of the tumors revealed the infiltration of neutrophils and T cells in mice treated with Salmonella. In conclusion, our results indicate that Salmonella exerts its tumoricidal effects and stimulates T cell activities by inhibiting IDO expression. Oral delivery of Salmonella may, represent a potential strategy for the treatment of tumor.