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Review

Current Status of Long Non-Coding RNAs in Human Cancer with Specific Focus on Colorectal Cancer

by
Maria Smolle
1,†,
Stefan Uranitsch
2,†,
Armin Gerger
3,
Martin Pichler
3 and
Johannes Haybaeck
1,*
1
Institute of Pathology, Medical University Graz, Auenbruggerplatz 25, A-8036 Graz, Austria
2
Department of Surgery, St John of God Hospital Graz, Marschallgasse 12, A-8020 Graz, Austria
3
Division of Oncology, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria
*
Author to whom correspondence should be addressed.
†
These authors have contributed equally to this work.
Int. J. Mol. Sci. 2014, 15(8), 13993-14013; https://doi.org/10.3390/ijms150813993
Submission received: 30 June 2014 / Revised: 23 July 2014 / Accepted: 5 August 2014 / Published: 12 August 2014
(This article belongs to the Collection Regulation by Non-coding RNAs)
Browse Figure
Versions Notes

Abstract

:
The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been elucidated, there is still a high number of lncRNAs with unknown or controversial functions. In this review, we provide an overview of different lncRNAs and their role in human cancers. In particular, we emphasize their importance in tumorigenesis of colorectal cancer, the third most common cancer worldwide.

1. Introduction

After the sequencing of the human genome was finished in 2003, it became evident that only 20,000 genes are protein-coding, while over 98% of all genes remain untranslated, giving rise to non-protein-coding RNAs (ncRNAs) [1]. Over the past decade, thousands of ncRNAs were identified in the eukaryotic transcriptome [2,3]. Traditionally, ncRNAs are divided into two groups according to their length: the short ncRNAs, such as microRNA (miRNA) and transfer RNA (tRNA), consisting of less than 200 nucleotides, and the long non-coding RNAs (lncRNAs), sized from 200 nucleotides up to 100 kb [4]. Members of this second group are Xist (X-inactive-specific transcript), playing an important role in X-chromosome inactivation, HOTAIR (homeobox gene antisense intergenic RNA), and the imprinted H19—one of the first lncRNA genes being reported [5,6,7,8].
Most lncRNAs are transcribed by RNA polymerase II, but some by RNA polymerase III [9]. While functional lncRNAs are usually polyadenylated many of them remain un-polyadenylated, such as BC200 and Occt4-pg5 [10,11].

1.1. Functions of LncRNAs

Presenting a heterogeneous group, lncRNAs play an important role in various biological processes, although most of them are poorly conserved [12,13].
Wang et al. [14] subdivided the molecular functions of lncRNAs into four archetypes: signaling, decoying, scaffolding and guiding. The advantage of using lncRNAs for regulative functions lies in avoiding time-consuming translation into proteins and some signaling lncRNAs exhibit regulatory transcriptionally relevant functions [14]. Decoying ncRNAs mainly have a negative effect on regulation by capturing and eliminating RNA-binding proteins (RBPs) which commonly are specific transcription factors [14]. As guides, lncRNAs can either change expression of adjacent genes (cis-acting guides), such as Xist, Air and COLDAIR, or, though less frequently, they control expression of distant genes (trans-acting guides), like HOTAIR and Jpx [14,15,16]. The fourth class of scaffolding lncRNAs bring together effectors with activating or repressive impact on transcription by binding them with several lncRNA-domains [14].
Vikram et al. [17] published another classification of lncRNAs depending on their location regarding their respective gene. They also devided lncRNAs in four groups: sense, antisense, intronic and intergenic lncRNAs. Sense lncRNAs are transcribed from the same strand of DNA as protein-coding genes, antisense lncRNAs from the opposite strand. In case of intronic lncRNAs the transcription unit lies within an intron of another gene whereas the region for transcriptation for intergenic lncRNAs lies outside of the coding region.
According to Pandolfi and colleagues [18] lncRNAs also bind to microRNA-response-elements (MREs) and do not only interact with other lncRNAs. In diverse experiments, competition for miRNAs could be revealed as an important factor for gene regulation of both lncRNAs and messengerRNAs [19,20,21,22].

1.2. LncRNAs in Cancer

Tumor cells proliferate autonomously, are insensitive for stimuli from the organism and produce factors enhancing cell division, avoiding apoptosis and stimulating vascular growth.
Hundreds of oncogenes and tumor suppressor-genes have been discovered, but many cellular mechanisms in tumors are still poorly understood [23]. Recently, the emphasis of researchers concerning tumorigenesis has switched to lncRNAs, as those “dark matters of the genome” are selectively over- or underexpressed in different tumors, as summarized in Table 1 [24].
Table
Table 1. Cancer and lncRNA expression.
Table 1. Cancer and lncRNA expression.
Type of CancerlncRNAExpressionRef.
Head- and Neck Cancer
nasopharyngeal carcinomaLINC00312down[25]
Brain Tumors
glioblastoma multiformeASLNC22381up[26]
ASLNC20819 up[26]
NeuroblastomancRANup[27,28]
Lung Cancer
non-small cell lung cancerTUG1down[29]
lung cancerMALAT-1up[30]
Soft-Tissue Sarcoma
OsteosarcomaTUG1up[29,31]
Tumors of the Genitourinary Tract
urothelial carcinomancRANup[32]
UCA-1up[33]
prostate cancerPlncRNA-1up[34]
MALAT-1up[35]
PCGEM1up[36]
PRNCR1up[36]
PCAT-1up[37]
epithelial ovarian cancerHOTAIRup[38]
UCA-1up[39]
MALAT-1down[39]
H19down[39]
Tumors of the Gastrointestinal Tract
esophagus squamous cell carcinomaPlncRNA-1up[40]
HOTAIRup[41]
gastric cancerHOTAIRup[42]
CCAT1-Lup[43]
H19up[44]
hepatocellular carcinomaH19up[45]
MALAT-1up[30]
HOTAIRup[46]
HULCup[47,48]
LncRNA-DrehDown[49]
MEG3 Down[50]
lncRNA-MVIHup[51]
MDIGup[52]
Colorectal Cancer
PCAT-1up[53]
PRNCR1up[54]
MALAT-1up[55]
CCAT1-Lup[56,57]
PVT-1up[58]
ncRANdown[27,58]
HOTAIRup[59]
LncRNAs acting like oncogenes, are up-regulated in tumor tissue. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) for example, which is expressed in human tissue, becomes up-regulated in various solid tumors, including liver, lung, breast and prostate cancer [30,60].
Some lncRNAs act like tumor-suppressors, such as the maternally expressed gene 3 (MEG3) which is commonly expressed in normal human tissue. However, its down-regulation in most human meningiomas [61] promotes an increase in the expression level of tumor suppressor-protein p53, and the transcription of p53-related, driving defective cells into apoptosis. However, MEG3 also inhibits dysregulated cell proliferation in the absence of p53, leading to the opinion that this lncRNA has a suppressive function in both, p53-dependent and -independent ways [62]. The next subchapters will describe role of lncRNAs in particular types of human cancers in more detail with a special focus on lncRNAs on colorectal cancer.

1.2.1. Head- and Neck Cancer

Nasopharyngeal Carcinoma
In nasopharyngeal carcinoma expression of LINC00312, an intergenic lncRNA with tumor-suppressive function, is significantly down-regulated [25]. Under physiological conditions LINC00312 inhibits proliferation in nasopharyngeal epithelium by preventing cell cycle passage from the G1 into S phase but increases cell adhesion, motility and invasion by down-regulating the expression of estrogene receptor alpha (ERα) [63]. A lower expression level of LINC00312 in nasopharyngeal tumor tissue is positively correlated with tumor size and clinical stage but negatively correlated with lymph node metastasis [25].

1.2.2. Brain Tumors

Glioblastoma Multiforme
In glioblastoma multiforme (GBM), 654 lncRNAs were shown to be up-regulated and 654 down-regulated at least fourfold in comparison to normal brain tissue [64]. Two up-regulated lncRNAs, ASLNC22381 and ASLNC20819, might play important roles in malignant behavior and relapse of GBM by targeting insulin-like growth factor (IGF-1) genes [26].

1.2.3. Lung Cancer

Non-Small Cell Lung Cancer
The lncRNA taurine-upregulated gene 1 (TUG1) is down-regulated in over 80% of non-small cell lung cancers (NSCLC; squamous cell carcinoma, adenocarcinoma) compared to normal tissue which is positively correlated with tumor size and pathological stage [29].
TUG1-expression is regulated by binding of p53 to a response element at the promotor region [29]. TUG1 epigenetically regulates the expression of HOXB7, an oncogene activating the AKT/MAPK (protein kinase B/mitogen activated protein kinase) pathways [65].

1.2.4. Soft-Tissue Sarcoma

Osteosarcoma
In osteosarcoma TUG1 usually is overexpressed causing high cell proliferation and a low apoptosis rate, whereas in other cancer tissues TUG1 is down-regulated [29,31]. This emphasizes the theory that lncRNAs are expressed in a more tissue-specific pattern than protein-coding RNAs, a feature that makes them attractive as potential diagnostic biomarkers [40,41].

1.2.5. Tumors of the Genitourinary Tract

Urothelial Carcinoma/Bladder Cancer
The long non-coding RNA urothelial carcinoma associated 1 (lncRNA-UCA1), a key player in cancer progression and metastasis formation of urinary bladder cancer, was shown to be up-regulated in bladder cancer [33]. However, the pathways contributing to its function are largely unknown. Xue et al. [66] identified a CCAAT/enhancer binding protein α (C/EBPα), which is interacting with lncRNA-UCA1 in cancer cells. C/EBPα bound to the core promoter region in vitro and in vivo [66]. Upon treatment with C/EBPα siRNA the expression of lncRNA-UCA1 was depressed, cell viability was reduced and apoptosis induced in vitro. Due to its high sensitivity and specificity, lncRNA-UCA1 can be used as a biomarker to detect bladder carcinoma in urine sediment [33]. Based on these data, lncRNA-UCA1 might also serve as a therapeutic target once the appropriate delivery systems and tools for targeting lncRNAs at specific locations will be developed.
UCA1 has three variant transcripts which were detected by northern blot analysis in the human bladder transitional cell carcinoma (TCC) cell line BLZ-211 by Wang and colleagues [67]. This group focused on the second transcript (2.2 kb) (UCA1a) which is identical to the cancer up-regulated drug resistant gene (CURD). Overexpression of UCA1a (CURD) was reported to lead to increased proliferation, migration and invasion of urinary bladder cancer cells. The increased apoptosis rate by cisplatin in UM-UC-2 cells was antagonized by the overexpression of CURD.
Zhu et al. [32] investigated the behavior of ncRAN, an lncRNA, in urinary bladder cancer cell lines. The expression was significantly higher in invasive tumor cells compared to normal tissue. An overexpression in the superficial tumor cell line (RT4) promoted cell proliferation, migration and invasion.
Prostate Cancer
The influence of lncRNAs on the androgen receptor is a point of interest due to the fact that the androgen receptor is a transcription factor and plays a key role in growth and survival of prostate cells. Therapeutic blocking of androgen receptors (ARs) leads to tumor regression in prostate cancer. The two lncRNAs prostate cancer noncoding RNA1 (PRNCR1) and prostate cancer gene expression marker 1 (PCGEM1) were reported by Yang [36] to bind to ARs and mediate gene transcription. They are overexpressed in aggressive prostate cancer and activate both ligand-dependent and ligand-independent AR-mediated proliferation. However, the association of PNCR1 and prostate cancer could not be replicated by others [68]. Ren et al. [35] investigated MALAT-1 in human prostate cancer tissue and in mouse xenografts and showed that MALAT-1 was upregulated in both. This was correlated with markers of poor prognosis, such as a high gleason score, prostate-specific antigen, tumor stage and castration-resistant prostate cancer. Silencing of MALAT-1 by siRNA transfection inhibited cell growth, invasion and migration and induced cell cycle arrest in the G0/G1 phase in castration resistant prostate cancer.
LncRNA PCAT-1 was investigated in prostate cancer (PC) by Presner et al. [69]. PCAT-1, located on chromosome 8q24, was reported to be upregulated in metastatic and localized PC. Polycomb Repressive Complex 2 (PRC2) is interacting with PCAT-1 to promote cell proliferation. PCAT-1 modulates the transcriptional regulation of 370 genes, 255 of which are upregulated, leading to an increased cell turnover. PCAT-1 represses the BRCA2 tumor suppressor gene which in consequence leads to less homologous recombination (HR). A mutation of BRCA2 leads to defective HR and accumulation of double-stranded DNA breaks [70]. High expression of PCAT-1 in PC tissue was reported to predict for low BRCA2 expression [69].
Epithelial Ovarian Cancer
The expression levels and clinical relevance of lncRNA HOTAIR in epithelial ovarian cancer (EOC) was investigated by Qui et al. [38]. They used surgically resected tissue samples of ovarian tumors, non-cancerous ovarian surface epithelial tissue and human ovarian cancer cell lines (SKOV3, SKOV3.ip1, HO8910, HO8910-PM and HEY-A8). The expression of HOTAIR was measured by qRT-PCR (real time reverse transcription polimerase chain reaction) and was significantly higher in the tumors than in normal epithelial ovarian tissue. Analyzing the clinical relevance of high HOTAIR levels in EOC a positive correlation with an advanced FIGO (International Federation of Gynecology and Obstetrics) stage, high histological grade of the tumor and occurrence of lymph node metastases was demonstrated [38]. The overexpression of HOTAIR was found to be independently associated with shorter disease free survival and poor overall survival of the patients [38].
A knockdown of HOTAIR in cell lines and in a mouse model in vivo was reported to inhibit migration and invasion in SKOV3.ip1, HO8910-PM, and HEY-A8 cells. These findings suggest that HOTAIR promotes EOC metastasis [38].
The human ovarian cancer cell lines SKOV3 and SKOV3.ip1 were used to determine the difference in the expression of lncRNAs in EOC by using a microarray approach. The SKOV3.ip1 cells had a higher metastatic potential than the other cell line [71]. Liu et al. [39] reported H19, LOC100292680 and MALAT-1 as down-regulated, UCA1, CCAT1, LOC645249, and LOC100128881 as up-regulated in SKOV3.ip1 cells.

1.2.6. Tumors of the Gastrointestinal Tract

Esophageal Squamous Cell Carcinoma
According to Wang et al. [34], PlncRNA-1 is up-regulated in esophageal squamous cell carcinoma (ESCC), the eighth most common cancer worldwide. In ESCCs with lymph node metastases PlncRNA-1 expression was higher than in carcinomas limited to the esophagus. Moreover, in vitro knock-down of PlncRNA-1 increased the apoptosis rate in tumor tissue significantly pointing to a suppressive effect of this lncRNA on controlled cell death [34].
Furthermore, the expression of the oncogenic lncRNA HOTAIR is elevated in ESCC in comparison to noncancerous tissue which indicates a poor prognosis [72].
Gastric Cancer
Wang et al. [73] analyzed the expression of lncRNAs in gastric adenocarcinoma (GCA) and compared the results to normal tissue. One-thousand, eight-hundred and eighty lncRNAs were significantly up-regulated, 294 were down-regulated. The most up-regulated lncRNA was ASHG19A3A028863 (fold change: 146.0139123) and the most down-regulated lncRNA ASHG19A3A007184 (fold change: 58.71047078). Song and colleagues [74] identified 135 lncRNAs which were altered more than two fold. The strongest down-regulated lncRNAs were FER1L4, uc001lsz, BG491697, AF131784, uc009ycs, BG981369, AF147447, HMlincRNA1600 and AK054588, the most up-regulated were H19, HMlincRNA717, BM709340, BQ213083, AK054978 and DB077273. Up-regulated H19 in gastic cancer cells accelerates cell proliferation while knockdown of H19 induced apoptosis [44]. The up-regulation of the lncRNA CCAT1, acting as oncogene, was correlated with tumor growth and lymph node metastasis according to Yang et al. [43].
The lncRNA HOTAIR was up-regulated in gastric cancer tissue and correlated with larger tumor size, advanced pathological stage, distant metastasis, lymph node metastasis and inferior cell differentiation. Patients with high HOTAIR expression had poorer prognosis concerning the overall survival than those with low levels of HOTAIR. Knockdown of HOTAIR in a murine xenograft model lead to a decrease in tumor volume and tumor weight. The level of HOTAIR expression was associated with the in vivo proliferation capacity of cancer cells [42].
Hepatocellular Carcinoma
H19 is exclusively expressed from the maternal allele and plays a key role in genomic imprinting. Still its function remains to be unclear [7]. H19 is upregulated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [75]. Lizuka et al. [76] described an imbalance of IGF2 expression levels and H19 transcripts and the positive correlation with the progression of HCC. The H19 gene was reported to interact with drug resistant liver cancer cells by regulating multi drug resistance 1 (MDR1) promoter methylation and induction of P-glycoprotein expression [77]. Overexpression of H19 mRNA and MDR1 was observed in doxorubicin-resistant R-HepG2 cells whereas knockdown of H19 in these cells suppressed MDR1/P-glycoprotein expression and sensitized the cells to doxorubicin toxicity [77]. E-cadherine (CDH1), keratin-8 (KRT-8), keratin-19 (KRT-19) and claudin 1 (CLDN1), the markers for epithelial-to-mesenchymal transition, can be decreased by H19 and suppress HCC progression [45]. Highly up regulated in liver cancer (HULC) is situated at chromosome 6p24.3 and is upregulated in HCC cells. HULC can be used as HCC biomarker as it was detected in plasma [47]. A correlation between HULC and hepatitis B virus X protein (HBx) was obsereved in hepatoma G2 cells and immortalized normal liver L-02 cells. HBx could upregulate HULC and promoted proliferation of hepatoma cells by suppressing p18 [48]. The LncRNA Dreh (HBx-related long non-coding RNA) can repress the expression of vimentin and change the normal cytoskeleton structure. It is downregulated by HBx and acts as a tumor suppressor in the HBV-HCC and inhibit the growth and metastasis in vitro and in vivo [49].
HOTAIR is also overexpressed in HCC and hepatoma cell lines. Knockdown of HOTAIR reduces the proliferation of the HCC cell line Bel7402 by suppressing matrix metalloproteinase-9 and vascular endothelial growth factor. Higher levels of HOTAIR were detected in patients with lymph node metastasis than in patients without [46]. The lncRNA maternally expressed gene 3 (MEG3) is involved in HCC progression and its expression is reduced in HCC tissue and cell lines compared to normal liver tissue. Braconi et al. [50] inducted MEG3 expression in HCC tissue and observed a decrease in cell growth and induced apoptosis.
Yuan et al. [51] identified the lncRNA-associated microvascular invasion in HCC (lncRNA MVIH), which was associated with angiogenesis of HCC. The group could promote tumor growth and intrahepatic metastasis in vivo and in vitro by inhibiting phosphoglycerate kinase 1 (PGK1) secretion. Mineral dust-induced gene (MDIG), another lncRNA, is also overexpressed in HCC [52]. Ogasawara et al. [78] detected that MDIG expression levels in surgically resected HCC were higher in tumors larger than 2 cm than in smaller ones. In poorly differentiated HCC the expression was higher than in well differentiated ones.

2. Colorectal Cancer

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide with an increasing incidence in men and women [79]. At early tumor stage, the five-year survival rate ranges from 60%–95% whereas in tumors at higher tumor stages the number decreases to just 35% [80,81]. Despite many studies on the pathogenesis of CRC, a unique scheme for CRC development could not be developed [82].

2.1. Clinical Presentation

CRC patients can be separated in non-symptomatic and symptomatic individuals. Many of the first group are diagnosed based on a positive colonoscopy result following a positive fecal occult blood test. Symptomatic patients often suffer from rectal bleeding, abdominal pain, changes in bowel habits, anemia and occult bleeding [83]. Due to the anatomical location, the symptoms can vary. Haematochezia and obstructive symptoms are more common for left sided tumors whereas patients with right sided tumors present more often with anaemia without visible haematochezia [84]. Patients can be admitted as emergency with obstructive symptoms like ileus or with signs of acute abdomen in case of tumor perforation. CRC is staged on the basis of the current issue of the TNM classification (classification of malignant tumors) [85].

2.2. Subtypes

CRC can either be inherited or sporadic. Currently, 10%–15% of all CRC cases are inherited diseases. Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are the most commonly CRC associated genetic disorders [86]. Clinical and familial criteria have been defined to identify patients with HNPCC-associated CRC. The Amsterdam II Criteria and Revised Bethesda Guidelines are routinely used [87,88]. Testing for microsatellite instability (MSI) and DNA mismatch repair genes (MMR) are obligatory if the mentioned pre-selection criteria are rated positive. HNPCC syndrome is caused by an autosomal dominant genetic mutation in one of the four MMR genes—MLH1, MSH2, MSH6, PMS2. DNA repair defects increase the number of somatic mutations. Carriers of a MMR gene mutation have a high risk to develop CRC [89].
Patients with FAP syndrom suffer from a germline mutation of the adenomatous polyposis coli (APC) gene located on chromosome 5q21 following an autosomal dominant inheritance. “De novo” mutations have been detected in 15%–20% of patients without family history [90]. The development of hundreds of adenomas in the colon and rectum, and extracolonic manifestations are the clinical criteria for diagnosing FAP and indicate genetic analysis. Almost 100% of FAP patients will develop CRC by the mean age of 40–50 years if not treated surgically at an early stage [91].

2.3. Tumor Markers

Carcinoembryonic antigen (CEA) levels may serve as biomarker during follow-up, but cannot be used as reliable screening or diagnostic tool because of a lack in sensitivity and specificity in the early detection of CRC [92,93,94,95]. Rising CEA levels in the follow-up period after surgery may indicate recurrent disease and the patient has to be restaged through computer tomography (CT) scan of the liver [96].

2.4. Staging and Therapy

Before surgery, abdominal ultrasound, colonoscopy, thoracic X-ray and CEA blood levels are routinely analyzed. In case of suspected distant metastasis extended CT scans (brain, abdomen) are recommended. In rectal cancer, patients additional magnetic resonance imaging (MRI) of the pelvis and transrectal endoscopic ultrasound are obligatory. The rectal location has to be evaluated by non-flexible endoscopy as well.
Based on the TNM classification, local versus radical, curative versus palliative surgery ranging from local excision to pelvic exenteration has to be performed. Preoperative radio-chemotherapy of rectal carcinomas and postoperative chemotherapy of patients with pT3-4 or N+ stage are part of the treatment options supplementing surgery [97]. Recently, many molecular markers including single nucleotide polymorphisms in protein-coding genes, inflammatory scores or microRNAs have been proposed as pathophysiological and prognostic factors in CRC [98,99,100].

2.5. LncRNAs in Colorectal Cancer

As mentioned above, recent investigations on lncRNAs have revealed their important roles in genesis and progression of various tumors. Similarly, in colorectal cancer many lncRNAs have been detected as potential biomarkers. Additionally, Figure 1 illustrates the functions of lncRNAs in CRC (Figure 1).
Ijms 15 13993 g001 1024
Figure 1. LncRNAs being involved in molecular pathogenesis of colorectal cancer: lncRNAs interact with specific molecular structures, induce different effects in tumor cells and influence the molecular pathogenesis of colorectal cancer.
Figure 1. LncRNAs being involved in molecular pathogenesis of colorectal cancer: lncRNAs interact with specific molecular structures, induce different effects in tumor cells and influence the molecular pathogenesis of colorectal cancer.
Ijms 15 13993 g001

2.5.1. MALAT-1

One of the most prominent lncRNAs is metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1; also known as HCN, NEAT2, NCRNA00 047 and PRO2853), located on chromosome 11q13.1 with a length of 8000 nt [30,55]. It was revealed that MALAT-1 is highly expressed in metastases of various tumors, such as non-small cell lung cancer, hepatocellular carcinoma and endometrial stromal sarcoma [30]. MALAT-1 can be subdivided into 5 fragments that are overexpressed in CRC tissue, all having different functions [55]. One of these fragments, 6918–8441 nt, enhances cell proliferation and invasion, while fragement 5434–6951 nt is important for normal cell function [55]. Therefore, up-regulation of fragment 6918–8411 nt in CRC tissue leads to increased tumor growth. An additional mutation in fragment 5434–6951 nt might promote tumorigenesis in CRC tissue [55].

2.5.2. PVT-1

The oncogenic lncRNA PVT-1 is up-regulated in CRC in comparison to normal colorectal tissue due to a copy number amplification of chromosome 8q24 on which the PVT-1 gene is located [58]. High levels of PVT-1 in CRC cells lead to increased tumor growth whereas knockdown activates genes of the TGF (transforming growth factor)-β family [58]. Patients suffering from CRC with extremely high levels of PVT-1 presented with greater venous invasion and larger size of lymph nodes in comparison to CRC patients with a lower rate of PVT-1 [58].

2.5.3. ncRAN

ncRAN, at first discovered as a lncRNA up-regulated in neuroblastoma indicating a poor prognosis, also plays a role in CRC [27,28]. According to Qi et al. [28] ncRAN is generally under-expressed in CRC in comparison to adjacent tissue. ncRAN inhibits CRC cell invasion and migration but does not affect CRC cell proliferation. Furthermore, it was discovered that CRC with poor differentiation have significantly lower ncRAN levels compared to highly differentiated CRC. Regarding overall survival of patients with CRC, the expression of ncRAN appears to be an important marker [28]. Moreover, in case of ncRAN, it is evident that lncRNAs have distinctive expression patterns in different tumors [101].

2.5.4. CCAT1-L

In CRC the lncRNA colorectal cancer associated transcript-1, long isoform (CCAT1-L), located on chromosome 8q24 shows upregulation which is positively related to tumor stage and progression [56,57]. According to Xiang and colleagues [57,102] the long isoform of CCAT1 (CCAT1-L) operates in the nucleus while the short isoform (CCAT1-S) is found in the cytoplasm. CCAT1-L is located on the MYC (myelocytomatosis)-locus 515 kb distant from MYC but it can interact with a transcriptional enhancer (MYC-335) by chromatine looping which subsequently interacts with the MYC-promotor [103]. Furthermore, knockdown of CCAT1-L leads to a decreased level of MYC mRNA, emphasising the theory that this lncRNA can regulate MYC-expression in cis [57].

2.5.5. CCAT2

Very recently, Ling et al. [104] reported the novel lncRNA colon cancer associated transcript 2 (CCAT2) encompassing the rs6983267 SNP (single nucleotide polymorphism) which is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. Furthermore, they showed interaction with Wnt signaling, an important signal transduction pathway in CRC. These findings were corroborated by a breast cancer study in in which the same group showed an association of CCAT2 with aggressive biological behavior [105]. In lung cancer, CCAT2 is up-regulated in NSCLC tissue and its expression level is associated with invasive potential [106].

2.5.6. PCAT-1

Prostate cancer-associated ncRNA transcripts 1 (PCAT-1) was reported to be correlated with poor prognosis in CRC patients [53]. The PCAT-1 gene is located on chromosome 8q24 [37]. Ge et al. [53] identified PCAT-1 overexpression in CRC tissue as an independent predictor of poor overall survival time in a cohort of patients. Distant metastases were positively associated with PCAT-1 overexpression of in CRC tumor cells. In prostate cancer PCAT-1 overexpression increased cell proliferation in vitro promoted by PRC2 although the underlying molecular mechanism in CRC is still unclear [37].

2.5.7. HOTAIR

The lncRNA HOTAIR was reported to be overexpressed in CRC. High expression levels were associated with poorer overall survival in the study cohort and were linked to liver metastasis. In vitro the overexpression increased the invasiveness of CRC cells [59].

2.5.8. PRNCR1

The association between polypmorphisms in prostate cancer non-coding RNA 1 (PRNCR1) on chromosome 8q24 and the risk of CRC was reported by Li and colleagues [54] who investigated five single nucleotide polymorphisms (SNPs). The alleles rs1456315G and rs13252298 were associated with increased tumor size and a decreased risk of developing CRC. The alleles rs7007694C and rs16901946G were reported to be associated with a decreased risk to develop poorly differentiated CRC while rs1456315G was associated with an increased risk. Due to this data SNPs in the lncRNA PRNCR1 may be related to the development of CRC [54].

3. Discussion

The detection of lncRNAs in the early 21st century opened up new possibilities in cancer research [1]. LncRNAs are larger than 200 nucleotides and can reach sizes of 100 kilobases [4]. As lncRNAs are not translated into proteins, their regulative functions can take place faster in comparison to proteins [14]. Various studies over the past few years have revealed the important role of lncRNAs in tumorigenesis [24].
The molecular mechanisms of some lncRNAs as well as their roles in different tumors have been very well established, however, intensive investigations on prominent lncRNAs such as MALAT-1 point out the fact, that lncRNAs have tissue specific purposes [30,41,60].
They can act either as oncogenes or tumorsuppressor-genes although some lncRNAs act like oncogenes in one tumor while displaying suppressory functions in another (Table 2). TUG-1 for example is underexpressed in non-small cell lung cancer while overexpression can be found in osteosarcoma cells compared to control tissue [29,31].
In addition, in colorectal cancer different lncRNAs have been detected as potential pathogenesis-driving factors. MALAT-1, HOTAIR, PVT-1 and CCAT1-L are up-regulated in colorectal cancer tissue while ncRAN is down-regulated [28,55,56,57,58,59]. However, some lncRNAs consist of several fragments, each of them with different functions [55].
In summary, lncRNAs seem to play an important and previously underestimated role in human cancer. Although for some of them a functional characterication has been successfully performed, the yet identified role of lncRNAs in human cancer seems rather to be the tip on the iceberg than anything else. Therefore, further investigations will be necessary to understand the numerous molecular mechanisms performed by lncRNAs in human cancer.
Table
Table 2. LncRNAs in Cancer.
Table 2. LncRNAs in Cancer.
NameFunctionCancerExpressionRef.
LINC00312cell-cycle inhibitionnasopharyngeal carcinomadown[25]
PlncRNA-1binds to androgene-receptorprostate cancerup[34]
suppressor of apoptosisesophagus squamous cell carcinomaup[40]
HOTAIRproliferation, invasionCRC (colorectal cancer)up[59]
HCC (hepatocellular carcinoma)up[46]
-gastric cancerup[42]
-esophagus squamous cell carcinomaup[41]
-epithelial ovarian cancer (EOC)up[38]
ASLNC22381targeting IGF-1 genesglioblastoma multiformeup[26]
ASLNC20819targeting IGF-1 genesglioblastoma multiformeup[26]
TUG1epigenetically regulating expression of HOXB7non-small cell lung cancerdown[29]
-osteosarcomaup[29,31]
PVT-1suppressor of TGF (transforming growth factor) βCRCup[58]
ncRANinhibits cell migration and invasionCRCdown[27,58]
-urothelial carcinomaup[32]
-neuroblastomaup[27,28]
CCAT1-LMYC-335 (enhancer) interactiongastric cancerup[43]
-CRCup[56,57]
MALAT-1invasion, progressionCRCup[55]
-HCCup[30]
-lung cancerup[30]
-prostate cancerup[35]
suppressory roleEOCdown[39]
H19interacts with E-cadherin, keratin 8 + 19, claudin-1; proliferationHCCup[45]
-gastric cancerup[44]
suppressory roleEOCdown[39]
UCA-1proliferation, migration, invasionEOCup[39]
-urothelial carcinomaup[33]
PCGEM1bind to androgen receptor (AR), transcriptationprostate cancerup[36]
-CRCup[54]
PRNCR1bind to AR, transcriptationprostate cancerup[36]
PCAT-1-CRCup[53]
proliferation, suppression of BRCA2 tumor suppression geneprostate cancerup[37]
HULCsuppressing p18, proliferationHCCup[47,48]
LncRNA-Drehinhibit growth and metastasishepatitis B virus-HCCdown[49]
MEG3inducing cell apoptosisHCCdown[50]
lncRNA-MVIHinvasion, angiogenesisHCCup[51]
MDIGhistological gradingHCCup[52]

4. Conclusions

Different lncRNAs involved in various human diseases have been investigated in recent years. As figured out in this article, these specific RNA transcripts can effectively influence molecular and cellular processes without being translated into proteins. In tumor cells, particular lncRNAs can be either up-regulated or down-regulated, resulting in significant changes of molecular pathogenesis and clinical stage.
Moreover, lncRNAs show a tissue specific up- or down-regulation, leading to the expectation that lncRNAs may represent new targets in tumor therapy.
In colorectal cancer, at least 8 lncRNAs show discrepancies in cellular regulation, though the very same lncRNA could be regulated conversely when examined in other tumor tissues.
Therefore, the meaning and function of lncRNAs has to be further investigated, as a single lncRNA often has more than only one feature in human cells. Furthermore, a consistent nomenclature of recently detected lncRNAs may facilitate the researcher’s work.

Acknowledgments

The authors are very grateful to Mag. Karin Osibow for critical reading, suggestions and linguistic support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489, 57–74. [Google Scholar] [CrossRef]
  2. Bu, D.; Yu, K.; Sun, S.; Xie, C.; Skogerbo, G.; Miao, R.; Xiao, H.; Liao, Q.; Luo, H.; Zhao, G.; et al. NONCODE v3.0: Integrative annotation of long noncoding RNAs. Nucleic Acids Res. 2012, 40, D210–D215. [Google Scholar] [CrossRef]
  3. Khalil, A.M.; Guttman, M.; Huarte, M.; Garber, M.; Raj, A.; Rivea Morales, D.; Thomas, K.; Presser, A.; Bernstein, B.E.; van Oudenaarden, A.; et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 2009, 106, 11667–11672. [Google Scholar] [CrossRef]
  4. Mattick, J.S. Non-coding RNAs: The architects of eukaryotic complexity. EMBO Rep. 2001, 2, 986–991. [Google Scholar] [CrossRef]
  5. Gupta, R.A.; Shah, N.; Wang, K.C.; Kim, J.; Horlings, H.M.; Wong, D.J.; Tsai, M.C.; Hung, T.; Argani, P.; Rinn, J.L.; et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010, 464, 1071–1076. [Google Scholar] [CrossRef]
  6. Chow, J.; Heard, E. X inactivation and the complexities of silencing a sex chromosome. Curr. Opin. Cell Biol. 2009, 21, 359–366. [Google Scholar] [CrossRef]
  7. Brannan, C.I.; Dees, E.C.; Ingram, R.S.; Tilghman, S.M. The product of the H19 gene may function as an RNA. Mol. Cell. Biol. 1990, 10, 28–36. [Google Scholar]
  8. Brown, C.J.; Ballabio, A.; Rupert, J.L.; Lafreniere, R.G.; Grompe, M.; Tonlorenzi, R.; Willard, H.F. A gene from the region of the human X inactivation center is expressed exclusively from the inactive X chromosome. Nature 1991, 349, 38–44. [Google Scholar] [CrossRef]
  9. Bierhoff, H.; Schmitz, K.; Maass, F.; Ye, J.; Grummt, I. Noncoding transcripts in sense and antisense orientation regulate the epigenetic state of ribosomal RNA genes. Cold Spring Harb. Symp. Quant. Biol. 2010, 75, 357–364. [Google Scholar] [CrossRef]
  10. Chen, W.; Bocker, W.; Brosius, J.; Tiedge, H. Expression of neural BC200 RNA in human tumours. J. Pathol. 1997, 183, 345–351. [Google Scholar] [CrossRef]
  11. Hawkins, P.G.; Morris, K.V. Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription 2010, 1, 165–175. [Google Scholar] [CrossRef]
  12. Kapranov, P.; Cheng, J.; Dike, S.; Nix, D.A.; Duttagupta, R.; Willingham, A.T.; Stadler, P.F.; Hertel, J.; Hackermuller, J.; Hofacker, I.L.; et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007, 316, 1484–1488. [Google Scholar] [CrossRef]
  13. Nagano, T.; Mitchell, J.A.; Sanz, L.A.; Pauler, F.M.; Ferguson-Smith, A.C.; Feil, R.; Fraser, P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 2008, 322, 1717–1720. [Google Scholar] [CrossRef]
  14. Wang, K.C.; Chang, H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 2011, 43, 904–914. [Google Scholar] [CrossRef]
  15. Orom, U.A.; Shiekhattar, R. Long non-coding RNAs and enhancers. Curr. Opin. Genet. Dev. 2011, 21, 194–198. [Google Scholar] [CrossRef]
  16. Nagano, T.; Fraser, P. No-nonsense functions for long noncoding RNAs. Cell 2011, 145, 178–181. [Google Scholar] [CrossRef]
  17. Vikram, R.; Ramachandran, R.; Abdul, K.S. Functional significance of long non-coding RNAs in breast cancer. Breast Cancer 2014. [Google Scholar] [CrossRef]
  18. Tay, Y.; Rinn, J.; Pandolfi, P.P. The multilayered complexity of ceRNA crosstalk and competition. Nature 2014, 505, 344–352. [Google Scholar] [CrossRef]
  19. Cazalla, D.; Steitz, J.A. Down-regulation of a host microRNA by a viral noncoding RNA. Cold Spring Harb. Symp. Quant. Biol. 2010, 75, 321–324. [Google Scholar] [CrossRef]
  20. Tay, Y.; Kats, L.; Salmena, L.; Weiss, D.; Tan, S.M.; Ala, U.; Karreth, F.; Poliseno, L.; Provero, P.; di Cunto, F.; et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 2011, 147, 344–357. [Google Scholar] [CrossRef]
  21. Karreth, F.A.; Tay, Y.; Perna, D.; Ala, U.; Tan, S.M.; Rust, A.G.; DeNicola, G.; Webster, K.A.; Weiss, D.; Perez-Mancera, P.A.; et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 2011, 147, 382–395. [Google Scholar] [CrossRef]
  22. Poliseno, L.; Salmena, L.; Zhang, J.; Carver, B.; Haveman, W.J.; Pandolfi, P.P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010, 465, 1033–1038. [Google Scholar] [CrossRef]
  23. Li, J.; Xuan, Z.; Liu, C. Long non-coding RNAs and complex human diseases. Int. J. Mol. Sci. 2013, 14, 18790–18808. [Google Scholar] [CrossRef]
  24. Qiu, M.T.; Hu, J.W.; Yin, R.; Xu, L. Long noncoding RNA: An emerging paradigm of cancer research. Tumour Biol. 2013, 34, 613–620. [Google Scholar] [CrossRef]
  25. Zhang, W.; Huang, C.; Gong, Z.; Zhao, Y.; Tang, K.; Li, X.; Fan, S.; Shi, L.; Li, X.; Zhang, P.; et al. Expression of LINC00312, a long intergenic non-coding RNA, is negatively correlated with tumor size but positively correlated with lymph node metastasis in nasopharyngeal carcinoma. J. Mol. Histol. 2013, 44, 545–554. [Google Scholar] [CrossRef]
  26. Baritaki, S.; Chatzinikola, A.M.; Vakis, A.F.; Soulitzis, N.; Karabetsos, D.A.; Neonakis, I.; Bonavida, B.; Spandidos, D.A. YY1 Over-expression in human brain gliomas and meningiomas correlates with TGF-beta1, IGF-1 and FGF-2 mRNA levels. Cancer Investig. 2009, 27, 184–192. [Google Scholar] [CrossRef]
  27. Yu, M.; Ohira, M.; Li, Y.; Niizuma, H.; Oo, M.L.; Zhu, Y.; Ozaki, T.; Isogai, E.; Nakamura, Y.; Koda, T.; 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, 931–938. [Google Scholar]
  28. Qi, P.; Xu, M.D.; Ni, S.J.; Shen, X.H.; Wei, P.; Huang, D.; Tan, C.; Sheng, W.Q.; Zhou, X.Y.; Du, X. 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. 2014. [Google Scholar] [CrossRef]
  29. Zhang, E.B.; Yin, D.D.; Sun, M.; Kong, R.; Liu, X.H.; You, L.H.; Han, L.; Xia, R.; Wang, K.M.; Yang, J.S.; et al. P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis. 2014, 5, e1243. [Google Scholar] [CrossRef]
  30. Ji, P.; Diederichs, S.; Wang, W.; Boing, S.; Metzger, R.; Schneider, P.M.; Tidow, N.; Brandt, B.; Buerger, H.; Bulk, E.; et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003, 22, 8031–8041. [Google Scholar] [CrossRef]
  31. Zhang, Q.; Geng, P.L.; Yin, P.; Wang, X.L.; Jia, J.P.; Yao, J. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac. J. Cancer Prev. 2013, 14, 2311–2315. [Google Scholar] [CrossRef]
  32. Zhu, Y.; Yu, M.; Li, Z.; Kong, C.; Bi, J.; Li, J.; Gao, Z.; Li, Z. ncRAN, a newly identified long noncoding RNA, enhances human bladder tumor growth, invasion, and survival. Urology 2011, 77, 510.e1–510.e5. [Google Scholar]
  33. Wang, X.S.; Zhang, Z.; Wang, H.C.; Cai, J.L.; Xu, Q.W.; Li, M.Q.; Chen, Y.C.; Qian, X.P.; Lu, T.J.; Yu, L.Z.; et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin. Cancer Res. 2006, 12, 4851–4858. [Google Scholar] [CrossRef]
  34. Wang, C.M.; Wu, Q.Q.; Li, S.Q.; Chen, F.J.; Tuo, L.; Xie, H.W.; Tong, Y.S.; Ji, L.; Zhou, G.Z.; Cao, G.; et al. Upregulation of the long non-coding RNA PlncRNA-1 promotes esophageal squamous carcinoma cell proliferation and correlates with advanced clinical stage. Dig. Dis. Sci. 2014, 59, 591–597. [Google Scholar] [CrossRef]
  35. Ren, S.; Liu, Y.; Xu, W.; Sun, Y.; Lu, J.; Wang, F.; Wei, M.; Shen, J.; Hou, J.; Gao, X.; et al. Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer. J. Urol. 2013, 190, 2278–2287. [Google Scholar] [CrossRef]
  36. Yang, L.; Lin, C.; Jin, C.; Yang, J.C.; Tanasa, B.; Li, W.; Merkurjev, D.; Ohgi, K.A.; Meng, D.; Zhang, J.; et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013, 500, 598–602. [Google Scholar] [CrossRef]
  37. Prensner, J.R.; Iyer, M.K.; Balbin, O.A.; Dhanasekaran, S.M.; Cao, Q.; Brenner, J.C.; Laxman, B.; Asangani, I.A.; Grasso, C.S.; Kominsky, H.D.; et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat. Biotechnol. 2011, 29, 742–749. [Google Scholar] [CrossRef]
  38. Qiu, J.J.; Lin, Y.Y.; Ye, L.C.; Ding, J.X.; Feng, W.W.; Jin, H.Y.; Zhang, Y.; Li, Q.; Hua, K.Q. Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol. Oncol. 2014, 134, 121–128. [Google Scholar] [CrossRef]
  39. Liu, S.P.; Yang, J.X.; Cao, D.Y.; Shen, K. Identification of differentially expressed long non-coding RNAs in human ovarian cancer cells with different metastatic potentials. Cancer Biol. Med. 2013, 10, 138–141. [Google Scholar]
  40. Derrien, T.; Johnson, R.; Bussotti, G.; Tanzer, A.; Djebali, S.; Tilgner, H.; Guernec, G.; Martin, D.; Merkel, A.; Knowles, D.G.; et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22, 1775–1789. [Google Scholar] [CrossRef]
  41. Cabili, M.N.; Trapnell, C.; Goff, L.; Koziol, M.; Tazon-Vega, B.; Regev, A.; Rinn, J.L. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011, 25, 1915–1927. [Google Scholar] [CrossRef]
  42. Liu, X.H.; Sun, M.; Nie, F.Q.; Ge, Y.B.; Zhang, E.B.; Yin, D.D.; Kong, R.; Xia, R.; Lu, K.H.; Li, J.H.; et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol. Cancer 2014, 13, 92. [Google Scholar] [CrossRef]
  43. Yang, F.; Xue, X.; Bi, J.; Zheng, L.; Zhi, K.; Gu, Y.; Fang, G. Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J. Cancer Res. Clin. Oncol. 2013, 139, 437–445. [Google Scholar]
  44. Yang, F.; Bi, J.; Xue, X.; Zheng, L.; Zhi, K.; Hua, J.; Fang, G. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 2012, 279, 3159–3165. [Google Scholar] [CrossRef]
  45. Zhang, L.; Yang, F.; Yuan, J.H.; Yuan, S.X.; Zhou, W.P.; Huo, X.S.; Xu, D.; Bi, H.S.; Wang, F.; Sun, S.H. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 2013, 34, 577–586. [Google Scholar] [CrossRef]
  46. Geng, Y.J.; Xie, S.L.; Li, Q.; Ma, J.; Wang, G.Y. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J. Int. Med. Res. 2011, 39, 2119–2128. [Google Scholar] [CrossRef]
  47. Xie, H.; Ma, H.; Zhou, D. Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. Biomed. Res. Int. 2013, 2013, 136106:1–136106:5. [Google Scholar]
  48. Du, Y.; Kong, G.; You, X.; Zhang, S.; Zhang, T.; Gao, Y.; Ye, L.; Zhang, X. Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J. Biol. Chem. 2012, 287, 26302–26311. [Google Scholar]
  49. Huang, J.F.; Guo, Y.J.; Zhao, C.X.; Yuan, S.X.; Wang, Y.; Tang, G.N.; Zhou, W.P.; Sun, S.H. Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology 2013, 57, 1882–1892. [Google Scholar] [CrossRef]
  50. Braconi, C.; Kogure, T.; Valeri, N.; Huang, N.; Nuovo, G.; Costinean, S.; Negrini, M.; Miotto, E.; Croce, C.M.; Patel, T. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 2011, 30, 4750–4756. [Google Scholar] [CrossRef]
  51. Yuan, S.X.; Yang, F.; Yang, Y.; Tao, Q.F.; Zhang, J.; Huang, G.; Yang, Y.; Wang, R.Y.; Yang, S.; Huo, X.S.; et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology 2012, 56, 2231–2241. [Google Scholar] [CrossRef]
  52. Chen, B.; Yu, M.; Chang, Q.; Lu, Y.; Thakur, C.; Ma, D.; Yi, Z.; Chen, F. Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin. Oncotarget 2013, 4, 1427–1437. [Google Scholar]
  53. Ge, X.; Chen, Y.; Liao, X.; Liu, D.; Li, F.; Ruan, H.; Jia, W. Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. Med. Oncol. 2013, 30, 588. [Google Scholar] [CrossRef]
  54. Li, L.; Sun, R.; Liang, Y.; Pan, X.; Li, Z.; Bai, P.; Zeng, X.; Zhang, D.; Zhang, L.; Gao, L. Association between polymorphisms in long non-coding RNA PRNCR1 in 8q24 and risk of colorectal cancer. J. Exp. Clin. Cancer Res. 2013, 32, 104. [Google Scholar] [CrossRef]
  55. 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, 169–175. [Google Scholar]
  56. Alaiyan, B.; Ilyayev, N.; Stojadinovic, A.; Izadjoo, M.; Roistacher, M.; Pavlov, V.; Tzivin, V.; Halle, D.; Pan, H.; Trink, B.; et al. Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence. BMC Cancer 2013, 13. [Google Scholar] [CrossRef] [Green Version]
  57. Xiang, J.F.; Yin, Q.F.; Chen, T.; Zhang, Y.; Zhang, X.O.; Wu, Z.; Zhang, S.; Wang, H.B.; Ge, J.; Lu, X.; et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014, 24, 513–531. [Google Scholar] [CrossRef]
  58. Takahashi, Y.; Sawada, G.; Kurashige, J.; Uchi, R.; Matsumura, T.; Ueo, H.; Takano, Y.; Eguchi, H.; Sudo, T.; Sugimachi, K.; et al. Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br. J. Cancer 2014, 110, 164–171. [Google Scholar] [CrossRef]
  59. Kogo, R.; Shimamura, T.; Mimori, K.; Kawahara, K.; Imoto, S.; Sudo, T.; Tanaka, F.; Shibata, K.; Suzuki, A.; Komune, S.; et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011, 71, 6320–6326. [Google Scholar] [CrossRef]
  60. Tano, K.; Mizuno, R.; Okada, T.; Rakwal, R.; Shibato, J.; Masuo, Y.; Ijiri, K.; Akimitsu, N. MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 2010, 584, 4575–4580. [Google Scholar] [CrossRef]
  61. Zhang, X.; Rice, K.; Wang, Y.; Chen, W.; Zhong, Y.; Nakayama, Y.; Zhou, Y.; Klibanski, A. Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: Isoform structure, expression, and functions. Endocrinology 2010, 151, 939–947. [Google Scholar] [CrossRef]
  62. Zhou, Y.; Zhong, Y.; Wang, Y.; Zhang, X.; Batista, D.L.; Gejman, R.; Ansell, P.J.; Zhao, J.; Weng, C.; Klibanski, A. Activation of p53 by MEG3 non-coding RNA. J. Biol. Chem. 2007, 282, 24731–24742. [Google Scholar] [CrossRef]
  63. Huang, C.; Wu, M.; Tang, Y.; Li, X.; Ouyang, J.; Xiao, L.; Li, D.; Li, G. NAG7 promotes human nasopharyngeal carcinoma invasion through inhibition of estrogen receptor alpha and up-regulation of JNK2/AP-1/MMP1 pathways. J. Cell. Physiol. 2009, 221, 394–401. [Google Scholar] [CrossRef]
  64. Han, L.; Zhang, K.; Shi, Z.; Zhang, J.; Zhu, J.; Zhu, S.; Zhang, A.; Jia, Z.; Wang, G.; Yu, S.; et al. LncRNA pro fi le of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis. Int. J. Oncol. 2012, 40, 2004–2012. [Google Scholar]
  65. Liao, W.T.; Jiang, D.; Yuan, J.; Cui, Y.M.; Shi, X.W.; Chen, C.M.; Bian, X.W.; Deng, Y.J.; Ding, Y.Q. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin. Cancer Res. 2011, 17, 3569–3578. [Google Scholar] [CrossRef]
  66. Xue, M.; Li, X.; Wu, W.; Zhang, S.; Wu, S.; Li, Z.; Chen, W. Upregulation of long non-coding RNA urothelial carcinoma associated 1 by CCAAT/enhancer binding protein alpha contributes to bladder cancer cell growth and reduced apoptosis. Oncol. Rep. 2014, 31, 1993–2000. [Google Scholar]
  67. Wang, Y.; Chen, W.; Yang, C.; Wu, W.; Wu, S.; Qin, X.; Li, X. Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer. Int. J. Oncol. 2012, 41, 276–284. [Google Scholar]
  68. Prensner, J.R.; Sahu, A.; Iyer, M.K.; Malik, R.; Chandler, B.; Asangani, I.A.; Poliakov, A.; Vergara, I.A.; Alshalalfa, M.; Jenkins, R.B.; et al. The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 2014, 5, 1434–1438. [Google Scholar]
  69. Prensner, J.R.; Chen, W.; Iyer, M.K.; Cao, Q.; Ma, T.; Han, S.; Sahu, A.; Malik, R.; Wilder-Romans, K.; Navone, N.; et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res. 2014, 74, 1651–1660. [Google Scholar] [CrossRef]
  70. Roy, R.; Chun, J.; Powell, S.N. BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat. Rev. Cancer 2011, 12, 68–78. [Google Scholar] [CrossRef]
  71. Yu, D.; Wolf, J.K.; Scanlon, M.; Price, J.E.; Hung, M.C. Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res. 1993, 53, 891–898. [Google Scholar]
  72. Chen, F.J.; Sun, M.; Li, S.Q.; Wu, Q.Q.; Ji, L.; Liu, Z.L.; Zhou, G.Z.; Cao, G.; Jin, L.; Xie, H.W.; et al. Upregulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis. Mol. Carcinog. 2013, 52, 908–915. [Google Scholar] [CrossRef]
  73. Wang, Y.; Gao, S.; Liu, G.; Jia, R.; Fan, D.; Feng, X. Microarray expression profile analysis of long non-coding RNAs in human gastric cardiac adenocarcinoma. Cell. Physiol. Biochem. 2014, 33, 1225–1238. [Google Scholar] [CrossRef]
  74. Song, H.; Sun, W.; Ye, G.; Ding, X.; Liu, Z.; Zhang, S.; Xia, T.; Xiao, B.; Xi, Y.; Guo, J. Long non-coding RNA expression profile in human gastric cancer and its clinical significances. J. Transl. Med. 2013, 11, 225. [Google Scholar] [CrossRef]
  75. Iizuka, N.; Oka, M.; Yamada-Okabe, H.; Mori, N.; Tamesa, T.; Okada, T.; Takemoto, N.; Tangoku, A.; Hamada, K.; Nakayama, H.; et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res. 2002, 62, 3939–3944. [Google Scholar]
  76. Iizuka, N.; Oka, M.; Tamesa, T.; Hamamoto, Y.; Yamada-Okabe, H. Imbalance in expression levels of insulin-like growth factor 2 and H19 transcripts linked to progression of hepatocellular carcinoma. Anticancer Res. 2004, 24, 4085–4089. [Google Scholar]
  77. Tsang, W.P.; Kwok, T.T. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 2007, 26, 4877–4881. [Google Scholar] [CrossRef]
  78. Ogasawara, S.; Komuta, M.; Nakashima, O.; Akiba, J.; Tsuneoka, M.; Yano, H. Accelerated expression of a Myc target gene Mina53 in aggressive hepatocellular carcinoma. Hepatol. Res. 2010, 40, 330–336. [Google Scholar] [CrossRef]
  79. Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin. 2011, 61, 212–236. [Google Scholar] [CrossRef]
  80. Kanthan, R.; Senger, J.L.; Kanthan, S.C. Molecular events in primary and metastatic colorectal carcinoma: A review. Pathol. Res. Int. 2012, 2012, 597497. [Google Scholar]
  81. O’Connell, J.B.; Maggard, M.A.; Ko, C.Y. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J. Natl. Cancer Inst. 2004, 96, 1420–1425. [Google Scholar] [CrossRef]
  82. Mogoanta, S.S.; Vasile, I.; Totolici, B.; Neamtu, C.; Streba, L.; Busuioc, C.J.; Mateescu, G.O. Colorectal cancer—Clinical and morphological aspects. Rom. J. Morphol. Embryol. 2014, 55, 103–110. [Google Scholar]
  83. Majumdar, S.R.; Fletcher, R.H.; Evans, A.T. How does colorectal cancer present? Symptoms, duration, and clues to location. Am. J. Gastroenterol. 1999, 94, 3039–3045. [Google Scholar] [CrossRef]
  84. Saidi, H.S.; Karuri, D.; Nyaim, E.O. Correlation of clinical data, anatomical site and disease stage in colorectal cancer. East Afr. Med. J. 2008, 85, 259–262. [Google Scholar]
  85. Edge, S.B.; Compton, C.C. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann. Surg. Oncol. 2010, 17, 1471–1474. [Google Scholar] [CrossRef]
  86. Vasen, H.F.; Moslein, G.; Alonso, A.; Aretz, S.; Bernstein, I.; Bertario, L.; Blanco, I.; Bulow, S.; Burn, J.; Capella, G.; et al. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam. Cancer 2010, 9, 109–115. [Google Scholar] [CrossRef]
  87. Vasen, H.F.; Watson, P.; Mecklin, J.P.; Lynch, H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999, 116, 1453–1456. [Google Scholar] [CrossRef]
  88. Umar, A.; Boland, C.R.; Terdiman, J.P.; Syngal, S.; de la Chapelle, A.; Ruschoff, J.; Fishel, R.; Lindor, N.M.; Burgart, L.J.; Hamelin, R.; et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004, 96, 261–268. [Google Scholar] [CrossRef]
  89. Bonadona, V.; Bonaiti, B.; Olschwang, S.; Grandjouan, S.; Huiart, L.; Longy, M.; Guimbaud, R.; Buecher, B.; Bignon, Y.J.; Caron, O.; et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011, 305, 2304–2310. [Google Scholar] [CrossRef]
  90. Aretz, S.; Uhlhaas, S.; Caspari, R.; Mangold, E.; Pagenstecher, C.; Propping, P.; Friedl, W. Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur. J. Hum. Genet. 2004, 12, 52–58. [Google Scholar] [CrossRef]
  91. Cruz-Correa, M.; Giardiello, F.M. Familial adenomatous polyposis. Gastrointest. Endosc. 2003, 58, 885–894. [Google Scholar] [CrossRef]
  92. Wang, W.; Li, Y.; Zhang, X.; Jing, J.; Zhao, X.; Wang, Y.; Han, C. Evaluating the significance of expression of CEA mRNA and levels of CEA and its related proteins in colorectal cancer patients. J. Surg. Oncol. 2014, 109, 440–444. [Google Scholar] [CrossRef]
  93. Zhao, X.W.; Jiang, B.; Han, C.Z.; Jing, J.X. Detection and clinical study of serum tumor markers in patients with colorectal cancer. Zhonghua Zhong Liu Za Zhi 2005, 27, 286–288. [Google Scholar]
  94. Tan, E.; Gouvas, N.; Nicholls, R.J.; Ziprin, P.; Xynos, E.; Tekkis, P.P. Diagnostic precision of carcinoembryonic antigen in the detection of recurrence of colorectal cancer. Surg. Oncol. 2009, 18, 15–24. [Google Scholar] [CrossRef]
  95. Duffy, M.J.; van Dalen, A.; Haglund, C.; Hansson, L.; Holinski-Feder, E.; Klapdor, R.; Lamerz, R.; Peltomaki, P.; Sturgeon, C.; Topolcan, O. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur. J. Cancer 2007, 43, 1348–1360. [Google Scholar] [CrossRef]
  96. Duffy, M.J.; Lamerz, R.; Haglund, C.; Nicolini, A.; Kalousova, M.; Holubec, L.; Sturgeon, C. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int. J. Cancer 2014, 134, 2513–2522. [Google Scholar] [CrossRef]
  97. Van de Velde, C.J.; Boelens, P.G.; Borras, J.M.; Coebergh, J.W.; Cervantes, A.; Blomqvist, L.; Beets-Tan, R.G.; van den Broek, C.B.; Brown, G.; van Cutsem, E.; et al. EURECCA colorectal: Multidisciplinary management: European consensus conference colon & rectum. Eur. J. Cancer 2014, 50, 1.e1–1.e34. [Google Scholar]
  98. Pichler, M.; Ress, A.L.; Winter, E.; Stiegelbauer, V.; Karbiener, M.; Schwarzenbacher, D.; Scheideler, M.; Ivan, C.; Jahn, S.W.; Kiesslich, T.; et al. MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients. Br. J. Cancer 2014, 110, 1614–1621. [Google Scholar] [CrossRef]
  99. Stotz, M.; Pichler, M.; Absenger, G.; Szkandera, J.; Arminger, F.; Schaberl-Moser, R.; Samonigg, H.; Stojakovic, T.; Gerger, A. The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer. Br. J. Cancer 2014, 110, 435–440. [Google Scholar] [CrossRef]
  100. Szkandera, J.; Pichler, M.; Absenger, G.; Stotz, M.; Weissmueller, M.; Samonigg, H.; Asslaber, M.; Lax, S.; Leitner, G.; Winder, T.; et al. A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients. Clin. Cancer Res. 2014, 20, 1687–1697. [Google Scholar]
  101. Perez, D.S.; Hoage, T.R.; Pritchett, J.R.; Ducharme-Smith, A.L.; Halling, M.L.; Ganapathiraju, S.C.; Streng, P.S.; Smith, D.I. Long, abundantly expressed non-coding transcripts are altered in cancer. Hum. Mol. Genet. 2008, 17, 642–655. [Google Scholar]
  102. Kam, Y.; Rubinstein, A.; Naik, S.; Djavsarov, I.; Halle, D.; Ariel, I.; Gure, A.O.; Stojadinovic, A.; Pan, H.; Tsivin, V.; 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. 2013. [Google Scholar] [CrossRef]
  103. Pomerantz, M.M.; Ahmadiyeh, N.; Jia, L.; Herman, P.; Verzi, M.P.; Doddapaneni, H.; Beckwith, C.A.; Chan, J.A.; Hills, A.; Davis, M.; et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 2009, 41, 882–884. [Google Scholar] [CrossRef]
  104. Ling, H.; Spizzo, R.; Atlasi, Y.; Nicoloso, M.; Shimizu, M.; Redis, R.S.; Nishida, N.; Gafa, R.; Song, J.; Guo, Z.; et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013, 23, 1446–1461. [Google Scholar] [CrossRef] [Green Version]
  105. Redis, R.S.; Sieuwerts, A.M.; Look, M.P.; Tudoran, O.; Ivan, C.; Spizzo, R.; Zhang, X.; de Weerd, V.; Shimizu, M.; Ling, H.; et al. CCAT2, a novel long non-coding RNA in breast cancer: Expression study and clinical correlations. Oncotarget 2013, 4, 1748–1762. [Google Scholar]
  106. Qiu, M.; Xu, Y.; Yang, X.; Wang, J.; Hu, J.; Xu, L.; Yin, R. CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer. Tumour Biol. 2014, 35, 5375–5380. [Google Scholar] [CrossRef]

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MDPI and ACS Style

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, 13993-14013. https://doi.org/10.3390/ijms150813993

AMA Style

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. International Journal of Molecular Sciences. 2014; 15(8):13993-14013. https://doi.org/10.3390/ijms150813993

Chicago/Turabian Style

Smolle, Maria, Stefan Uranitsch, Armin Gerger, Martin Pichler, and Johannes Haybaeck. 2014. "Current Status of Long Non-Coding RNAs in Human Cancer with Specific Focus on Colorectal Cancer" International Journal of Molecular Sciences 15, no. 8: 13993-14013. https://doi.org/10.3390/ijms150813993

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