Potential of long non‐coding RNAs in cancer patients: From biomarkers to therapeutic targets

Because of high specificity and easy detection in the tissues, serum, plasma, urine and saliva, interest in exploring the potential of long non‐coding RNAs (lncRNAs) in cancer patients continues to increase. LncRNAs have shown potential as a biomarker in the diagnosis and prognosis of bladder cancer, prostate cancer, gastric cancer, pancreatic cancer, breast cancer and many other cancer types. Some lncRNAs have also been used as adjunct to improve the specificity and sensitivity of existing biomarkers. The molecular tools such as RNA‐seq, RNA‐FISH, ic‐SHAPE and quantitative real‐time PCR have been used for examining the lncRNAs' potential. Some lncRNAs such as PCA3 is now routinely used in the clinic for the diagnosis of prostate cancer. Single nucleotide polymorphisms (SNPs) in lncRNAs can also be used as a predictor of cancer risk. Although ongoing studies continue to unravel the underlying mechanism, some lncRNAs have been used as therapeutic targets for the selective killing of cancer cells in patients. Thus lncRNAs are emerging as convenient and minimally invasive diagnostic/prognostic markers, and also as therapeutic target. Companies such as the Curna Inc., MiNA Therapeutics Ltd. and RaNA Therapeutics Inc. have been taking steps to develop lncRNA based strategies against cancer. In this review, we discuss the potential of lncRNAs as biomarkers and therapeutic targets in cancer patients.     

长链非编码RNAs在乳腺癌中的表达及其功能

无蛋白编码功能的非编码RNAs（ncRNAs）具有多种生物学功能。长链非编码RNAs（LncRNAs）是近年来发现的ncRNAs的一员,其转录长度200 nt～100 kb。许多长链非编码RNAs异常表达具有促进或抑制肿瘤发生、发展的生物学功能,包括乳腺癌。由于其在调控基因表达中的基础性作用,和其参与潜在的肿瘤发生的生物学机制,它们是一类有前途的癌症生物标志物。本文突出LncRNAs在乳腺癌中的新兴作用,并探讨其在乳腺癌的诊断、治疗和预后等相关潜在的临床应用价值。     

Emerging role of long non-coding RNA in the development of gastric cancer

Gastric cancer is a common, worldwide malignancy and has a poor prognosis due to late diagnosis. Long non-coding RNAs (lncRNAs) are a significant subtype of RNA molecules with a length longer than 200 nucleotides (nt) that rarely encode proteins. In recent decades, deregulation of lncRNAs has been shown to be involved in tumorigenesis and tumor progression in various human carcinomas, including gastric cancer. Accumulating evidence has shown that some lncRNAs may function as diagnostic biomarkers or therapeutic targets for gastric cancer. Thus, exploring the specific functions of lncRNAs will help both gain a better understanding of the pathogenesis and develop novel treatments for gastric cancer. In this review, we highlight the expression and functional roles of lncRNAs in gastric cancer, and analyze the potential applications of lncRNAs as diagnostic markers and therapeutic targets.     

Long noncoding RNA: an emerging paradigm of cancer research

Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).     

LncRNAs: key players and novel insights into cervical cancer

Cervical cancer contributed the second highest number of deaths in female cancers, exceeded only by breast cancer, carrying high risks of morbidity and mortality. There was a great need and urgency in searching novel treatment targets and prognosis biomarkers to improve the survival rate of cervical cancer patients. Many long non-coding RNAs (lncRNAs) were emerging as pivotal regulators in various biological processes and took vitally an effect on the oncogenesis and progression of cervical cancer. In this review, we summarized the origin and overview function of lncRNAs; highlighted the roles of lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance; and outlined the molecular mechanisms of lncRNAs in cervical cancer from the aspects of the interaction of lncRNAs with proteins/mRNAs (especially in HPV protein) and miRNAs, as well as RNA N-methyladenosine (m6A) methylation of lncRNAs. Meanwhile, the application of lncRNAs as biomarkers in cervical cancer prognosis and predictors for metastasis was also discussed. An overview of these researches will be valuable for broadening horizons into mechanisms, selection of meritorious biomarkers for diagnosis as well as prognosis, and future targeted therapy of cervical cancer.     

LncRNA：非小细胞肺癌诊断治疗的新策略

肺癌是全球最常见的恶性肿瘤,是全世界癌症相关死亡的主要原因.LncRNA是指一类至少包含200个核苷酸且不具有编码蛋白质功能的RNA.许多lncRNA都具有促进或抑制NSCLC发展及恶化的功能.由于其调节基因表达方面的基础作用,连同其在肿瘤生成的生物学机制,它们是一类有前途的组织或血液生物标志物.本文我们强调lncRNA在NSCLC的新兴作用,并讨论其作为诊断和预后的生物标志物及治疗靶点的潜在临床应用.     

The non-coding transcriptome as a dynamic regulator of cancer metastasis

Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered “housekeeping” genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients’ prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms.     

长链非编码RNA调控癌症细胞信号通路的研究进展

迄今为止,研究人员应用功能基因组学方法发现了多种类型的长链非编码RNA。长链非编码RNA能够调控基因的表达,并且在包括癌症等疾病发生发展过程中起着重要的作用。长链非编码RNA调控基因的表达过程有多种机制参与,例如对转录、翻译、蛋白质修饰及RNA-蛋白复合体形成或者蛋白-蛋白复合体形成等过程的调控。本文主要探讨长链非编码RNA调控肿瘤细胞信号通路的研究进展。     

Research Progress on Long Non-coding RNAs and Drug Resistance of Breast Cancer

Breast cancer, as the foremost cause of women’s death in the world, is highly metastatic and mutable. Resistance to drugs for chemotherapies, endocrine therapies, and targeted therapies is an important factor that impacts the prognosis of breast cancer. Long non-coding ribonucleic acids (LncRNAs) are crucial regulators of intracellular gene expressions. Some researchers have suggested that expression level of several types of LncRNAs were closely related to the prognosis of patients with breast cancer. LncRNAs significantly impact biological processes such as drug transport, detoxication, apoptosis, epithelial to mesenchymal transition (EMT), and autophagy by regulating intracellular signaling pathways such as multi-drug resistance gene 1 (MDR1), nuclear factor erythroid 2-related factor 2 (NRF2), phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), transforming growth factor-β (TGF-β), BRCA1/2, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This paper will summarize research progress on correlations between LncRNA and drug resistance of breast cancer. It will particularly expound molecular mechanisms through which LncRNAs regulate drug resistance of breast cancer. It will further discuss the feasibility as molecular markers for forecasting drug resistance of breast cancer and may be becoming new targets for treating breast cancer in the future.     

Down-regulation and Clinic-pathological Correlation of SIK-1 and SIK-1-LNC in Non-small Cell Lung Cancer Patients

Background: Non-small-cell lung cancer (NSCLC) is currently the leading cause of mortality cancer. Introducing noninvasive approaches to diagnose NSCLC, especially at an early phase, might improve the disease’s prognosis. Long noncoding RNAs (lncRNAs), which are important regulators of the expression genes inside the cells, have been linked to a range of biological processes, such as cancer progression and metastasis, including NSCLC. The present work aims to determine the potential involvement of SIK-1-LNC and SIK-1 in NSCLC pathogenesis and the possible use of these molecules as novel biomarkers or therapeutic targets. Methods: In this work, the expression levels of SIK-1-LNC and SIK-1 in 50 pairs of NSCLC tumor and tumor marginal tissues were evaluated. So, after total RNA extraction and complementary DNA synthesis, the SIK-1-LNC and SIK-1 expression levels were evaluated by real-time PCR. In the study groups, clinical and pathological characteristics of the NSCLC patients were also examined. Results: Our findings showed that tumor samples had much lower levels of SIK-1 and SIK-1-LNC expression than tumor margin samples. SIK-1-LNC expression was correlated with SIK-1 levels in NSCLC samples. Interestingly, both stage and lymph node metastasis features of the tumor were associated significantly with SIK-1 and SIK-1-LNC expression levels. A ROC curve analysis indicated a biomarker index of 0.69 and 0.74 for SIK-1 and SIK-1-LNC, respectively. Conclusion: Collectively, our study emphasized the role of SIK-1-LNC and SIK-1 downregulation in NSCLC oncogenesis. Additionally, SIK-1 and SIK-1-LNC, particularly the latter, have shown remarkable potential to be utilized as new NSCLC biomarkers and therapeutic targets.     

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     

Long noncoding RNAs and neuroblastoma

Neuroblastoma is a disease that affects infants and despite intense multimodal therapy, high-risk patients have low survival rates (<50%). In recent years long noncoding RNAs (lncRNAs) have become the cutting edge of cancer research with inroads made in understanding their roles in multiple cancer types, including prostate and breast cancers. The roles of lncRNAs in neuroblastoma have just begun to be elucidated. This review summarises where we are with regards to lncRNAs in neuroblastoma. The known mechanistic roles of lncRNAs during neuroblastoma pathogenesis are discussed, as well as the relationship between lncRNA expression and the differentiation capacity of neuroblastoma cells. We speculate about the use of some of these lncRNAs, such as those mapping to the 6p22 hotspot, as biomarkers for neuroblastoma prognosis and treatment. This novel way of thinking about both neuroblastoma and lncRNAs brings a new perspective to the prognosis and treatment of high-risk patients.     

长链非编码RNA及其在非小细胞肺癌中的表达和作用

长链非编码RNA(long non-coding RNAs,lncRNAs)是一类转录本长度超过200个核苷酸的非编码RNA(non-coding RNAs,ncRNAs),它们不编码蛋白质,而是以RNA的形式通过转录,转录后和表观遗传等多种调控机制发挥生物学功能,包括生长发育、骨髓造血、细胞凋亡和细胞增殖等生命进程中的一系列重要过程。肺癌是全球癌症死亡的主要原因,它是由不同病因引起的一系列疾病,可分为小细胞肺癌(small-cell lung cancer,SCLC)和非小细胞肺癌(non-small cell lung cancer,NSCLC)两种类型。肺癌的基本特征是基因组遗传和表观遗传发生改变;然而,肺癌发生的具体机制目前仍不明确。近年来的研究资料表明,lncRNAs的异常表达与包括肺癌在内的多种癌症的发生发展有关。本文着重研究lncRNAs在NSCLC中的表达和作用,并讨论其作为早期诊断,指导预后的生物标志物以及治疗靶点的潜在临床应用。