Mirnas And Long Noncoding Rnas As Biomarkers In Human Diseases Pdf
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Noncoding RNA s are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly growing number of studies has unravelled associations between aberrant noncoding RNA expression and human diseases. This research is opening new avenues to novel therapeutic approaches.
- The Role of microRNAs, Long Non-coding RNAs, and Circular RNAs in Cervical Cancer
- The roles of long noncoding RNAs in breast cancer metastasis
- Long Noncoding RNAs as Novel Biomarkers Have a Promising Future in Cancer Diagnostics
Since the discovery and classification of non-coding RNAs, their roles have gained great attention. In this respect, microRNAs and long non-coding RNAs have been firmly demonstrated to be linked to regulation of gene expression and onset of human diseases, including rare genetic diseases; therefore they are suitable targets for therapeutic intervention. This issue, in the context of rare genetic diseases, is being considered by an increasing number of research groups and is of key interest to the health community. In an increasing number of rare genetic diseases, analysis of microRNAs and long non-coding RNAs has been proven a promising strategy.
The Role of microRNAs, Long Non-coding RNAs, and Circular RNAs in Cervical Cancer
Prolonged infection of uterine cervix epithelium with human papillomavirus HPV and constitutive expression of viral oncogenes have been recognized as the main cause of the complex molecular changes leading to transformation of cervical epithelial cells.
Viral encoded circE7 has also demonstrated to overexpress E7 oncoprotein thus contributing to cell transformation. Cervical SCC is generally preceded by persistent squamous intraepithelial lesions SIL caused by HPV infection, therefore the detection of viral nucleic acids has shown to be valuable for the effective prevention of cervical cancer development in oncologic screening programs 3.
The E6 and E7 oncoproteins encoded by high risk HPVs are considered the main players of the multistep transformation process affecting the infected cervical cells. Indeed, they are able to inhibit p53 and pRb oncosuppressors, respectively, and to interact with a plethora of cell signaling factors regulating cell cycle, genome stability and epigenetic modifications 4 , 5. Moreover, the HPV E5 protein has also a relevant role in tumor cell invasion and metastasis for its ability to increase the expression of the epidermal growth factor receptor EGFR and c-MET, the latter being also critical for viral gene expression 6 , 7.
Nevertheless, the gradually accumulation of genetic and epigenetic alterations in HPV infected cells is also crucial for the ultimate progression to cervical cancer. In addition, activating mutations creating de novo transcription factor binding sites in regulatory regions, such as the TERT promoter sequence, have been identified in a significant fraction of cervical SCC Figure 1.
Other regulatory functions include their reciprocal interaction on primary miRNA transcription processes, binding to double-stranded DNA to form triple helixes as well as interaction with RNA G-quadruplex structures that interfere at specific gene regulatory sites Several miRNAs have oncogenic or tumor suppressor activities and play a fundamental role in cancer development, progression and dissemination A recent meta-analysis of miRNA profiles in cervical neoplasia cases and normal cervical epithelium samples identified 42 up regulated and 21 down regulated miRNAs among different stages of cervical neoplasia Despite being not translated into full-length proteins, lncRNAs are implicated in a variety of biological activities such as regulation of gene transcription mediated by their interaction with chromatin-modifying complexes at specific regulatory regions, decoy for transcription factors and miRNAs as well as scaffolding for functional ribonucleoprotein complexes organization 26 , Deregulation of lncRNAs expression is associated with cardiovascular and neurodegenerative diseases as well as with cancer development 27 , The single-stranded closed RNA molecules circRNA are a new class of non-coding RNAs, originating from back-splicing of pre-mRNAs, that have several biological functions in normal cells including the ability to act as sponges to efficiently subtract microRNAs and proteins CircRNAs have shown to be aberrantly expressed in a tissue-specific manner in cancer cells and to contribute to cancer development by perturbing cell proliferation, migration, and angiogenesis processes Several studies indicated that circRNAs play a significant role in cervical cancer development by different molecular mechanisms, which among them miRNA sponging is the most important The aim of this review is to summarize the recent studies on the role of miRNAs, lncRNAs, and circRNAs as well as their reciprocal regulation in different stages of cervical neoplasia.
Moreover, it provides an overview of the potential impact of non-coding RNAs in the diagnosis and therapy of cervical cancer. Many studies have evaluated the expression levels of miRNAs in cervical neoplasia biopsies as well as in exfoliated cervical cells, in cervical mucus and in the serum of women diagnosed with cervical cancer Table 1.
The first study describing the differential expression of six miRNAs let-7b, let-7c, miR, miRb, miRb, and miR in human cervical carcinoma cell lines in comparison with normal cervical samples was published by Lui et al. Numerous investigations since then have been conducted in order to characterize the mechanisms causing miRNAs deregulation as well as their expression pattern in cervical cancer tissues vs.
Indeed, genetic alterations of miRNA loci such as gene deletions, amplifications, or mutations as well as epigenetic silencing such as DNA methylation or deregulation of miRNA processors and transcription factors have been all associated with aberrant expression of miRNAs in cervical cancer For example, Wilting et al.
Moreover, Muralidhar et al. Table 1. Numerous studies over the past decade have analyzed the miRNAs expression to identify significant variations during the transition from low to high grade cervical neoplasia and to invasive cervical cancer in order to define novel biomarkers for cervical cancer diagnosis, prognosis and cancer stage 24 , Pereira et al.
Only five miRNAs miRa, miR, miR, miRa, and miRp were found specifically deregulated in pre-neoplastic lesions but not in cervical carcinoma Subsequently, many research groups reported the identification of specific miRNA signatures during the transition from SIL to cervical cancer with variable results mainly due to the small sample size, the type of specimens i.
He et al. All studies analyzing miRNA profile in human cancerous and non-cancerous cervical tissues were included in such analysis. This approach allowed to identify 42 up regulated and 21 down-regulated miRNAs in different stages of cervical neoplasia.
The functional target of miRc-3p is the BMI1 polycomb ring finger proto-oncogene which is highly expressed in several cancer types, including cervical cancer Thus, the miRc-3p and the BMI1 factor may represent novel biomarkers for diagnosis as well as for target therapy in cervical cancer patients. Among these, miRp and miRp, which are predicted to target PTEN and MARK1 tumor-associated genes, have shown to be associated with metastatic potential of cervical cancer and to have a great potential as prognostic biomarkers or therapeutic targets , The expression levels of miRNAs consistently altered in all stages of cervical neoplasia may be directly deregulated by early viral proteins produced soon after infection.
Gocze et al. The E6 protein has also shown to increase miRb levels which in turn inhibits metastasis suppressor TIMP-2 expression and promotes epithelial-mesenchymal transition, migration and invasion of cervical cancer cells Integration of HPV DNA into host genome, with disruption of E2 viral gene and host chromosomal loci, is a critical event in cancer development and progression.
Interestingly, the viral status has shown to affect the levels of several miRNAs. Mandal et al. Conversely, down regulation of miRc and expression of its target gene CKS1B was observed only in cases harboring HPV16 episomes but not in cancer tissues with the integrated virus Therefore, miRa and miRc could represent useful biomarkers of cervical neoplasia progression if will be validated in clinical studies.
The HPV genome encodes the HPVmiR-H and HPVmiR-H which, besides being essential for viral infection and maintenance, are able to target critical cell genes, including those regulating cell cycle progression, migration, and immunological response Development of therapeutic strategies able to increase miR levels and re-expression of tumor suppressors may be effective to improve the clinical outcomes in cervical cancer patients.
Recently, Pardini et al. Among the 24 studies included in the analysis 17 and 13 miRNAs were found up or down regulated, respectively, in relation to cervical carcinoma progression These findings suggest that specific panels including commonly deregulated miRNAs may serve as effective diagnostic biomarkers for early diagnosis and disease progression as well as for therapy in cervical cancer patients.
Interestingly, Tian et al. Moreover, the levels of miRa, miR, and miR were also found deregulated in cervical exfoliated cells in association with cancer progression Accordingly, Ye et al.
Among these, miRa expression achieved the highest sensitivity These results indicate that miRNA expression profiles may represent promising biomarkers for the early diagnosis of high grade cervical lesions and cervical cancer. Profiling of miRNAs in cervical mucus has also shown to be a good strategy for the identification of cervical neoplastic lesions Indeed, four miRNAs miRp, miRb-5p, miRa, and miRp detected in cervical mucus have been shown effective for diagnosis of cervical adenocarcinoma and high-grade intraepithelial lesions.
However, more investigations are needed in order to establish the clinical value of miRNA detection in cervical mucus. Few studies evaluated the parallel expression of miRNAs in cervical cancer biopsies and in serum samples and the potential of circulating miRNAs as cancer biomarkers.
Chen et al. Among these, the miR, miRa, miR, miR, miRp, miR, and miRp were all over expressed in patients sera consistently with their high levels in cervical cancer tissues More recently, Shukla et al.
Among them, miRp, miRp, and miRp were over expressed while miRp was down regulated both in serum samples and tumor biopsies of cervical cancer patients. Moreover, an inverse correlation was observed between the miRp and miRp levels and the expression of their target genes MTF2 and ST18, respectively, in cervical cancer biopsies. The MTF2 is a polycomb-like PCL protein which, in association with the polycomb repressive complex 2 PRC2 , mediates transcriptional repression and regulates several biological processes including cell differentiation The ST18 genes has shown to inhibit colony formation of cancer cells in soft agar and to regulate pro-apoptotic and pro-inflammatory gene expression in fibroblast and in pancreatic B-cells , Further studies need to be performed to fully characterize the role of such genes in cervical carcinogenesis.
Few studies investigated the expression of specific circulating miRNAs in distinct stages of cervical carcinoma. Yu et al. Importantly such reduction was significantly associated with lymph node metastasis suggesting its potential use as circulating prognostic marker for cervical cancer invasion and metastasis Several other circulating miRNAs have been proposed to be predictive of lymph node metastasis in patients with early stages cervical cancer 39 , 97 , Among these, promising candidate biomarkers for their limited variations between tumor tissue and serum are represented by miR, miRa, miR, miR, miRp and miR Table 2.
The 2. HOTAIR levels have observed to be consistently high in cervical cancer tissues and associated with lymph node metastasis and reduced overall survival Moreover, the HOTAIR levels are higher also in the serum of cervical cancer patients and significantly associated with increased tumor size, lymph vascular space invasion, lymph node metastasis, and reduced survival These data indicated that HOTAIR might represent a novel diagnostic circulating biomarker as well as a promising therapeutic target in cervical cancer.
It was the first lncRNA identified as a riboregulator and shown to be expressed in fetal tissues and adult muscles as well in many kinds of cancer , Kim et al. The metastasis-associated lung adenocarcinoma transcript 1 MALAT1 , first identified in non-small cell lung cancer, is an 8, nucleotides lncRNA located in the chromosome 11q MALAT1 has shown to promote epigenetic changes and to modulate gene expression, nuclear organization as well as regulation of alternative splicing by acting as decoy for splicing factors It is found largely expressed in many cancer types in relation to the accumulation of aberrant splicing products The sponging of miR by MALAT1 has suggested to be involved in the mechanisms of radio-resistance in cervical cancer radiotherapy LncRNA colon cancer-associated transcript 2 CCAT2 is a 1, nucleotide sequence located in the chromosome 8q24 and expressed in microsatellite-stable colorectal cancers Next, CCAT2 has shown to be over expressed and defined as biomarker of poor prognosis in gastric, bladder, non-small cell lung, small cell lung, breast, and ovary cancers as well as in esophageal squamous cell carcinoma and glioma In cervical cancer patients the high expression of CCAT2 is correlated to advanced FIGO stage, lymph node metastasis, deep cervical invasion and reduced survival However, the molecular mechanism mediating the activity of CCAT2 in cervical cancer remain uncharacterized.
Indeed, it is reported to be over expressed in melanoma, non-small cell lung, esophageal cancer and under expressed in gastric cancer 19 , , The expression levels of SPRY4-IT1 have been found higher in cervical cancer than in normal tissues and associated with advanced clinical stages and shorter overall survival of cervical cancer patients This effect is associated with suppression of EMT changes, increased E-cadherin levels and decreased the N-cadherin and vimentin expression Growth arrest-specific transcript 5 GAS5 is nucleotide lncRNA encoded by a sequence located in the chromosome 1q25 GAS5 has tumor suppressor activity in several cancer types Accordingly, its decreased expression has a strong association with tumor development and worse clinical outcome in cervical cancer patients Moreover, inhibition of GAS5 in cervical cancer cells has shown to increase the proliferation, migration and invasion confirming its oncosuppressor activity in the cervical cancer progression Gao et al.
It is over expressed in cervical cancer in association with advanced tumor stages, increasing tumor size, invasion and poor prognosis MEG3 is expressed in many normal tissues and its loss has been reported in many cancer types.
The over expression of MEG3 can inhibit proliferation and increase apoptosis in cancer cells either in a p53 dependent or independent manner Expression of MEG3 is low both in cervical cancer tissues and in cervical cancer cell lines. Increased levels of MEG3 in cervical cancer cell lines have shown to inhibit cell proliferation, induce cell cycle arrest and cause apoptosis
The roles of long noncoding RNAs in breast cancer metastasis
One database of transcriptomes of potential interest for readers of this review is the NURSA website www. Table 1 highlights features of these ncRNAs and their roles in cellular processes. Enhancers are relatively insensitive to position and distance of their target genes and about half are intragenic, which can result in inhibition or attenuation of nascent transcript elongation Cinghu et al. Table 1 Summary of ncRNAs in humans, excluding rRNA and tRNA, with their size, cellular location, aspects of biogenesis, function, citations for reviews for roles in various endocrine-related cancers and websites. Moreover, these RNAs are chemically modified, e. This review provides a brief overview of the identity, regulation and roles of miRNAs and lncRNAs in selected endocrine-related cancers. Because of the scope of published literature on these topics, this review is not a comprehensive analysis of lncRNAs and miRNAs in breast, prostate, endometrial and thyroid cancers.
MiRNAs, ncRNAs of approximately 19—25 nucleotides in length, are involved in gene expression regulation either via degradation or silencing of the messenger RNAs mRNAs and have roles in multiple biological processes, including cell proliferation, differentiation, migration, angiogenesis, and apoptosis. LncRNAs can activate or repress gene expression through various mechanisms, acting alone or in combination with miRNAs and other molecules as part of various pathways. Our synthesis provides insight into the mechanisms involved in TNBC progression and has potential to aid the discovery of new diagnostic and therapeutic strategies. TNBC is characterized by the absence of estrogen receptor ER , progesterone receptor PR , and human epidermal growth factor receptor-2 HER2 , relative to normal tissue or other types of BC, as well as a high proliferative index determined by mitotic or Ki proliferative indices , high histological grade, and high rates of metastasis 2 — 4. TNBCs frequently undergo early metastasis to visceral organs and brain 5 — 7 and are more often diagnosed at an advanced stage. Furthermore, this neoplasm is often diagnosed at a relatively young age and is a major cause of female mortality 8 — Among these molecular subtypes, the BL2 subtype has the worst prognosis, and LAR tumors are associated with the best overall survival OS rates.
Long Noncoding RNAs as Novel Biomarkers Have a Promising Future in Cancer Diagnostics
Cancers have a high mortality rate due to lack of suitable specific early diagnosis tumor biomarkers. Emerging evidence is accumulating that lncRNAs long noncoding RNAs are involved in tumorigenesis, tumor cells proliferation, invasion, migration, apoptosis, and angiogenesis. Furthermore, extracellular lncRNAs can circulate in body fluids; they can be detected and strongly resist RNases. Many researchers have found that lncRNAs could be good candidates for tumor biomarkers and possessed high specificity, high sensitivity, and noninvasive characteristics. In this review, we summarize the detection methods and possible sources of circulating lncRNAs and outline the biological functions and expression level of the most significant lncRNAs in tissues, cell lines, and body fluids whole blood, plasma, urine, gastric juice, and saliva of different kinds of tumors.
Long noncoding RNAs lncRNAs are a relatively well-characterized class of noncoding RNA ncRNA molecules, involved in the regulation of various cell processes, including transcription, intracellular trafficking, and chromosome remodeling. Their deregulation has been associated with the development and progression of various cancer types, the fact which makes them suitable as biomarkers for cancer diagnosis and prognosis. In recent years, detection of cancer-associated lncRNAs in body fluids of cancer patients has proven itself as an especially valuable method to effectively diagnose cancer. Cancer diagnosis and prognosis employing circulating lncRNAs are preferential when compared to classical biopsies of tumor tissues, especially due to their noninvasiveness, and have great potential for routine usage in clinical practice. Thus, this review focuses on summarizing the perspectives of lncRNAs as biomarkers in cancer, based on evaluating their expression profiles determined in body fluids of cancer patients. Most of the generated lncRNA transcripts are usually spliced, capped, and polyadenylated in a similar manner as mRNA molecules [ 3 ]. However, after being identified as a class of RNA molecules in [ 11 ], studies that followed revealed lncRNA importance and indispensability in various cellular processes, including transcription, intracellular trafficking, and chromosome remodeling [ 3 , 12 ].