Linc-ROR in Cancer and Disease: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by José Alberto Peña Flores Portillo.

Cancer is responsible for more than 10 million deaths every year. Metastasis and drug resistance lead to a poor survival rate and are a major therapeutic challenge. Substantial evidence demonstrates that an increasing number of long non-coding RNAs are dysregulated in cancer, including the long intergenic non-coding RNA, regulator of reprogramming (linc-ROR), which mostly exerts its role as an onco-lncRNA acting as a competing endogenous RNA that sequesters micro RNAs.

  • linc-ROR
  • lincRNA-ROR
  • lncRNA
  • cancer progression
  • cancer

1. Introduction

Cancer is a group of multifactorial diseases responsible for at least 10 million deaths around the world in 2020 alone [1]. Human cancer diversity exceeds the 200 types, observing clear differences among the origin of cells, acquisition of somatic mutations, variability in altered transcription pathways, and influences in the microenvironment of local tissues [2]. As cancer advances, new mutations produce a greater genetic heterogeneity to form the primary tumor, eventually eroding the basal membrane and spreading to other regions via the circulatory system [3,4][3][4]. This event is called metastasis and proposes a challenge to scientists and clinicians since its occurrence leads to a high recurrence and poor survival rate. Chemotherapy is a very common treatment for cancer patients, but unfortunately, most tumors exert drug resistance, resulting in around 90% of deaths in cancer patients [5]. Epigenetic processes such as DNA methylation, histone acetylation, and lncRNA interaction regulate drug transporters and metabolic enzymes, thus promoting cancer chemoresistance [6].
A vast collection of evidence shows that only 2% of the transcribed human genome codes for proteins, whereas the remaining 98% of RNAs are non-coding [7,8][7][8]. Recent advances in sequencing technology have shifted the prior assumption that non-coding RNA (ncRNA) was a “junk” transcriptional product to transcripts comprising signals that control gene expression and are essential both in normal physiological function and in disease [8,9][8][9].
Since the discovery of small regulatory ncRNAs in the 1990s, substantial progress has been made to catalog a rapidly increasing number of both short and long ncRNAs [10]. MicroRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and PIWI interacting RNA (piRNA) are the four major ncRNA types with distinct functions in cancer [11]. While miRNAs usually bind to targeted mRNA to degrade it [12[12][13],13], lncRNAs regulate gene expression by exerting multiple mechanisms including the recruitment of polymerase II and diverse transcription factors [14[14][15],15], regulating alternative splicing of pre-mRNAs [16[16][17],17], sequestering miRNAs to prevent them from performing their function [18,19,20][18][19][20] or acting as a scaffold on protein–protein interactions [21,22,23][21][22][23].

2. Overview of Long Non-Coding RNAs

Long non-coding RNAs (lncRNAs), also known as competing endogenous RNAs (ceRNAs) [27][24], are a heterogeneous RNA family that comprise transcripts of 200 nucleotides or longer and are coded in the genome but not translated into proteins [28,29][25][26]. According to GENCODE, more than 56,000 lncRNA transcripts in almost 19,000 genes have been identified in humans [30][27]. Recent evidence suggests that lncRNAs are implicated in several cancer progression mechanisms including proliferation [31[28][29],32], differentiation [33[30][31],34], autophagy [35[32][33],36], epithelial–mesenchymal transition (EMT) [37][34], invasion [38[35][36][37],39,40], and metastasis [41,42][38][39]. LncRNAs are often found as modulators of signaling cascades at the epigenetic, transcriptional, posttranscriptional, translational, or posttranslational levels [43][40]. Cancer-controlling lncRNAs are classified as proto-oncogenic or tumor suppressors based on their function, being the tumorigenic lncRNAs expressed as cancer drivers that activate the cell cycle and exert anti-apoptosis effects [44][41]. On the other hand, tumor suppressors are generally downregulated in tumor biopsies, and evidence suggests that overexpression of these lncRNAs halts some of the cancer mechanisms [43][40]. Based on their structural origin and relative position to protein-coding genes, lncRNAs can be classified as (a) divergent (pancRNA) when they originate from the same promoter region as the protein-coding gene, but from the opposite strand; (b) convergent when genes are encoded on opposite strands, facing each other and convergently transcribed; (c) overlapping when genes extend along the same or opposite strand; (d) enhancer RNAs expressed as uni- or bidirectional transcripts; (e) intronic, when transcribed from an intron of another gene; (f) host lncRNA for miRNA; and (g) intergenic lncRNA (lincRNA) when the transcript is located distant from other genes [45,46][42][43]. Additionally, covalently closed circular RNAs (circRNAs) are produced by the back splicing of exons, requiring spliceosomal machinery for their biogenesis [47][44]. Over the last few years, substantial advances in RNA sequencing have allowed the identification of both physiological and pathological involvement of lncRNAs through four basic mechanisms: signal, decoy, guide, and scaffold [48,49,50][45][46][47]. Some lncRNAs function as signals to regulate the initiation, elongation, or termination of actions by transcription factors [51][48]. Other lncRNAs function as decoys by binding to transcription protein complexes to deviate from their target DNA [50][47]. Most lncRNAs have been related to act as molecular sinks for miRNAs, mediating gene expression by acting on splicing regulators and other genetic and epigenetic components [52][49]. In diabetes, the overexpression of lncRNA maternally expressed gene 3 (MEG3) was shown to suppress endothelial–mesenchymal transition (endMT) in diabetes retinopathy through inhibition of the PI3K/Akt/mTOR signaling pathway [53][50]; similarly, lncRNA H19 overexpression prevented glucose-induced endMT in human retinal endothelial cells [54][51]. The knockdown of lncRNA myocardial infarction-associated transcript (MIAT) decreased the proliferation and migration of cultured human carotid artery smooth muscle cells (SMCs) through the regulation of the EGR1-ELK1-ERK pathway in atherosclerosis and carotid artery disease [55][52]; Ye et al. [56][53] reported MIAT as a miR-149-5p sponge to positively modulate the expression of anti-phagocytic molecule CD47, inhibiting efferocytosis in advanced atherosclerosis. Regarding neurodegenerative diseases, significant advances have been made in the identification of novel lncRNAs and their involvement in disease etiology and progression. In Parkinson’s disease (PD) mice, the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was highly expressed and promoted neuroinflammation through inducing inflammasome activation and reactive oxygen species (ROS) production [57][54]. In another study, animal experiments suggested that lncRNA taurine up-regulated 1 (TUG1) downregulation significantly improved the motor coordination ability of PD mice and inhibited the expression of inflammatory factors [58][55]; correspondingly, TUG1 expression was significantly upregulated in synovial fibroblast-like synoviocytes, activating invasion, migration, glucose metabolism, and inhibited apoptosis via miR-34a-5p interaction in rheumatoid arthritis [59][56], reinforcing the results of previous studies where its expression induces the production of inflammatory factors. A plethora of studies have shown the dysregulation of many lncRNAs in cancer, often found as regulators in tumorigenesis, progression, metastasis, and drug resistance by modulating signaling cascades in many transcriptional and translational levels [60][57]. For instance, lncRNA HOXC-AS3 was found to mediate the oncogenesis of gastric cancer by the activation of abnormal histone modification [61][58]; in a similar fashion, Su et al. [62][59] found the same transcript overexpressed in human non-small-cell lung cancer specimens and cells, promoting growth and metastasis. The novel lncRNA UPLA1 (upregulation promoting LUAD-associated transcript-1) was highly expressed in the nucleus of lung adenocarcinoma cells, significantly improving the growth of tumors by promoting the Wnt/β-catenin signaling pathway [63][60]. Another novel lncRNA, uc.134, was found to be downregulated in hepatocellular carcinoma tissue samples, repressing cancer progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation [64][61].

3. Linc-ROR in Disease

Long intergenic non-coding RNAs (lincRNAs) are RNAs autonomously transcribed that do not overlap annotated coding genes [65][62]. The long intergenic non-coding RNA, regulator of reprogramming (linc-ROR) consists of a four exon-long transcript with a length of 2603 nucleotides, localized in chromosome 18q21.31 and identified by chromatin lysine 4 and lysine 36 marks [66][63]. Most of the sequence is composed of long and short interspersed retro transposable elements (LINEs and SINEs along with long terminal repeats (LTRs)) called retrotransposons [67][64]. There is evidence that linc-ROR acts as a molecular sink for many miRNAs with many potential binding sites demonstrated by bioinformatic tool analysis. For instance, miR-145 complementarily binds to the ROR sequence between 2055 bp and 2059 bp [68][65]; for miR-205-5p, a binding site at ROR 791–810 bp sequence and 317–345 bp sequence for miR-34a-5p has been reported [69][66]. The binding between linc-ROR and miR-194-3p was determined via a luciferase reporter gene assay with two binding sites predicted by DIANA-LncBase, the first at 1906–1923 bp, and the second at 2378–2389 bp [70][67]. Many other reports have predicted different binding sites for miRNAs, positioning linc-ROR as a competing endogenous RNA. Linc-ROR was first identified in pluripotent stem cells as a ceRNA of miRNAs involved in core transcription factors regulatory circuitry [71][68]. In addition, Zou et al. [72][69] demonstrated that linc-ROR maintained SOX2 gene expression through competitive binding to miR-145, achieving pluripotency maintenance in human amniotic epithelial stem cells. Another study showed that linc-ROR is downregulated in osteoporosis by inhibiting osteoblast proliferation via targeting miR-145-5p, highlighting its positive correlation in cell proliferation and stemming [73][70]. Similarly, Feng et al. [74][71] studied the role of linc-ROR in bone marrow mesenchymal stem cell chondrogenesis and cartilage formation; the results revealed that linc-ROR functioned as a miRNA sponge for miR-138 and miR-145, activating SOX9 expression and chondrogenesis activity. Linc-ROR has also been documented as an angiogenesis promoter through the downregulation of miR-26 and activation of NF-kappa B and JAK1/STAT2 signaling pathways [75][72]. Little research has been made concerning the role of linc-ROR in cardiovascular diseases. In a study on the crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs), it was found that linc-ROR downregulated its target miR-145-5p leading to activation of the endothelial nitric oxide synthase (eNOS) pathway, therefore increasing the survival rate of both CMECs and CMs [76][73]. Another research found a significant upregulation of linc-ROR in a hypoxia/reoxygenation (H/R) injury model, acting as a sponge for miR-138, aggravating H/R-induced myocardial cell injury [77][74]. In a viral myocarditis cell model, linc-ROR destroyed the mRNA stability of Forkhead Box P Factor 1 (FOXP1) by binding polypyrimidine tract binding protein 1 (PTBP1), promoting coxsackievirus B3-induced cardiomyocyte inflammation [78][75]. Regarding the relationship of linc-ROR with mental and neurodegenerative diseases, little evidence has also been reported. Tamiskar et al. [79][76] measured expression levels of several lncRNAs in the circulation of Parkinson’s disease patients to try to establish a possible correlation; linc-ROR was higher in PD patients compared with controls, revealing linc-ROR dysregulation. A similar study in schizophrenia patients revealed the presence of a sex-based dysregulation of lncRNAs when compared with healthy subjects, with linc-ROR upregulated and correlated with age [80][77]. Moreover, linc-ROR and other seven lncRNAs were found upregulated in the circulation or post-mortem brain tissues of schizophrenia patients [81][78]. Conversely, Hasemian et al. [82][79] also quantified expression levels of lncRNAs in the peripheral blood of epileptic patients and found no significant difference in the expression of linc-ROR between patients and controls. In a different study, the p53 regulatory pathway was correlated with linc-ROR upregulation in ischemia-induced apoptosis, exerting a combined effect on ischemic stroke recurrence [83][80]. Similarly, expression of linc-ROR increased significantly in middle cerebral artery occlusion in mice and it also promoted ASK-1/STRAP/14-3-3 complex formation to inhibit the activation of TNF-α/ASK-1-mediated apoptosis of human brain microvascular endothelial cells, indicating a potential role in cerebral hypoxia-induced injury [84][81]. The involvement of linc-ROR in cancer proliferation and metastasis has been documented, suggesting an important role in the clinicopathological characteristics of tumors, therefore considered an oncogene that affects prognosis, survival rate, and higher recurrence rate [85][82]. Intriguingly, a few studies have positioned linc-ROR as a tumor-suppressor lncRNA, proposing it could be involved in several mechanistic pathways exerting multiple and even opposite functions [86,87,88][83][84][85]. Functional and regulatory mechanisms of linc-ROR in distinct types of cancer are summarized in Table 1.
Table 1. Functional and regulatory mechanisms of linc-ROR in cancer.
Type of Cancer Target/Relation Effect Reference
Breast MAPK/ERK pathway Promotes estrogen-independent proliferation [89][86]
miR-194-3p Promotes rapamycin resistance [70][67]
N- and E-cadherin, vimentin Promotes 5-FU and paclitaxel resistance and EMT [90][87]
miR-205, ZEB1, ZEB2 Promotes tamoxifen resistance and EMT [69][66]
LC2, Beclin 1 Promotes tamoxifen resistance by autophagy [91][88]
miR-205, ZEB2 Promotes EMT [92][89]
Estrogen and progesterone receptors Promotes lymph node metastasis [93,94][90][91]
Reproductive factors Higher risk [95][92]
hnRNPI, AUF1 Promotes proliferation and tumorigenesis [96][93]
MLL1/H3K4/TIMP3 Promotes progression [97][94]
CTBP1-AS2, SPRY4-IT1 Promotes pathogenesis [98][95]
miR-145/ARF6 Promotes metastasis and invasion [99][96]
miR-145/MUC1/E-cadherin Promotes metastasis and invasion [100][97]
TGF-β pathway Promotes proliferation and invasion [101][98]
miR-34a Promotes autophagy and gemcitabine resistance [66][63]
Wnt/β-catenin pathway Promotes viability, migration, and invasion [102][99]
ND Promotes metastasis [103][100]
Ovarian

and Endometrial		 Wnt/β-catenin pathway Promotes EMT and metastasis [104][101]
ND Promotes proliferation, invasion, and metastasis [105][102]
CA125 Promotes lymph node metastasis [106][103]
miR-145/FLNB Promotes EMT and invasion [107][104]
miR-145 Promotes stemness [108][105]
miR-34a, Notch Promotes proliferation and suppresses apoptosis [109][106]
Gastric SALL4 Promotes maintenance and aggressiveness [110][107]
miR-519d-3p/HMGA2 Promotes proliferation, EMT and cisplatin resistance [111][108]
miR-212-3p/FGF7 Promotes proliferation, migration, and invasion [112][109]
Vimentin, E-cadherin, β-catenin, c-Myc Promotes EMT and lymph node metastasis [113][110]
OCT4, SOX2, NANOG, CD133 Promotes proliferation and invasion [114][111]
MRPI Promotes Adriamycin and vincristine resistance [115][112]
ADAR, FUS Increased survival rate [86][83]
HOXA-AS1 Downregulated [116][113]
miR-580-3p/ANXA10 Suppresses proliferation, migration, and invasion [117][114]
Lung miR-145/FSCN1 Promotes docetaxel resistance [118][115]
NA Promotes distant and lymph node metastasis [119][116]
EML4-ALK Promotes stemness and crizotinib resistance [120][117]
P53/miR-145 Promotes proliferation, migration, and invasion [121][118]
PI3K/Akt/mTOR Suppresses cisplatin resistance [88][85]
Liver miR-145/ZEB2 Promotes EMT and metastasis [25][119]
miR-145/RAD18 Promotes radioresistance [122][120]
IL-1β Promotes release of pro-inflammatory cytokines [123][121]
E-cadherin, vimentin, TWIST1 Promotes EMT and Adriamycin resistance [124][122]
DEPCD1 Promotes progression and angiogenesis [125][123]
miR-876-5p/FOXM1 Promotes sorafenib resistance [126][124]
TGF-β Promotes sorafenib resistance [127][125]
miR-145/HIF-1α Promotes survival during hypoxic stress [128][126]
P53 Promotes arsenic trioxide resistance [129][127]
miR-223-3p/NF2 Promotes proliferation and invasion [130][128]
OCT4, NANOG, SOX2, p53, CD133 Promotes proliferation [131][129]
Pancreatic ZEB1 Promotes EMT and aggressiveness [132][130]
Hippo/YAP pathway Promotes EMT, proliferation, and invasion [24][131]
HIF1-α/ZEB1 Promotes EMT [133][132]
miR-145, NANOG Promotes proliferation and decreases migration [68][65]
Let-7 family Promotes migration, invasion, and EMT [134][133]
Head and Neck miR-145-5p Promotes stemness [135][134]
ND Promotes progression and metastasis [136][135]
LMO4/AKT/PI3K Promotes proliferation and invasion [137][136]
p-AKT/p-VEGFR2 Promotes proliferation, migration, and angiogenesis [138][137]
P53 Promotes proliferation, metastasis and inhibits apoptosis [139,140][138][139]
ND Downregulated in plasma [141][140]
P53    
Esophageal miR-15b, miR33a, miR-129, miR-145, miR-206 Promotes proliferation, motility, chemoresistance, and renewal capacity [142][141]
ND Promotes initiation and progression [143][142]
miR-204-5p/MDM2/p53 Suppresses apoptosis [144][143]
miR-145/FSCNI Promotes metastasis [145][144]
miR-145/LMNB2 Promotes proliferation and migration [146][145]
Colorectal miR-145 Promotes stemness and metastasis [147][146]
hnRNPI, AUF1 Promotes proliferation and tumorigenesis [96][93]
NA Related with larger tumor size, metastasis, and mortality [148][147]
P53/miR-145 Promotes radioresistance and suppresses apoptosis [149][148]
miR-145 Promotes lower survival rate [150][149]
EGFR Promotes proliferation invasion, and migration [151][150]
miR-6833-3p/SMC4 Promotes proliferation and lower survival rate [152][151]
P53 Promotes proliferation and viability [153,154][152][153]
CCAT1 Promotes metastasis [155][154]
Kidney and Bladder SOX2, Nanog, POU5F1 Promotes stemness, infiltration and shorter survival [156][155]
ZEB1 Promotes proliferation, metastasis, EMT, and inhibits apoptosis [157][156]
P53, c-Myc Promotes shorter survival rate [158][157]
miR-206/VEGF Promotes proliferation and metastasis [159][158]
TESC Promotes tumorigenesis [160][159]
Thyroid and

Parathyroid		 TESC/ALDH1A1/

TUBB3/PTEN		 Promotes progression [161][160]
miR-145 Promotes EMT [162][161]
ND Promotes EMT and metastasis [163][162]
ND Suppresses progression [164][163]
Brain and Retina ND Promotes poor overall survival [165][164]
EGFR Promotes proliferation and stemness [166][165]
KLF4/CD133 Suppresses proliferation [87][84]
ND Promotes proliferation and angiogenesis [167][166]
Akt pathway Suppresses proliferation [168][167]
miR-32-5p/Notch Promotes EMT, invasion and metastasis [169][168]
Bone miR-153-3p/ABCB1 Promotes cisplatin resistance [170][169]
miR-185-3p/YAP1 Promotes growth and metastasis [171][170]
miR-206 Relates to advanced TNM, metastasis and poor survival [172][171]
Skin P53, PI3K/Akt Promotes proliferation [173][172]
Prostate miR-145/Oct4 Promotes proliferation, invasion, and tumorigenicity [174][173]

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