|Year : 2020 | Volume
| Issue : 8 | Page : 22-33
The relevance of long noncoding RNAs in colorectal cancer biology and clinical settings
Atefeh Talebi1, Mazaher Azizpour2, Shahram Agah1, Mohsen Masoodi1, Gholam Reza Mobini3, Abolfazl Akbari1
1 Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Department of Orthopedic Surgery, Aalborg University Hospital, Aalborg, Denmark
3 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
|Date of Submission||20-May-2018|
|Date of Decision||24-Jul-2018|
|Date of Acceptance||05-Dec-2018|
|Date of Web Publication||10-Oct-2019|
Colorectal Research Center, Iran University of Medical Sciences, Sattarkhan Ave., Niyayesh Street, Tehran
Source of Support: None, Conflict of Interest: None
Colorectal cancer (CRC) is one of the most frequent causes of cancer-related death worldwide. The prognosis of the malignancy and patient survival is commonly poor. Therefore, the discovery of pertinent biomarkers is essential to provide an accurate diagnosis and effective therapy. Newly, a group of noncoding RNAs named long noncoding RNAs (lncRNAs) has been found to involve in CRC development and progression. In this review, we highlighted the biological function of lncRNAs and reviewed their potentials as clinical tools in the CRC. A literature search of PubMed, EMBASE, MEDLINE, Web of Science, Scopus, and Cochrane Library using the MeSH terms “CRC,” “long noncoding RNA,” “lncRNA,” and relevant was completed. The review included all articles that reported on the significance and role of lncRNAs in CRC development and clinical settings. All identified articles were cross-referenced for further articles, and any unavailable online were retrieved from hardcopy archive libraries. CRC-related lncRNAs could regulate a number of cellular processes, and their dysregulations have been suggested as potential biomarkers.
Keywords: Colorectal cancer, diagnosis, long noncoding RNAs, prognosis
|How to cite this article:|
Talebi A, Azizpour M, Agah S, Masoodi M, Mobini GR, Akbari A. The relevance of long noncoding RNAs in colorectal cancer biology and clinical settings. J Can Res Ther 2020;16, Suppl S1:22-33
|How to cite this URL:|
Talebi A, Azizpour M, Agah S, Masoodi M, Mobini GR, Akbari A. The relevance of long noncoding RNAs in colorectal cancer biology and clinical settings. J Can Res Ther [serial online] 2020 [cited 2021 May 19];16:22-33. Available from: https://www.cancerjournal.net/text.asp?2020/16/8/22/268778
| > Introduction|| |
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and considered as the third mainly cause of cancer-related death worldwide.,, The carcinogenesis of CRC involves sequential alterations in genetic and epigenetic genes ultimately resulting in the progression of malignant cells to invasive carcinoma. The developed malignancy usually is detected in the late clinical stage, which prognosis and survival of CRC patients frequently are poor.,, The existing clinical and pathological diagnostic and prognostic factors for the cancer have various limitations in evaluating the patient outcome. Hence, it is essential to inspect and develop proficient biomarkers for diagnosis and prognosis of CRC to improve therapeutic strategies and patient survival. Although the current genetic signs have revealed a promising clinical significance, further investigations are needed to confirm these biomolecules as routine clinical biomarkers.,
Recently, a number of investigations have emphasized the biological function of noncoding RNAs (ncRNA), especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in the pathogenesis of CRC. LncRNAs are known as transcribed RNA molecules with 200 nucleotides in length and without an open reading frame. These RNA molecules are functionally imperative in either transcriptional or posttranscriptional regulation. These nonprotein coding transcripts have been demonstrated to involve in numerous key cellular processes, including cell differentiation, proliferation, migration, and invasion.,, Recently, a number of lncRNAs have been shown to function as oncogenes or tumor suppressors in CRC development. In addition, the expression level of some lncRNAs has been correlated with clinicopathological features, serving them as promising predictors of patient outcomes. Therefore, the potential of these molecules has increasingly been revealed for diagnostic, prognostic, and therapeutic applications., In this review, we overview the recent findings about the biological function of CRC-related lncRNAs and their potential applications as biomarkers in CRC [Table 1]. We highlighted the biological function of lncRNAs and their potentials as clinical tools in the CRC. A literature search of PubMed, EMBASE, MEDLINE, Web of Science, Scopus, and Cochrane Library using the MeSH terms “CRC,” “long noncoding RNA,” “lncRNA,” and relevant was completed. It was reviewed the latest articles regarding the 82 CRC-related lncRNAs reported up to August 2018. The review included all articles that reported on the significance and roles of lncRNAs in CRC development and clinical settings. All identified articles were cross referenced for further articles, and unavailable online articles were retrieved from hard-copy archive libraries [Figure 1]. This review study may be valuable in understanding the underlying mechanisms in CRC development and progression as well as designing the targeted cancer therapies.
|Table 1: Description of colorectal cancer-related lncRNAs and their biological and clinical significance|
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|Figure 1: LncRNAs as potential effectors in colorectal cancer development|
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| > Lncrnas: Biogenesis and Biological Functions|| |
LncRNAs are a family of nonprotein-coding RNAs transcribed by RNA polymerase II enzyme. LncRNAs are characterized by a size of ≥200 nucleotides in length and lack of an open reading frame. These RNA transcripts may be transcribed from a different locus of the whole genome, including intronic, intergenic, even pseudogenes, and retrotransposons. Furthermore, they have a number of binding sites to interact with DNA, proteins, or other RNA molecules. A range of biological functions, including cell differentiation, proliferation, invasion, and apoptosis have identified for various classified lncRNAs. Transcriptome sequencing databases imply that half of the human genome transcribes for lncRNA. Despite the majority of ncRNAs, the function of lncRNAs has not fully been characterized. A range of genetic- or epigenetic-mediated cellular processes is regulated by lncRNAs. Gene transcription and translation, histone modification, and microRNA machinery may be regulated by lncRNAs,, More recently, it has been revealed that this transcribed RNAs potentially function as suppressors or promoters of gene expression to develop human cancers., Thus, the expression profile of the functional lncRNAs may alter in cancers. Increasing evidence suggests that the dysregulation of these cancer-associated lncRNAs potentially provide diagnostic, prognostic, and therapeutic biomarkers.,,,,,,,,,,,,, The experimental confirmation and bioinformatics prediction using the Cancer Genome Atlas database (http://cancergenome.nih.gov/) is especially helpful to validate the underlying mechanisms, as well as evaluate the biological role and diagnostic performance.
CRC-associated lncRNAs: Biological and clinical significance
A number of lncRNAs have been reported to function as oncogenes or tumor suppressors in CRC development.,,,,,,,,,,,,,,,,,,,,,,,,,,,,, As well, the expression levels of some lncRNAs correlate with CRC clinicopathological features, serving them as promising predictors of patient outcomes.,,,,,,,,,,,, Therefore, the potential of these molecules is increasingly revealed for diagnostic, prognostic, and therapeutic applications. Here, we overview the recent findings about the biological function of lncRNAs and their potentials as prognostic biomarkers in CRC. We searched Scopus, Web of Science, PubMed, MEDLINE, EMBASE, and the Cochrane Library for studies reporting the biological or clinical significance of lncRNAs in CRC. All references from related studies were checked, and any study was not found online was retrieved from archived library sources. The identified original, prospective cohort, and retrospective cohort studies were included in our study.
Oncogenic lncRNAs upregulated in colorectal cancer
Prostate cancer-associated ncRNA transcripts 1
Prostate cancer-associated ncRNA transcripts 1 (PCAT-1), as a long intergenic noncoding RNA, is transcribed from gene at chromosome 8q24. This lncRNA was firstly reported to be overexpressed in prostate cancer and established to relate with a prognosis of the cancer patients. LncRNA PCAT-1 could promote cell proliferation through association with polycomb repressive complex 2 as a transcriptional repressor. The high levels of PCAT-1 associated with cancer patients' survival rate. PCAT-1 also was shown to upregulate in CRC tissues and correlate with the overall survival and lymph node metastasis. It has also been reported a correlation between PCAT-1 overexpression and the progression of CRC. Related findings presented a molecular mechanism by which PCAT-1 is implicated in CRC progression, indicating it as a suitable target, and an independent prognostic factor for CRC.
Colon cancer-associated transcript-1
Colon cancer-associated transcript-1 (CCAT1) is a lncRNA with 11.88 kb in length that upregulates in CRC tissue. CCAT1 gene is located on chromosome 8q24.21 and is placed within a strong super-enhancer in vicinity of transcription factor c-Myc.,, CCAT1 could regulate Myc transcription and promote chromatin turnover., The elevated expression level of CCAT1 was also correlated with the tumor node metastasis (TNM) stage, lymph node metastasis, and survival rate.In vitro experiments showed that CCAT1 could function in CRC carcinogenesis and it may be served as a clinical outcome biomarker. The plasma expression level of CCAT1 has also been confirmed it as a predictive biomarker for CRC screening.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA with8.75 kb in length transcribed from the nuclear-enriched transcript-2 gene. This lncRNA is also known NEAT2, noncoding nuclear-enriched abundant transcript 2. A number of carcinogenic functions of MALAT1 have been described in various cancers such as pancreatic, liver, cervical, and colon cancers. Moreover, related studies in CRC cell lines demonstrated a range of functional roles for MALAT1 in CRC carcinogenic processes including cell proliferation and invasion. MALAT1 could promote cell colony formation, migration and invasion mediated by PRKA (kinase anchor protein 9). Some researchers showed that the high expression level of MALAT1 is correlated with clinicopathological parameters and poor prognosis in CRC patients, and suggested MALAT1 as an independent prognostic risk factor., Further investigations indicated that the overexpression of MALAT1 could partially be responsible for oxaliplatin-induced EMT and chemoresistant in CRC cells. Altogether, MALAT1 could potentially be a valuable prognostic biomarker and a therapeutic target for CRC.
Gastric adenocarcinoma predictive long intergenic noncoding
Long intergenic noncoding RNA (lincRNA) named gastric adenocarcinoma predictive long intergenic noncoding (GAPLINC) was firstly identified in gastric cancer. This lincRNA is located on chromosome 18 and its synonym names are TCONS_00026238, LINC01540, and lncRNA-uc002 kmd. 1. The functional and experimental studies confirmed the effect of GAPLINC on CRC cell proliferation, migration, and invasion. It was identified that this lncRNA might play an imperative role in CRC carcinogenesis. Furthermore, the clinical findings showed that the high expression of GAPLINC correlates with invasion, lymph node metastasis, and TNM stage and poor survival rate in CRC patients. Taken together, it was suggested that GAPLINC could promote cell proliferation and metastasis and represents a potential prognostic biomarker and therapeutic target in CRC patients.,,
Regulator of reprogramming
A new lncRNA, with 2.6 kb in length named lincRNA-regulator of reprogramming (RoR), was characterized in induced pluripotent stem cells (iPSCs). LincRNA-RoR could play an important role in the biology of iPSCs by regulation of cellular stress pathways.,, LincRNA-RoR can act as a p53 repressor in response to DNA damage and hypoxic stress. Furthermore, lincRNA-RoR has been reported to be active as a molecular sponge for miR-145 to modulate the metastasis and drug resistance in breast cancer., The regulation of P53/miR-145 pathway by lincRNA-ROR indicated a biological role of this RNA molecule for stress-induced approach in CRC therapy. Interestingly, the altered expression of lncRNA ROR has been reported to determine efficiency of CRC radiotherapy. Experimental studies showed that the expression level of lncRNA-ROR was elevated in CRC cell lines and tissues compared to normal controls and its overexpression significantly promote cell proliferation. In vitro studies demonstrated that lncRNA-ROR could regulate cell proliferation, viability, and apoptosis, providing potential and prospective therapeutic targets for CRC.
Activated by transforming growth factor beta
LncRNA-ATB (lncRNA activated by transforming growth factor beta [TGF-β]) is upregulated in several cancers including hepatocellular carcinoma, prostate, and CRC.,, The activation of this lncRNA is mediated by cytokine TGF-β that acts as a moderator in tumor transformation, migration, invasion, and metastasis. lncRNA-ATB increases colonization of migrating cells by promoting the function of interleukin-11-STAT3 signaling pathway. The biological roles of lncRNA-ATB in regulating E-cad and other EMT-related markers expression in CRC were elucidated in vitro. The expression levels of lncRNA-ATB in CRC tissues also are correlated with clinicopathological features. According to related evidences, lncRNA-ATB is involved in the progression of CRC and may be served as a novel indicator of poor prognosis in patients.
The lnc-H19, an antisense long noncoding RNA with a 120 kb, is located on the H19 gene locus. It has been found that lnc-H19 overexpress in range of malignancies including breast cancer, esophageal squamous cell carcinoma, and CRC. H19 overexpresses in CRC tissues and cell lines. This lncRNA could play a key role in the progression of CRC by promoting cell motility, migration, and aggression. This lnc-RNA could mediate CRC metastasis through upregulating metastasis-related proteins. Furthermore, a H19-miR138-HMGA1 pathway in regulating the migration and invasion of CRC was validated, providing new insight for the treatment of CRC. Moreover, the functional studies represented a potential mechanism underlying the resistance to treatment with 1,25 (OH) 2D3 in CRC. The high expression of H19 in CRC associated with poor prognosis and metastasis of the disease. In addition, rs2839698 in H19 was related to increased risk of CRC, which may be used as a potential prognostic biomarker.
Gastric carcinoma high-expressed transcript 1
LncRNA gastric carcinoma high-expressed transcript 1 (lncRNA-GHET1) was first found to upregulate in gastric cancer. GHET1 could play an essential role in cell proliferation through increasing c-Myc mRNA expression and stability. The expression of GHET1 in CRC tissues was established to considerably increase compared to normal epithelial cells and tissues. GHET1 overexpression in CRC cell lines has been confirmed to have a biological role in cell proliferation, cell cycle progression, migration, and invasion. GHET1 also could regulate EMT-related gene expression to progress CRC. Taken together, the experimental and clinical findings suggest the potential use of GHET1 as a prognostic marker and therapeutic target of CRC.
HOXA transcript at the distal tip
LncRNAHOXA transcript at the distal tip (HOTTIP) with 3.8 kb, is located at the 5' end of HOXA cluster and regulates HOXA genes., A more recent study confirmed fundamental role of HOTTIP in CRC development. HOTTIP is overexpressed in CRC tissues in comparison with normal tissues. Moreover, the expression level of HOTTIP has been reported to be correlated positively with advanced pathological tumor stage, tumor size, and distant metastasis.In vivo experiments showed that HOTTIP can promote the growth of tumor, suggesting it may be served as a prognosis predictor and candidate for CRC therapy.
Taurine upregulated gene1
Taurine upregulated gene1 (TUG1) is a 9.7 kb and highly conserved gene locating on chromosome 22q12.,, TUG1 was shown to involve in CRC progression and metastasis, thus it was proposed as a prognostic biomarker and therapeutic target for the malignancy. Previous studies showed the expression levels of TUG1 were elevated in CRC tumor tissue and strongly correlated with the survival rate of the CRC patients. Furthermore, TUG1 overexpression could stimulate EMT-related gene expression and promote colony formation, migration and metastasis in CRC. Accordingly, it has been confirmed that TUG1 could increase the cell proliferation and migration and inhibit colon cancer cell apoptosis.
Urothelial cancer associated1
Urothelial cancer associated 1 (UCA1) with 7.37 kb is located on chromosome 19p13. LncRNA UCA1 could regulate cell proliferation, apoptosis, and cell cycle progression of CRC cells. Furthermore, a correlation between UCA1 expression and clinicopathological features of CRC patients, including larger tumor size, less differentiated histology, and greater tumor depth has been found. Furthermore, the expression level of UCA1 in CRC patients was associated with poor prognosis. Multivariate analysis indicated that UCA1 over-expression could be as an independent predictor for CRC. UCA1 upregulates in CRC and negatively correlates with survival rate of the patients. Functional studies revealed a function of UCA1 in promoting cell growth and decreasing the apoptosis of CRC cells. The findings confirmed UCA1 as a new potential oncogene and prognostic factor for CRC.
Plasmacytoma variant translocation 1
LncRNA plasmacytoma variant translocation 1 (PVT1) gene is located on 8q24. The overexpression of lncRNA PVT1 has been suggested as a powerful predictor of tumor progression and patient survival in a diverse range of cancer types, such as pancreatic cancer, gastric cancer, hepatocellular cancer, ovarian and breast cancer. PVT1 can promote CRC cells proliferation and reduce apoptosis. The high PVT1 expression correlates with poor prognosis of CRC patients. Further analyses showed that PVT1 expression level was an independent prognostic factor of overall survival in CRC patients. This lncRNA can regulate cell proliferation and cell apoptosis by affecting c-Myc expression. Taken together, the findings indicated that the overexpression of PVT1 predicts the prognosis of CRC patients, providing insights into future investigations on CRC therapeutic strategies.
Differentiation antagonizing nonprotein coding RNA
Differentiation antagonizing nonprotein coding RNA (DANCR) is a 7.94 kb transcript that its gene is located on chr4q12. LncRNA DANCR play a fundamental role in maintenance of stemness features of stem cells. Recent studies have shown this lncRNA involves in CRC carcinogenesis. The high expression levels of DANCR were shown to be associated with TNM stage and distant metastasis in CRC. LncRNA-DANCR overexpression also was associated with aggressive progression and poor prognosis in CRC. Multivariate analysis showed that lncRNA-DANCR might be considered as an independent predictor for clinical outcome of CRC patients.
The novel lncRNA prostate cancer noncoding RNA 1 (PRNCR1) is located in a susceptible area of human genomic. More recently, one investigation confirmed the biological function and clinical significance of PRNCR1 in CRC. The expression profiling of PRNCR1 and functional studies by antisense oligonucleotide in CRC tissues and cell lines revealed that PRNCR1 could promote cell proliferation. Furthermore, diagnostic value of PRNCR1 has been suggested by finding a correlation between the lncRNA expression levels and CRC clinicopathologic characteristics.
Cancer liver metastasis associated transcript-3
Cancer liver metastasis associated transcript-3 (CLMAT3) or TR05005298 gene is mapped on chromosome 14. Anin vitro study demonstrated that lncRNA-CLMAT3 expression was significantly elevated in CRC cells proliferation. As well, it was observed that lncRNA CLMAT3 could affect cell proliferation and apoptosis by inducing G0/G1 cell-cycle arrest. The high expression levels of CLMAT3 are significantly associated with liver metastasis and lymph node metastasis. Besides, the overexpression of lncRNA-CLMAT3 was shown to be correlated with reduced overall survival. Altogether, this lncRNA was considered as a potential independent prognostic factor in CRC patients with liver metastasis.
The gene of lncRNA FTX is located in chrXq13.2 at an intron within the X-inactivation center region. LncRNA FTX is notably overexpressed in CRC tissues and correlated with differentiation grade, lymphvascular invasion, and clinical stage. Another study showed the high expression of FTX in CRC patients with poor prognosis. Supplementary analysis showed that the upregulated expression of lncRNA FTX was correlated with overall survival, suggesting it as a valuable prognostic biomarker for CRC patients.
FEZ family zinc finger 1 antisense RNA 1
FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) is located in chr7q31.32 on the opposite strand of gene FEZF1. The expression levels of FEZF1-AS1 are positively correlated with lymphatic metastasis, designating the lncRNA as a possible effector in CRC metastasis. The high expression levels of FEZF1-AS1 in CRC were significantly correlated with shorter survival rate. Further analyses indicated that the upregulation of FEZF1-AS1 was an independent prognostic factor of outcomes in CRC patients.
Upregulated in colorectal cancer
A lincRNA termed upregulated in CRC (UCC) was newly reported to be overexpressed in CRC tissues and cell lines. Experimental findings in CRC cell lines and xenograft tumors confirmed the roles of UCC in cell proliferation and invasion. The expression levels of UCC associate with tumor stage and lymph node metastasis. Upregulation of UCC was shown to promote cell growth and invasion, indicating UCC as a valuable molecular target for CRC therapy.
Linc00659 has been characterized as an oncogenic lncRNA that its expression level is considerably increased in CRC. This lncRNA could promote cell cycle progression and enhance colon cancer cell growth, by repressing PI3K-AKT signaling. The high expression levels of linc00659 are also correlated with poor survival in patients with CRC, pointing to a value of this lncRNA for CRC therapy.
P53-induced noncoding RNA
P53-regulated lncRNA also named p53-induced noncoding RNA (PINCR), is upregulated followed by DNA damage in CRC cells and promotes tumor growth and chemotherapeutic resistance. Molecular investigations on CRC cells confirmed a function of PINCR in response to DNA damage in CRC cells through p53 signaling network. PINCR could induce some p53 signaling-related genes involved in G1 and apoptosis, suggesting an oncogenic role for this lncRNA.
HOXA cluster antisense RNA 2
HOXA cluster antisense RNA 2 (HOXA-AS2), an lncRNA with a length of 1048 bp locating in the HOXA region, was found to be upregulated in CRC and associated with a larger tumor size and advanced cancer stages. HOXA-AS2 was also revealed to promote cancer cell proliferation. HOXA-AS2 could repress a number of transcription factors involved in CRC proliferation, including p21 (CDKN1A) and KLF2, and exert an oncogenic function. Therefore, this lncRNA may be served as a therapeutic target for CRC.
Serine peptidase inhibitor, Kunitz type 1 antisense RNA1
Serine peptidase inhibitor, Kunitz type 1 antisense RNA1 (SPINT1-AS1) is a newly lncRNA overexpressed in CRC tissues compared to adjacent normal tissues. The high expression of SPINT1-AS1 was correlated with distant metastasis, and shorter survival rate of CRC, indicating it as a potential prognostic factor. Altogether, related findings demonstrated a critical role of lncRNA SPINT1-AS1 in CRC progression, designating it as a candidate prognostic biomarker and therapeutic target.
TP73 antisense RNA 1
Long noncoding RNA TP73 antisense RNA 1 (TP73-AS1) has been reported as an upregulated lncRNA in CRC patients. Overexpression of TP73-AS1 was associated with advanced stages of the cancer. TP73-AS1 can upregulate the expression of TGFα in CRC cells, promoting the cell growth, proliferation, migration, and invasion in vitro. These findings indicated that TP73-AS1 is involved in CRC progression by modulating TGFα expression.
lncRNA LINC01510 was identified as a lncRNA with a high expression in CRC tissues and cell lines. LINC01510 could promote cycle progression and increase cell proliferation. LINC01510 also was demonstrated to contribute to upregulation of oncogene MET expression. Clinical investigations revealed that the high expression levels of LINC01510 were associated with the clinicopathological features and advanced stages. Overall, related data suggested LINC01510 as a candidate prognostic biomarker and a molecular target for CRC therapy.
Lnc00152, as a newly identified lncRNA, upregulates in CRC and increase the cell proliferation and invasiveness of CRC cells in vitro, partly by promoting EMT. The overexpression of lnc00152 was found to be correlated with the shorter overall survival of CRC patients. Cooperatively, these findings revealed a critical role of lnc00152 in CRC cell growth, indicating it as a potential therapeutic target.
Small nucleolar RNA host gene 20
Small nucleolar RNA host gene 20 (SNHG20) is mapped to chromosome 17q25.2. Biological and clinical significance of long noncoding transcript SNHG20 is inadequately realized in oncology. LncRNA SNHG20 is up-regulated in human CRC tissues and cell lines. Functional studies revealed that lncRNA SNHG20 promotes CRC cell proliferation, invasion and migration, and cell cycle progression. The experimental data suggested that SNHG20 involves in carcinogenesis and functions as a potential therapeutic target in CRC. The high expression levels of SNHG20 associate with poor prognosis of patients with CRC. Moreover, the expression pattern of SNHG20 was presented as an independent prognostic factor for overall survival in CRC patients.
Suppressor lncRNAs downregulated in the colorectal cancer
Growth arrest-specific transcript 5
Growth arrest-specific transcript 5 (GAS5) is transcribed from a gene located in chromosome 1q25. LncRNA GAS5 could bind the glucocorticoid receptor, regulating cell metabolism, and apoptosis. The suppressor activity of GAS5 has been revealed in various malignancies such as breast, prostate, renal, and gastric cancer.In vitro andin vivo studies showed that overexpression of GAS5 reduces cell proliferation. In human CRC, the expression levels of GAS5 are reversely associated with larger tumor size and advanced TNM stage and overall survival time. Multivariate analysis showed that GAS5 expression was a significant independent predictor of poor survival of CRC patients. The results demonstrated a potential value for GAS5 as a prognostic and diagnostic marker and a therapeutic target of CRC.
lncRNA BC029135 is a newly recognized lncRNA that was reported to be downregulated in CRC tissues than in adjacent normal tissues. The high expression of lncRNA BC029135 can decrease the invasion of cells by suppressing Wnt/β-catenin signaling in CRC cells. Related findings could provide new insights for CRC clinical settings and new evidence for targeted therapy.
HOXA transcript antisense RNA, myeloid-specific 1
HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1 gene) is located in the HOX gene cluster on chromosome 7p15 between HOXA1 and HOXA2 genes. Other names for the lncRNA HOTAIRM1 gene are C00U924339 and GC07P027137. HOTAIRM1 regulates the CRC cell proliferation as a tumor suppressor. In addition, the downregulation of circulating HOTAIRM1 could be served as a biomarker for CRC. The authors also suggested the combined HOTAIRM1 and CEA assay as a valuable tool for the early diagnosis of CRC.
More recently, some researchers identified a new functional lncRNA known as lnc-GNAT1. The overexpression of lnc-GNAT1 could reduce the liver metastasis of CRC cells. A correlation between lnc-GNAT1-1 and Raf kinase inhibitor protein (RKIP) expression both in CRC cell lines and in patients' tissues was found. It was suggested that lnc-GNAT1-1 could act as a tumor suppressor via regulating RKIP-NF-κB-Snail circuit in CRC. The expression levels of lnc-GNAT1-1 in primary tissue and plasma was shown to decrease in CRC patients and correlate with clinicopathological features. Taking the information together, lnc-GNAT1 could predict poor prognosis and act as an independent prognostic factor for CRC patients.
Noncoding RNA expressed in aggressive neuroblastoma (ncRAN) is a RNA transcript locating in chromosome 17q25. The biological functions of the lncRNA shown in cell proliferation, migration and invasion functions of lncRNA-ncRAN in bladder and CRC were. The expression pattern of ncRNA was revealed to be tumor dependent. Recent studies reported a downregulation of ncRAN in CRC tumors and cell lines compared to normal samples. The decreased expression of ncRAN was associated with liver metastasis, poor differentiation and overall survival rate. Thus, related studies identified ncRAN as a new potential early diagnostic biomarker for CRC.
lncRNA ncRuPAR is a lately discovered noncoding transcript, mapping on chromosome 5q13. LncRNA ncRuPAR could implicate in tumor growth, invasion, and metastasis in a number of cancers including gastric and colon cancers. NcRuPAR is overexpressed in CRC tissues in comparison with adjacent normal tissues. Moreover, the expression levels of ncRuPAR were significantly associated with differentiation status, TNM stage and lymph node metastasis. Taken together, ncRuPAR was suggested as a potential biomarker for prognosis of CRC.
Maternally expressed gene3
Maternally expressed gene3 (MEG3) is located on chromosome14q32 at maternally imprinted DLK1-MEG3 locus. The downregulation of MEG3 has been reported in a range of cancers including bladder, brain, breast, colon, liver, lung, and prostate.,,,, Increasing evidences support MEG3 as a lncRNA tumor suppressor and regulator of cell proliferation. MEG3 expression is downregulated in CRC tissues in comparison with normal tissues. Further experiments revealed that MEG3 could inhibit CRC cell proliferation in vitro. In addition, MEG3 expression level is reversely correlated with high histological grade, tumor invasion, and advanced TNM stage. Taken all together, MEG3 is involved in the development and progression of CRC by regulating cell proliferation and may be considered as a potential diagnostic and prognostic biomarker.
Long noncoding RNARP11-462C24.1, with a length of 1136 bp, is located on chromosome 4q25. RP11-462C24.1 may function in CRC development and progression., Moreover, the decreased expression of RP11-462C24.1 was significantly correlated with lymph node metastasis and poor disease-free survival. Multivariate analysis demonstrated RP11-462C24.1 could act as an independent prognostic factor for CRC. Significant difference of serum levels of RP11-462C24.1 also was shown in CRC patients compared to normal individuals. Statistical analysis also implied this lncRNA has a potential value as diagnostic marker for CRC.
Tumour suppressor candidate 7
Lnc RNA tumour suppressor candidate 7 (TUSC7), known as LOC285194, is located on chr3q13.31. Current studies revealed a potential tumor-suppressor role of lncRNA TUSC7 in several cancers such as pancreatic ductal adenocarcinoma and CRC.,In vitro andin vivo investigations showed that TUSC7 could be a potential target of p53 by which suppresses tumor cell growth. Furthermore, the expression levels of TUSC7 are lower in tumor tissues from CRC patients and CRC cell lines compared to adjacent normal tissues and normal intestinal mucous cell line., More analysis identified that the expression level of TUSC7 is reversely correlated with tumor size, tumor stage, distant metastasis, and poorer prognosis. In addition, TUSC7 inhibits CRC cell proliferation partly by targeting miR-211-3p-related signaling pathway. TUSC7 also was shown to induce cell cycle arrest and inhibit CRC cell invasion. Thus, lncRNA TUSC7 was suggested as a potential biomarker candidate for CRC prognosis.
| > Conclusions|| |
The biological functions of lncRNAs in gene regulation at various levels have been shown in CRC. In addition, the expression levels of circulating lncRNAs may be correlated with clinical TNM stage, lymph node metastasis, and overall survival. Thus, their promising applications as noninvasive tumor biomarkers have been demonstrated in CRC diagnosis and prognosis. However, further understanding the underlying molecular mechanisms and regulation of lncRNAs for the better characterization supports their clinical use to improve cancer settings including early diagnosis and prognosis. So far, only a few numbers of lncRNAs have been characterized as defined biomarkers and there are numerous unsettled issues as clinical biomarkers. For instance, the expression level of some circulating lncRNAs is too low to detect by routine amplification techniques. The discovery of specific and sensitive biomarkers among diverse cancer-related lncRNAs is also a massive challenge. However, determining the value of lncRNAs by supplementary functional studies in animal models and human clinical trials may create a milestone in oncology in the near future.
We thank the supported grant of deputy of research, Iran University of Medical Sciences (No. 95-03-182-29685).
Financial support and sponsorship
This study was supported by Iran University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Eslamizadeh S, Heidari M, Agah Sh, Faghihloo E, Ghazi H, Mirzaei A, et al
. The role of microRNA signature as diagnostic biomarkers in different clinical stages of colorectal cancer. Cell J 2018;20:220-30.
Akbari A, Ghahremani MH, Mobini GR, Abastabar M, Akhtari J, Bolhassani M, et al.
Down-regulation of miR-135b in colon adenocarcinoma induced by a TGF-β receptor I kinase inhibitor (SD-208). Iran J Basic Med Sci 2015;18:856-61.
Akbari A, Mobini GR, Maghsoudi R, Akhtari J, Faghihloo E, Farahnejad Z, et al.
Modulation of transforming growth factor β signaling transducers in colon adenocarcinoma cells induced by staphylococcal enterotoxin B. Mol Med Rep 2016;13:909-14.
Mirzaei A, Tavoosidana G, Rad AA, Rezaei F, Tavakoli-Yaraki M, Kadijani AA, et al.
Anew insight into cancer stem cell markers: Could local and circulating cancer stem cell markers correlate in colorectal cancer? Tumour Biol 2016;37:2405-14.
Mobini GR, Ghahremani MH, Amanpour S, Dehpour AR, Akbari A, Hoseiniharouni SM, et al.
Transforming growth factor beta-induced factor 2-linked X (TGIF2LX) regulates two morphogenesis genes, Nir1 and Nir2 in human colorectal. Acta Med Iran 2016;54:302-7.
Akbari A, Farahnejad Z, Akhtari J, Abastabar M, Mobini GR, Mehbod ASA. Staphylococcus aureus enterotoxin B down-regulates the expression of transforming growth factor-beta (TGF-β) signaling transducers in human glioblastoma. Jundishapur J Microbiol 2016;9:e27297–e27297.
Mirzaei A, Madjd Z, Kadijani AA, Tavakoli-Yaraki M, Modarresi MH, Verdi J, et al.
Evaluation of circulating cellular DCLK1 protein, as the most promising colorectal cancer stem cell marker, using immunoassay based methods. Cancer Biomark 2016;17:301-11.
Zhang M, Liu Y, Yu B, Kang J, Chen Y. Over-expression of long non-coding RNA GAPLINC promotes colorectal cancer cell metastasis and poor prognosis. Int J Clin Exp Med 2016;9:3203-8.
Deng L, Yang SB, Xu FF, Zhang JH. Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge. J Exp Clin Cancer Res 2015;34:18.
Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, et al.
The human long non-coding RNA-roR is a p53 repressor in response to DNA damage. Cell Res 2013;23:340-50.
Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, et al.
LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis 2014;5:e1287.
Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, et al.
Endogenous miRNA sponge lincRNA-roR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell 2013;25:69-80.
Cheng EC, Lin H. Repressing the repressor: A lincRNA as a microRNA sponge in embryonic stem cell self-renewal. Dev Cell 2013;25:1-2.
Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, et al.
Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res 2014;24:513-31.
McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C, et al.
CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest 2016;126:639-52.
Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, Halle D, Grinbaum R, Roistacher M, et al.
Colon cancer associated transcript-1: A novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer 2012;130:1598-606.
Alaiyan B, Ilyayev N, Stojadinovic A, Izadjoo M, Roistacher M, Pavlov V, et al.
Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence. BMC Cancer 2013;13:196.
He X, Tan X, Wang X, Jin H, Liu L, Ma L, et al.
C-myc-activated long noncoding RNA CCAT1 promotes colon cancer cell proliferation and invasion. Tumour Biol 2014;35:12181-8.
Zhao W, Song M, Zhang J, Kuerban M, Wang H. Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma. Int J Clin Exp Pathol 2015;8:14131-40.
Yang MH, Hu ZY, Xu C, Xie LY, Wang XY, Chen SY, et al.
MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 9. Biochim Biophys Acta 2015;1852:166-74.
Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, et al.
Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated wnt/β-catenin signal pathway. PLoS One 2013;8:e78700.
Smolle M, Uranitsch S, Gerger A, Pichler M, Haybaeck J. Current status of long non-coding RNAs in human cancer with specific focus on colorectal cancer. Int J Mol Sci 2014;15:13993-4013.
Ji Q, Zhang L, Liu X, Zhou L, Wang W, Han Z, et al.
Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. Br J Cancer 2014;111:736-48.
Zheng HT, Shi DB, Wang YW, Li XX, Xu Y, Tripathi P, et al.
High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. Int J Clin Exp Pathol 2014;7:3174-81.
Kita Y, Yonemori K, Osako Y, Baba K, Mori S, Maemura K, et al.
Noncoding RNA and colorectal cancer: Its epigenetic role. J Hum Genet 2017;62:41-7.
Li P, Zhang X, Wang H, Wang L, Liu T, Du L, et al.
MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2. Mol Cancer Ther 2017;16:739-51.
Yang P, Chen T, Xu Z, Zhu H, Wang J, He Z, et al.
Long noncoding RNA GAPLINC promotes invasion in colorectal cancer by targeting SNAI2 through binding with PSF and NONO. Oncotarget 2016;7:42183-94.
Li H, Jiang X, Niu X. Long non-coding RNA reprogramming (ROR) promotes cell proliferation in colorectal cancer via affecting P53. Med Sci Monit 2017;23:919-28.
Yang P, Yang Y, An W, Xu J, Zhang G, Jie J, et al.
The long noncoding RNA-ROR promotes the resistance of radiotherapy for human colorectal cancer cells by targeting the p53/miR-145 pathway. J Gastroenterol Hepatol 2017;32:837-45.
Iguchi T, Uchi R, Nambara S, Saito T, Komatsu H, Hirata H, et al.
Along noncoding RNA, lncRNA-ATB, is involved in the progression and prognosis of colorectal cancer. Anticancer Res 2015;35:1385-8.
Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al.
Along noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 2014;25:666-81.
Yue B, Qiu S, Zhao S, Liu C, Zhang D, Yu F, et al.
LncRNA-ATB mediated E-cadherin repression promotes the progression of colon cancer and predicts poor prognosis. J Gastroenterol Hepatol 2016;31:595-603.
Chen S, Bu D, Ma Y, Zhu J, Chen G, Sun L, et al.
H19 overexpression induces resistance to 1,25(OH) 2D3 by targeting VDR through miR-675-5p in colon cancer cells. Neoplasia 2017;19:226-36.
Yang Q, Wang X, Tang C, Chen X, He J. H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1. Int J Oncol 2017;50:1801-9.
Yang W, Ning N, Jin X. The lncRNA H19 promotes cell proliferation by competitively binding to miR-200a and derepressing β-catenin expression in colorectal cancer. Biomed Res Int 2017;2017:2767484.
Li S, Hua Y, Jin J, Wang H, Du M, Zhu L, et al.
Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population. Oncotarget 2016;7:25470-7.
Ohtsuka M, Ling H, Ivan C, Pichler M, Matsushita D, Goblirsch M, et al.
H19 noncoding RNA, an independent prognostic factor, regulates essential rb-E2F and CDK8-β-catenin signaling in colorectal cancer. EBioMedicine 2016;13:113-24.
Zhou J, Li X, Wu M, Lin C, Guo Y, Tian B. Knockdown of long noncoding RNA GHET1 inhibits cell proliferation and invasion of colorectal cancer. Oncol Res 2016;23:303-9.
Xie H, Zhu D, Xu C, Zhu H, Chen P, Li H, et al.
Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in hirschsprung disease. Biochem Biophys Res Commun 2015;463:569-74.
Ren YK, Xiao Y, Wan XB, Zhao YZ, Li J, Li Y, et al.
Association of long non-coding RNA HOTTIP with progression and prognosis in colorectal cancer. Int J Clin Exp Pathol 2015;8:11458-63.
Lian Y, Ding J, Zhang Z, Shi Y, Zhu Y, Li J, et al.
The long noncoding RNA HOXA transcript at the distal tip promotes colorectal cancer growth partially via silencing of p21 expression. Tumour Biol 2016;37:7431-40.
Sun J, Ding C, Yang Z, Liu T, Zhang X, Zhao C, et al.
The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition. J Transl Med 2016;14:42.
Zhai HY, Sui MH, Yu X, Qu Z, Hu JC, Sun HQ, et al.
Overexpression of long non-coding RNA TUG1 promotes colon cancer progression. Med Sci Monit 2016;22:3281-7.
Yi S, Xiao-Jiang Y, Zhen-Jun L, Gang L, Wu-Jin X, Wei-Xia J. UCA1, a long noncoding RNA, promotes the proliferation of CRC cells via p53/p21 signaling. Open Life Sci 2016;11:206-10.
Han Y, Yang YN, Yuan HH, Zhang TT, Sui H, Wei XL, et al.
UCA1, a long non-coding RNA up-regulated in colorectal cancer influences cell proliferation, apoptosis and cell cycle distribution. Pathology 2014;46:396-401.
Guo K, Yao J, Yu Q, Li Z, Huang H, Cheng J, et al.
The expression pattern of long non-coding RNA PVT1 in tumor tissues and in extracellular vesicles of colorectal cancer correlates with cancer progression. Tumour Biol 2017;39:1010428317699122.
Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, et al.
Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br J Cancer 2014;110:164-71.
Liu Y, Zhang M, Liang L, Li J, Chen YX. Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol 2015;8:11480-4.
Yang L, Qiu M, Xu Y, Wang J, Zheng Y, Li M, et al.
Upregulation of long non-coding RNA PRNCR1 in colorectal cancer promotes cell proliferation and cell cycle progression. Oncol Rep 2016;35:318-24.
Ye LC, Ren L, Qiu JJ, Zhu DX, Chen T, Chang WJ, et al.
Aberrant expression of long noncoding RNAs in colorectal cancer with liver metastasis. Tumour Biol 2015;36:8747-54.
Ye LC, Chen T, Zhu DX, Lv SX, Qiu JJ, Xu J, et al.
Downregulated long non-coding RNA CLMAT3 promotes the proliferation of colorectal cancer cells by targeting regulators of the cell cycle pathway. Oncotarget 2016;7:58931-8.
Guo XB, Hua Z, Li C, Peng LP, Wang JS, Wang B, et al.
Biological significance of long non-coding RNA FTX expression in human colorectal cancer. Int J Clin Exp Med 2015;8:15591-600.
Chen N, Guo D, Xu Q, Yang M, Wang D, Peng M, et al.
Long non-coding RNA FEZF1-AS1 facilitates cell proliferation and migration in colorectal carcinoma. Oncotarget 2016;7:11271-83.
Huang FT, Chen WY, Gu ZQ, Zhuang YY, Li CQ, Wang LY, et al.
The novel long intergenic noncoding RNA UCC promotes colorectal cancer progression by sponging miR-143. Cell Death Dis 2017;8:e2778.
Tsai KW, Lo YH, Liu H, Yeh CY, Chen YZ, Hsu CW, et al.
Linc00659, a long noncoding RNA, acts as novel oncogene in regulating cancer cell growth in colorectal cancer. Mol Cancer 2018;17:72.
Chaudhary R, Gryder B, Woods WS, Subramanian M, Jones MF, Li XL, et al.
Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to matrin 3. Elife 2017;6. pii: e23244.
Ding J, Xie M, Lian Y, Zhu Y, Peng P, Wang J, et al.
Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer. Oncogenesis 2017;6:e288.
Li C, Li W, Zhang Y, Zhang X, Liu T, Zhang Y, et al.
Increased expression of antisense lncRNA SPINT1-AS1 predicts a poor prognosis in colorectal cancer and is negatively correlated with its sense transcript. Onco Targets Ther 2018;11:3969-78.
Cai Y, Yan P, Zhang G, Yang W, Wang H, Cheng X, et al.
Long non-coding RNA TP73-AS1 sponges miR-194 to promote colorectal cancer cell proliferation, migration and invasion via up-regulating TGFα. Cancer Biomark 2018;23:145-56.
Cen C, Li J, Liu J, Yang M, Zhang T, Zuo Y, et al.
Long noncoding RNA LINC01510 promotes the growth of colorectal cancer cells by modulating MET expression. Cancer Cell Int 2018;18:45.
Chen ZP, Wei JC, Wang Q, Yang P, Li WL, He F, et al.
Long non-coding RNA 00152 functions as a competing endogenous RNA to regulate NRP1 expression by sponging with miRNA-206 in colorectal cancer. Int J Oncol 2018;53:1227-36.
Zheng Q, Lin Y, Chen P, Fan YP. The long noncoding RNA BC0209135 inhibits the cell invasion through wnt/β-catenin signaling in colorectal cancer. Eur Rev Med Pharmacol Sci 2018;22:3763-70.
Wan L, Kong J, Tang J, Wu Y, Xu E, Lai M, et al.
HOTAIRM1 as a potential biomarker for diagnosis of colorectal cancer functions the role in the tumour suppressor. J Cell Mol Med 2016;20:2036-44.
Yin DD, Liu ZJ, Zhang E, Kong R, Zhang ZH, Guo RH. Decreased expression of long noncoding RNA MEG3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Tumour Biol 2015;36:4851-9.
Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al.
Activation of p53 by MEG3 non-coding RNA. J Biol Chem 2007;282:24731-42.
Qi P, Xu MD, Ni SJ, Shen XH, Wei P, Huang D, et al.
Down-regulation of ncRAN, a long non-coding RNA, contributes to colorectal cancer cell migration and invasion and predicts poor overall survival for colorectal cancer patients. Mol Carcinog 2015;54:742-50.
Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, et al.
Apituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab 2003;88:5119-26.
Shi D, Zheng H, Zhuo C, Peng J, Li D, Xu Y, et al.
Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer. Med Oncol 2014;31:31.
Wang C, Yu J, Han Y, Li L, Li J, Li T, et al.
Long non-coding RNAs LOC285194, RP11-462C24.1 and nbla12061 in serum provide a new approach for distinguishing patients with colorectal cancer from healthy controls. Oncotarget 2016;7:70769-78.
Xu J, Zhang R, Zhao J. The novel long noncoding RNA TUSC7 inhibits proliferation by sponging miR-211 in colorectal cancer. Cell Physiol Biochem 2017;41:635-44.
Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q. LincRNA-roR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res 2015;13:330-8.
Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al.
Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 2011;29:742-9.
Ge X, Chen Y, Liao X, Liu D, Li F, Ruan H, et al.
Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. Med Oncol 2013;30:588.
Kam Y, Rubinstein A, Naik S, Djavsarov I, Halle D, Ariel I, et al.
Detection of a long non-coding RNA (CCAT1) in living cells and human adenocarcinoma of colon tissues using FIT-PNA molecular beacons. Cancer Lett 2014;352:90-6.
Haerian MS, Baum L, Haerian BS. Association of 8q24.21 loci with the risk of colorectal cancer: A systematic review and meta-analysis. J Gastroenterol Hepatol 2011;26:1475-84.
Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM, et al.
Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007;39:989-94.
Arun G, Diermeier S, Akerman M, Chang KC, Wilkinson JE, Hearn S, et al.
Differentiation of mammary tumors and reduction in metastasis upon malat1 lncRNA loss. Genes Dev 2016;30:34-51.
Xu C, Yang M, Tian J, Wang X, Li Z. MALAT-1: A long non-coding RNA and its important 3' end functional motif in colorectal cancer metastasis. Int J Oncol 2011;39:169-75.
Wu Y, Lu W, Xu J, Shi Y, Zhang H, Xia D, et al.
Prognostic value of long non-coding RNA MALAT1 in cancer patients. Tumour Biol 2016;37:897-903.
Hu Y, Wang J, Qian J, Kong X, Tang J, Wang Y, et al.
Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res 2014;74:6890-902.
Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, et al.
Large intergenic non-coding RNA-roR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 2010;42:1113-7.
Karimi A, Majidzadeh-A K, Madjd Z, Akbari A, Habibi L, Akrami SM. Effect of Copper Sulfate on Expression of Endogenous L1 Retrotransposons in HepG2 Cells (Hepatocellular Carcinoma). Biol Trace Elem Res 2015;165:131-4.
Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 2007;1775:21-62.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-90.
Berteaux N, Aptel N, Cathala G, Genton C, Coll J, Daccache A, et al.
Anovel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression. Mol Cell Biol 2008;28:6731-45.
Gao T, He B, Pan Y, Xu Y, Li R, Deng Q, et al.
Long non-coding RNA 91H contributes to the occurrence and progression of esophageal squamous cell carcinoma by inhibiting IGF2 expression. Mol Carcinog 2015;54:359-67.
Deng Q, He B, Gao T, Pan Y, Sun H, Xu Y, et al.
Up-regulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with colorectal cancer. PLoS One 2014;9:e103022.
Li LJ, Zhu JL, Bao WS, Chen DK, Huang WW, Weng ZL, et al.
Long noncoding RNA GHET1 promotes the development of bladder cancer. Int J Clin Exp Pathol 2014;7:7196-205.
Yang F, Xue X, Zheng L, Bi J, Zhou Y, Zhi K, et al.
Long non-coding RNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-myc mRNA stability. FEBS J 2014;281:802-13.
Sasaki YT, Sano M, Kin T, Asai K, Hirose T. Coordinated expression of ncRNAs and HOX mRNAs in the human HOXA locus. Biochem Biophys Res Commun 2007;357:724-30.
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al.
Along noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 2011;472:120-4.
Young TL, Matsuda T, Cepko CL. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol 2005;15:501-12.
Han Y, Liu Y, Gui Y, Cai Z. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. J Surg Oncol 2013;107:555-9.
Zhang Q, Geng PL, Yin P, Wang XL, Jia JP, Yao J, et al.
Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac J Cancer Prev 2013;14:2311-5.
Ni B, Yu X, Guo X, Fan X, Yang Z, Wu P, et al.
Increased urothelial cancer associated 1 is associated with tumor proliferation and metastasis and predicts poor prognosis in colorectal cancer. Int J Oncol 2015;47:1329-38.
Jing F, Jin H, Mao Y, Li Y, Ding Y, Fan C, et al.
Genome-wide analysis of long non-coding RNA expression and function in colorectal cancer. Tumour Biol 2017;39:1010428317703650.
Huang C, Yu W, Wang Q, Cui H, Wang Y, Zhang L, et al.
Increased expression of the lncRNA PVT1 is associated with poor prognosis in pancreatic cancer patients. Minerva Med 2015;106:143-9.
Kong R, Zhang EB, Yin DD, You LH, Xu TP, Chen WM, et al.
Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16. Mol Cancer 2015;14:82.
Ding C, Yang Z, Lv Z, DU C, Xiao H, Peng C, et al.
Long non-coding RNA PVT1 is associated with tumor progression and predicts recurrence in hepatocellular carcinoma patients. Oncol Lett 2015;9:955-63.
Guan Y, Kuo WL, Stilwell JL, Takano H, Lapuk AV, Fridlyand J, et al.
Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res 2007;13:5745-55.
Kretz M, Webster DE, Flockhart RJ, Lee CS, Zehnder A, Lopez-Pajares V, et al.
Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev 2012;26:338-43.
Saus E, Brunet-Vega A, Iraola-Guzmán S, Pegueroles C, Gabaldón T, Pericay C, et al.
Long non-coding RNAs as potential novel prognostic biomarkers in colorectal cancer. Front Genet 2016;7:54.
Iwaya T, Sato K, Kume K, Nishizuka S, Wakabayashi G, Mimori K. Overexpression of Long Noncoding RNA FTX was Associated with Colorectal Cancer Progression. [abstract]. In: Proceedings of the 106th
Annual Meeting of the American Association for Cancer Research; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 162.
Li C, Zhou L, He J, Fang XQ, Zhu SW, Xiong MM, et al.
Increased long noncoding RNA SNHG20 predicts poor prognosis in colorectal cancer. BMC Cancer 2016;16:655.
Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell 1988;54:787-93.
Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 2009;28:195-208.
Pickard MR, Mourtada-Maarabouni M, Williams GT. Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta 2013;1832:1613-23.
Qiao HP, Gao WS, Huo JX, Yang ZS. Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pac J Cancer Prev 2013;14:1077-82.
Guo X, Deng K, Wang H, Xia J, Shan T, Liang Z, et al.
GAS5 inhibits gastric cancer cell proliferation partly by modulating CDK6. Oncol Res Treat 2015;38:362-6.
Yin D, He X, Zhang E, Kong R, De W, Zhang Z, et al.
Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Med Oncol 2014;31:253.
Yang Y, Shen Z, Yan Y, Wang B, Zhang J, Shen C, et al.
Long non-coding RNA GAS5 inhibits cell proliferation, induces G0/G1 arrest and apoptosis, and functions as a prognostic marker in colorectal cancer. Oncol Lett 2017;13:3151-8.
Díaz-Beyá M, Brunet S, Nomdedéu J, Pratcorona M, Cordeiro A, Gallardo D, et al.
The lincRNA HOTAIRM1, located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature. Oncotarget 2015;6:31613-27.
Ye C, Shen Z, Wang B, Li Y, Li T, Yang Y, et al.
Anovel long non-coding RNA lnc-GNAT1-1 is low expressed in colorectal cancer and acts as a tumor suppressor through regulating RKIP-NF-κB-snail circuit. J Exp Clin Cancer Res 2016;35:187.
Yu M, Ohira M, Li Y, Niizuma H, Oo ML, Zhu Y, et al.
High expression of ncRAN, a novel non-coding RNA mapped to chromosome 17q25.1, is associated with poor prognosis in neuroblastoma. Int J Oncol 2009;34:931-8.
Zhu Y, Yu M, Li Z, Kong C, Bi J, Li J, et al.
NcRAN, a newly identified long noncoding RNA, enhances human bladder tumor growth, invasion, and survival. Urology 2011;77:510.e1-5.
Liu L, Yan B, Yang Z, Zhang X, Gu Q, Yue X, et al.
NcRuPAR inhibits gastric cancer progression by down-regulating protease-activated receptor-1. Tumour Biol 2014;35:7821-9.
Darmoul D, Gratio V, Devaud H, Lehy T, Laburthe M. Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells. Am J Pathol 2003;162:1503-13.
Adams GN, Rosenfeldt L, Frederick M, Miller W, Waltz D, Kombrinck K, et al.
Colon cancer growth and dissemination relies upon thrombin, stromal PAR-1, and fibrinogen. Cancer Res 2015;75:4235-43.
Yan B, Gu W, Yang Z, Gu Z, Yue X, Gu Q, et al.
Downregulation of a long noncoding RNA-ncRuPAR contributes to tumor inhibition in colorectal cancer. Tumour Biol 2014;35:11329-35.
Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer 2011;129:773-9.
Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, et al.
MicroRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 2011;30:4750-6.
Cao X, Zhuang S, Hu Y, Xi L, Deng L, Sheng H, et al.
Associations between polymorphisms of long non-coding RNA MEG3 and risk of colorectal cancer in chinese. Oncotarget 2016;7:19054-9.
Wang P, Ren Z, Sun P. Overexpression of the long non-coding RNA MEG3 impairsin vitro
glioma cell proliferation. J Cell Biochem 2012;113:1868-74.
Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: A tumor suppressor. J Mol Endocrinol 2012;48:R45-53.
Tong YS, Zhou XL, Wang XW, Wu QQ, Yang TX, Lv J, et al.
Association of decreased expression of long non-coding RNA LOC285194 with chemoradiotherapy resistance and poor prognosis in esophageal squamous cell carcinoma. J Transl Med 2014;12:233.
Ding YC, Yu W, Ma C, Wang Q, Huang CS, Huang T, et al.
Expression of long non-coding RNA LOC285194 and its prognostic significance in human pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol 2014;7:8065-70.
Qi P, Xu MD, Ni SJ, Huang D, Wei P, Tan C, et al.
Low expression of LOC285194 is associated with poor prognosis in colorectal cancer. J Transl Med 2013;11:122.
Liu Q, Huang J, Zhou N, Zhang Z, Zhang A, Lu Z, et al.
LncRNA loc285194 is a p53-regulated tumor suppressor. Nucleic Acids Res 2013;41:4976-87.