The Intergenic Type LncRNA (LINC RNA) Faces in Cancer with In Silico Scope and a Directed Lens to LINC00511: A Step toward ncRNA Precision

Background: Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis. Main body: LincRNAs can regulate cancer progression through different mechanisms and are considered as potential drug targets. Genetic variations such as single nucleotide polymorphisms (SNPs) in lincRNAs may affect gene expression and messenger ribonucleic acid (mRNA) stability. SNPs in lincRNAs have been found to be associated with different types of cancer, as well. Specifically, LINC00511 has been known to promote the progression of multiple malignancies such as breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, and others, making it a promising cancer prognostic molecular marker. Conclusion: LincRNAs have been proved to be associated with different cancer types through various pathways. Herein, we performed a comprehensive literature and in silico databases search listing lncRNAs, lincRNAs including LINC00511, lncRNAs’ SNPs, as well as LINC00511 SNPs in different cancer types, focusing on their role in various cancer types and mechanism(s) of action.


Introduction
The study of epigenetics, namely, non-protein coding RNAs (ncRNAs), has had significant increased attention recently [1].ncRNAs are involved in a variety of physiological activities, including the regulation of gene expression and RNA splicing [2].Long ncRNAs (lncRNA) have a length of more than 200 nucleotides and do not code for proteins [3]; at every stage of gene expression, they act as either an indicator-, decoy-, or scaffold-, and guide-lncRNA [4].A variety of human disorders have been linked to abnormal lncRNA expression [5].For example, Nicotinamide nucleotide transhydrogenase-antisense 1 (NNT-AS1) overexpression has been observed in a variety of malignancies, including osteosarcoma, cervical cancer (CC), breast cancer (BC), colorectal cancer (CRC) [6], gastric cancer (GC), Hepatocellular carcinoma (HCC), and non-small cell lung cancer (NSCLC).The biological roles and expression levels of lncRNA transcripts may be affected by variations in lnc gene loci [7].
Non-Coding RNA 2023, 9, 58 2 of 40 find new treatment targets, in other words, to find precision prognostic molecular markers.According to their different genetic origins, lncRNAs can be categorized into five groups: sense, antisense, intronic, bidirectional, and intergenic lncRNAs.Sense-lncRNA coincides with the exons of the corresponding protein-coding gene on the sense RNA strand.Antisense lncRNA is derived from the antisense (AS) RNA strand of the protein-coding gene [9].Intronic lncRNA is the lncRNA that originates from the introns of the protein-coding gene [10].Moreover, from the promoter of a protein-coding gene, bidirectional lncRNA is transcribed, but in the opposite direction.Finally, long intergenic non-protein coding RNAs (LincRNAs) are the lncRNAs that are situated between two protein-coding genes [11].RNA polymerase II (Pol II) is primarily responsible for lncRNAs transcription, making them processed in a less efficient manner and more retained in the nucleus rather than the cytoplasm.Nuclear lncRNAs have a role in condensate formation or can be bound to chromatin [12].

LncRNAs and, in Particular, LINC RNA Worth Studying
LincRNAs make more than 50% of lncRNAs [13].LincRNAs are lncRNAs that are interspersed between coding genes and do not overlap any protein-coding sequences.LincRNAs perform physiological processes like inflammation during infection [14].Lin-cRNAs exhibit tissue-specific expression [15], being essential for many cellular activities including the control of gene expression [16].LincRNAs have a pathological role during cancer development [14], when the control of gene expression is perturbed after lincRNA overexpression or mutation.

Review Methodology
A manual online search into two medical e-databases, PUBMED and Google Scholar, for ("lincRNA") AND ("lincRNA Role in Carcinogenesis") AND ("lncRNA linc00511") AND ("lincRNA SNPs") AND ("future promising biomarkers") was done in September, 2022.Priority was given to meta-analysis, randomized clinical studies, systematic review, original papers, and narrative reviews, since, but not limited to, 2010.

Review Aim
Introducing lncRNAs and their classification, briefly listing "LincRNAs in different cancer types" after identifying lncRNAs and lincRNAs via in silico databases search, mentioning LincRNAs' role and mechanism of action in various cancer types, highlighting "LINC00511 in several cancer types", and finally, listing published documented "Single nucleotide polymorphisms (SNPs) variants of lncRNAs and LINC00511 in different cancer types and SNPs role/mechanism of action influencing cancer risk".

What Are LincRNAs?
From the intergenic spaces between two genes, polymerase enzyme II transcribes lincRNAs.The majority of annotated lincRNAs have several exons, cap, and a poly(A) tail that are similar to those of mRNA [25].LincRNAs have a wide range of functions, including regulating epigenetic changes and regulating gene expression, as well as acting as scaffolds for protein signaling complexes [26].LincRNA genes differ from mRNAencoding genes in that they perform crucial roles such as chromatin remodeling and genome architectural remodeling, RNA stabilization or enhancer-associated activity [27], and finally, transcription regulation/control of neighbor genes as well [28].

LincRNA Role in Chromatin Remodeling
LincRNAs control gene expression through interacting with chromatin-modifying complexes to alter the later state [29].Chromatin-modifying enzymes can be repressive or activating, or these enzymes may occasionally have bivalent domains that perform both activities (repression-activation) [30].As shown in Figure 1a, lincRNAs can function in a cis-acting manner (cis-acting lincRNA) or trans-acting manner on gene expression.Cisacting lincRNAs influence the expression of genes on the same chromosome close to their transcriptional location.On the contrary, trans-acting lincRNAs regulate gene expression at distinct, distant loci on a different chromosome [31].For example, a cis-acting lincRNA HOXA transcript at the distal tip (HOTTIP) induces the expression of the HOXA gene.Trans-acting lincRNA HOX transcript antisense RNA 12 (HOTAIR12) silences HOXD gene as well as genes on other chromosomes [27].LincRNAs interact with/via transcription factors (TFs) directly or indirectly to drive chromatin-modifying enzymes bound to RNA toward particular genomic locations [32].
pression at distinct, distant loci on a different chromosome [31].For example, a cis-acting lincRNA HOXA transcript at the distal tip (HOTTIP) induces the expression of the HOXA gene.Trans-acting lincRNA HOX transcript antisense RNA 12 (HOTAIR12) silences HOXD gene as well as genes on other chromosomes [27].LincRNAs interact with/via transcription factors (TFs) directly or indirectly to drive chromatin-modifying enzymes bound to RNA toward particular genomic locations [32].

LincRNA Role in DNA Damage Repair (DDR)
LincRNAs take part in various stages of the DNA repairing process.LincRNA-p21 regulates apoptosis and cancer cell growth by blocking the translation of the target gene and activating p53 signaling [33] as the lincRNA-p21/dec.downstream target gene/p53 axis.LincRNA-p21 was found to interact with heterogeneous nuclear ribonucleoprotein-K (hnRNP-K), a protein that is directed to the tumor suppressor p53 promoters target genes, leading to transcriptional repression of p53-regulated genes [34].LINC Regulator Of Reprogramming (Linc-ROR) regulates p53 translation, resulting in driving tumorigenesis in many cancers [35].As a result of exposure to either exogenous or endogenous environmental stressors, DNA double-strand breaks (DSBs) abrasions occur in both DNA strands, damaging them [36].LincRNAs have role in DSB repair through two pathways, namely, homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathway.NHEJ involves ligation of the break ends without the need for a homologous template.Whereas in HR, a homologous template sequence is needed [37].Prostate cancer associated transcript-1 (PCAT-1) is the first lincRNA known to play a role in DSBs repair [38].

LincRNA Role as a Competitive Endogenous RNA (ceRNA)
The interaction between lncRNAs/micro-RNAs/mRNAs makes up a complex regulatory network system, known as the competitive endogenous (ceRNA) network [39].ceRNAs play a remarkable role in cancer and gene regulation.RNA-induced silencing complex (RISC) maintains this interaction and determines the post transcriptional regu-

LincRNA Role in DNA Damage Repair (DDR)
LincRNAs take part in various stages of the DNA repairing process.LincRNA-p21 regulates apoptosis and cancer cell growth by blocking the translation of the target gene and activating p53 signaling [33] as the lincRNA-p21/dec.downstream target gene/p53 axis.LincRNA-p21 was found to interact with heterogeneous nuclear ribonucleoprotein-K (hnRNP-K), a protein that is directed to the tumor suppressor p53 promoters target genes, leading to transcriptional repression of p53-regulated genes [34].LINC Regulator Of Reprogramming (Linc-ROR) regulates p53 translation, resulting in driving tumorigenesis in many cancers [35].As a result of exposure to either exogenous or endogenous environmental stressors, DNA double-strand breaks (DSBs) abrasions occur in both DNA strands, damaging them [36].LincRNAs have role in DSB repair through two pathways, namely, homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathway.NHEJ involves ligation of the break ends without the need for a homologous template.Whereas in HR, a homologous template sequence is needed [37].Prostate cancer associated transcript-1 (PCAT-1) is the first lincRNA known to play a role in DSBs repair [38].

LincRNA Role as a Competitive Endogenous RNA (ceRNA)
The interaction between lncRNAs/micro-RNAs/mRNAs makes up a complex regulatory network system, known as the competitive endogenous (ceRNA) network [39].ceRNAs play a remarkable role in cancer and gene regulation.RNA-induced silencing complex (RISC) maintains this interaction and determines the post transcriptional regulation level of gene expression [40].As shown in Figure 1b, lincRNAs have the potential to compete for micro-RNA (miR) and behave as a miR sponge.This later process attenuates miR activity and increases the expression of target mRNA genes [39].LINC00691 is an example of ceRNA that competes for miR-1256 and regulates the expression or suppression of tumorigenicity 5 (ST5), leading to the suppression of sarcoma [41].LINC00511, overexpressed in BC, has been found to sponge miR-185-3p [42].Utilizing scaffolding molecules, which can bring several components together and direct them to enhance their activities, is one method by which the cell can overcome the difficulty of coordinating certain interactions [43].In the nucleus, scaffold Polycomb repressive complex proteins (PRCP) lincRNA has an impact on the accessibility of chromatin, gene expression, and the structure of the nucleus [44].Terminal differentiation-induced non-coding RNA (TINCR) lncRNA facilitates the post-transcriptional stability and accumulation of mRNAs that promote epidermal development by scaffolding staufen1, an RNA-binding protein, with the TINCR lincRNA box motif [27].
Also, LINC00473 contributes to the proliferation and migration of GC by acting as a ceRNA of miR-16-5p [52].Moreover, LINC00355 can promote the progression of GC by the regulation of the wingless-INT (Wnt)/β-catenin signaling pathway [53].In addition, Linc01555 contributes to GC cell proliferation through interacting with the Notch signaling pathway [54,55].HOTAIR is upregulated in Laryngeal squamous cell carcinoma (LSCC), inducing invasiveness, progression, and resistance to apoptosis in LSCC cells through promoting PTEN methylation [56].Moreover, LINC00673 promotes the progression of lung adenocarcinoma through the activation of the Wnt/B-catenin pathway [57,58].Again, MALAT-1 contributes to the development of different types of cancer through interaction with Serine/Arginine splicing factors and changing their distribution to nuclear speckle domains [59].Furthermore, Myocardial Infarction Associated Transcript (MIAT) can promote neuroblastoma by the modulation of MYCN and Paired-like homeobox 2b (PHOX2B) driver genes [60].Upregulation of RUNX3 that targets DR5 leading to activation of NK cells [50] Tumor suppressor

Overexpression of LINC00657
Human CC tissues vs normal tissues and CC cell lines SiHa, HeLa, C33A, Caski vs. normal cervical squamous cell line Ect1/E6E7

LincRNAs List in Breast Cancer (BC)
Linc-ROR could promote BC metastasis through sponging miR-205, miR-145, resulting in epithelial-mesenchymal transition (EMT) induction [61].LincRNA-BC2 is upregulated in BC, with interaction with BC associated protein antigens 1 and 2 (BRCA1 and BRCA2), which are predicted by RNA-Protein Interaction Prediction (RPISeq) [62].Moreover, LINC00299 was found to be a promising biomarker for triple negative BC (TNBC) by its hypermethylation [63].It has been reported that LINC00641 can be a target for BC treatment, since it inhibits proliferation, invasion, and migration of BC cells via sponging miR-194-5p [64].LINC00993 suppresses the TNBC growth in vitro and in vivo by generating G0/G1 arrest and regulation of the genes related to cell cycle such as p21 and p53 [65].LINC00885 was reported to act as ceRNA and regulate BC cells growth.In addition, LINC00885 is associated with early stage BC through the activation of epidermal growth factor receptor (EGFR), epiregulin (EREG), and forkhead box M1 (FOXM1) pathways and signaling pathways linked to TP53 signaling [66].Liao et al. have found that Linc-APOC1P1-3 expression induces proliferation and inhibits apoptosis of BC cells via binding tubulin to decrease α-tubulin acetylation and, therefore, inactivates caspase-3 [67].Researchers pointed to Linc-HOTAIR interaction with Polycomb Repressive Complex 2 (PRC2) promoting BC metastasis [68].LINC00657 was found to play a role in the biological behavior of BC such as invasion, migration, proliferation, and apoptosis.It can sponge miR-590-3p and upregulates Golgi Phosphoprotein 3 (GOLPH3) [69].LINC00511 was found by our group to be overexpressed in BC patient's blood, with sponging miR-185-3p, and was considered as an early diagnostic biomarker for BC [42].BC cell migration and proliferation was promoted by LINC00460 via sponging miR-320a and upregulation of MAL2 [70].In addition, LINC00922 could induce BC invasion, metastasis, progression, and regulation of EMT, by NKD2 methylation [71].All lincRNAs roles and mechanisms of action in BC are mentioned in Table 2. LINC01088 was found to bind to miR-548b-5p and miR-548c-5p to upregulate G3BP1 expression, resulting in the enhancement of CRC progression with immune scape and finally, changing cancer cell phenotypes [72].
As summarized in Table 2 "Long intergenic non-coding RNAs (lincRNAs) and their involvement in cancer", LincRNAs have several important functions, such as chromatin remodeling, DNA damage/repair, and acting as ceRNA or protein scaffold.There are various lincRNAs that have a role in different types of cancer, leading to an increase or decrease in its risk with different mechanisms.The International Cancer Genome Consortium (ICGC) data portal [73,74] identified LINC00511 gene as 2265-bp, which is localized on chromosome 17q24.3with five exons https://dcc.icgc.org/genes/ENSG00000227036[75].Bulk tissue gene expression for LINC00511 (ENSG00000227036.6)from the Genotype-Tissue Expression (GTEx) project helped to study tissue-specific gene expression and regulation, where 54 non-diseased tissue sites samples were collected from 1000 individuals for molecular assays.GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2) https://www.gtexportal.org/home/gene/LINC00511. Figure 2 shows the LINC00511 expression in different tissues.The highest expression of LINC00511 was found in the sun-exposed skin tissues.

LINC00511 in Cancer
LINC00511 was first discovered by Cabanski et al. in 2015 [76].LINC00511 is dysregulated in multiple malignancies including glioma, BC, ovarian cancer, CC, osteosarcoma, HCC, lung cancer, TSCC, renal cell cancer, papillary thyroid carcinoma, pancreatic cancer, GC [77], and CRC [78].This dysregulation has a role in facilitating the prognosis of cancer [79].First, LINC00511 sponge miRNAs and alter the expression of their targets.Second, through interacting with enzymes and TFs associated to DNA methylation, LINC00511 can control tumor suppressors or oncogenes to promote tumorigenesis [77].Additionally, LINC00511 promotes cell proliferation, cell cycle progression, tumorigenesis, invasion, and metastasis [75].According to Lu et al., LINC00511 can promote tumor growth and metastasis and induce stemness in malignancies.In order to prevent cancer metastasis, it may be possible to employ LINC00511-modifying modalities [80].Role of LINC00511 Expression in Different Types of Cancer (Table 3).

LINC00511 in Cancer
LINC00511 was first discovered by Cabanski et al. in 2015 [76].LINC00511 is dysregulated in multiple malignancies including glioma, BC, ovarian cancer, CC, osteosarcoma, HCC, lung cancer, TSCC, renal cell cancer, papillary thyroid carcinoma, pancreatic cancer, GC [77], and CRC [78].This dysregulation has a role in facilitating the prognosis of cancer [79].First, LINC00511 sponge miRNAs and alter the expression of their targets.Second, through interacting with enzymes and TFs associated to DNA methylation, LINC00511 can control tumor suppressors or oncogenes to promote tumorigenesis [77].Additionally, LINC00511 promotes cell proliferation, cell cycle progression, tumorigenesis, invasion, and metastasis [75].According to Lu et al., LINC00511 can promote tumor growth and metastasis and induce stemness in malignancies.In order to prevent cancer metastasis, it may be possible to employ LINC00511-modifying modalities [80].Role of LINC00511 Expression in Different Types of Cancer (Table 3).Human CRC tissues vs. adjacent normal tissues and CRC cell lines HCT116, HT-29, LoVo, SW480, SW620, immortalized human colonic mucosal epithelial cell line NCM460, and female athymic BALB/c mice for implantation 29c-3p Upregulation of NFIA [82] Human CRC tissues vs. normal tissues and CRC cell lines HT-29, HCT8, HCE8693, SW620 vs. normal cell line NCM460

LINC00511 Role in Pancreatic Cancer (PC)
LINC00511 competitively endogenously inhibits hsa-miR-29b-3p activity to upregulate vascular endothelial growth factor A (VEGFA), promoting pancreatic ductal adenocarcinoma (PDAC) stemness.Therefore, LINC00511 is considered as a promising biomarker that can be used to predict PDAC patients prognosis following surgery, and could be a therapeutic target [98].

LINC00511 Role in Hepatocellular Cancer (HCC)
LINC00511 could competitively interact with miR-424 to promote HCC proliferation and metastasis [99].LINC00511 promotes HCC development by competing with miR-195 and positively correlating with Eyes absent homolog 1 (EYA1) [100].Moreover, LINC00511 accelerate HCC progression, acting as a prognostic biomarker for the disease.However, it has an adverse interaction with miRNA-29c in HCC [101].It is noteworthy to mention that LINC00511 promotes HCC invasion via affecting exosome secretion and invadopodia formation [102].

LINC00511 Role in Different Types of Breast Cancer (BC)
It has been reported that the LINC00511/miR-150/MMP13 axis contributes to BC proliferation and migration.LINC00511 has the ability to sponge miR-150, leading to regulation of expression of Matrix Metallopeptidase 13 (MMP13) and promoting cell migration [110].DNA hypomethylation induces LINC00511 expression and LINC00511 promotes BC growth by upregulating Wnt family member 10A (Wnt10A), E2F transcription factor 2 (E2F2), Transforming growth factor-alpha (TGF-A), and MET [111].The LINC00511/miR-185-3p/E2F1/Nanog axis promotes the BC cells growth, via sponging miR-185-3p and target E2F1 protein that binds with the Nanog promoter region to activate its transcription [80].LINC00511 has been proved to increase the expression of BC cells as well as the transcriptional control of downstream genes through an elevated LINC00511/miR-185-3p axis.Therefore, LINC00511 can be considered a marker for BC early diagnosis [42].LINC00511 is a TNBC-specific lncRNA that functions as an oncogene to control tumor metastasis and prognosis [112].LINC00511 enhances ER-negative BC cell growth by altering cell proliferation and apoptosis by accelerating the G1/S transition and suppressing apoptosis [113].Zhang et al. has proved that LINC00511 downregulation enhances paclitaxel cytotoxicity in BC cells by acting as a miR-29c molecular sponge [114].Moreover, inhibition of LINC00511 reduces its competitive binding to miR185, leading to higher STXBP4 expression and better radiation response in BC [115].
As well summarized in Table 3 "LINC00511 and its contribution in different cancer types", different studies have proved that LINC00511 is upregulated in various types of cancer.For example, in CRC, LINC00511 promotes the progression of the disease through sponging miR-153-5p, miR-29-3p, and miR-625-5p.In addition, LINC00511 induces the proliferation of lung cancer by sponging miR-625-5p, miR-195-5p, and miR-150-5p.The progression of CC can be promoted by LINC00511 through sponging miR-324-5p and miR-497-5p.LINC00511 can stimulate GC tumorigenesis by sponging miR-195-5p, miR-515-p, miR-124-3p, and miR-625-5p.Moreover, LINC00511 can induce BC oncogenesis through sponging miR-150, miR-185, miR-185-3p, and miR-29, in addition to other discussed types of cancer that can be induced by LINC00511.Although different studies have reported that LINC00511 is upregulated in OS, one study has proved that it is downregulated in OS and inhibits cell proliferation.

LncRNAs SNPs in Different Cancer Types and Their Mechanism of Action
Unveiling the relationship between lncRNAs SNPs or specifically, LINC RNA SNPs and disease mechanism(s) is an important research gap to investigate, as future prospective, to relate cancer incidence or progression/remission to specific variants.This will be a step toward ncRNA precision, fulfilling big pharma's shift toward targeting RNA for treatment instead of DNA or classical cancer-hallmarks.In the human genome, Over 10 million SNPs have been identified resulting in gene variants, which change the cell's protein production machinery [116].SNPs can affect RNA-RNA interaction (lncRNA-miRNA interactions) through a ceRNA mechanism, where lncRNA could competitively bind miRNAs [117].It has been reported that SNPs within lncRNA transcripts can impact the structure and function of lncRNA, whereas SNPs in an lncRNA's promoter region might affect its expression level [116].Furthermore, lncRNAs SNPs that change the structure of the lncRNA influence the interaction between the RNA Binding Proteins (RBPs) and lncRNA, resulting in the regulation of several biological pathways [118].It has been found that lincRNA SNPs in exon loci may alter the secondary structure of the lincRNA.For example, SNP rs1456315 G/A in lincRNA PRNCR1alters its secondary structure and hence, the conformation and stability of lincRNA, even causing changes in its interacting partners [117].

LncRNAs SNPs List in Breast Cancer, Their Role and Mechanism of Action (Table 4)
CDKN2B-AS1, also named ANRIL, is an lncRNA that can interfere with the expression of neighboring genes, control cell proliferation and apoptosis, and is upregulated in BC.Researchers proved that SNP rs310965215 in ANRIL altered cells' ability to proliferate, invade, and migrate by sponging miR-4440 [119].Another study demonstrated that SNPs rs1333045, rs1333048, rs4977574, and rs10757278 in ANRIL increase BC risk [120].However, MALAT1 SNPs (rs3200401, rs619586, and rs7927113) have an association with BC susceptibility.Fortunately, genotypes AG and AG + GG of MALAT1 SNP rs619586 protect against BC, and CT of rs3200401 reduces BC risk [121].Growth Arrest Specific 5 (GAS5) is a tumor suppressor and is downregulated in many cancer types including BC [122].The GAS5 SNP rs145204276 del allele may inhibit BC development by increasing the promoter activity via binding to the TF specificity protein 1 [123].Cancer susceptibility candidate 15 (CASC15) is a very active lncRNA in silico and is found on chromosome 6p22.3.An interaction between lncRNA CASC15 polymorphisms and susceptibility of BC has been found; rs7740084 and rs1928168 reduced BC risk, whereas, there is a correlation between rs9393266 and BC risk [124].Similarly, HOTAIR SNP rs920778 elevates BC risk and might interact with the clinical reproductive factors [125].MiR2052HG rs34841297 regulates miR-4456 expression, which alters BC cells proliferation and invasion, increasing BC susceptibility [126].LINC00520 is found on human chromosome 14q22.3[127] and is upregulated in various tumors including LSCC, nasopharyngeal carcinoma, and renal cell carcinoma.Increased TNBC susceptibility may be exploited by LINC00520 SNP rs8012083 [128].Also, SNP rs527616 in lncRNA AQP4-AS1 increases BC susceptibility [129].SOX2OT is an lncRNA located in the SOX2 gene in the intronic region.Via affecting the expression of SOX2OT, lncRNA SOX2OT SNP rs9839776 increases BC risk [130].Again, lncRNA H19 SNPs (rs3741219, rs217727, and rs2839698) increase BC risk, whereas rs3741216 decreased it [131].SRA is an lncRNA upregulated in BC and its expression correlates with levels of ER and PR.SNP rs10463297 in lncRNA SRA increased BC risk through affecting SRA mRNA expression [132].SNPs rs11657109, rs17780195, and rs9906859 in LINC00511 may protect against BC, being related to LINC00511 secondary structure and expression [133].Our group is currently investigating LINC00511 SNPs in BC as well as CRC patients' blood samples (publication in progress).LincRNA-ROR SNP rs4801078 was correlated to BC risk, being affected by the interplay between linc-ROR SNPs and reproductive factors [134].

LncRNAs SNPs List in Lung Cancer, Their Role and Mechanism of Action (Table 5)
NEAT1 is a lncRNA located on chromosome 11q13.1,and is a component of paraspeckles.As seen in Table 5, SNP rs2239895 in lncRNA NEAT1 increases the risk of lung squamous cell carcinoma [135].CCAT1 is located on chromosome 8q24.21and is overexpressed in several tumors such as GC, CRC, and HCC.SNP rs1948915 in lncRNA CCAT1 is associated with decreased lung cancer susceptibility, in the study's female population cohort [136].Researchers have found that SNP rs219741 in lncRNA LOC105369301 elevates the risk of NSCLC, while SNP rs498238 in lncRNA LINC01833 and SNP rs16901995 in lnc-NDUFS6-5:5 all reduce the NSCLC risk [137].Compared to people with the homozygous wild AA genotype/heterozygote GA genotype, those with the homozygous GG genotype SNP rs7248320 in lncRNA AC008392.1 had a lower chance of developing NSCLC [138].Researchers have reached a point that SNP rs4759314 (AG genotype) in lncRNA HOTAIR can increase the risk of lung cancer development, while SNP rs12826786 ("CT" and "CT + TT" genotypes) decreased this risk [139].
Moreover, SNPs rs920778 and rs1899663 in lncRNA HOTAIR have been found to increase lung cancer susceptibility [140].Epidermal growth factor receptor (EGFR) wild type lung adenocarcinoma, the GAS5 SNP rs145204276, may aid in tumor stage, distal metastases, and lymph node metastasis prediction [141].PRNCR1 is an lncRNA located on chromosome 8q24.21and is a popular oncogene in prostate cancer [142].A study has found that the PRNCR1 SNP rs1456315 T allele compared with the C allele and the lncRNA CCAT2 SNP rs6983267 G allele, compared with the T allele, increased lung cancer risk.These SNPs affect the lncRNA secondary structure as well as the miRNAs target [143].There has been an association between SNP rs3200401 in lncRNA MALAT1 and susceptibility of lung squamous cell carcinoma and NSCLC, via altered MALAT1's structural properties and downstream genes contributing to the formation and progression of cancer [144].HOXA11-AS is a lncRNA whose ectopic expression plays important roles in different cancer types.SNP rs17427875 (T allele) in HOXA11-AS increases the risk of lung adenocarcinoma, whereas SNP rs11564004 (G allele) plays a protective role, with TFs as mediators [145].SNP rs217727 (A/A homozygous genotype) in lncRNA H19 is associated with elevated lung cancer risk, particularly adenocarcinoma and squamous cell carcinoma [146].LncRNA LOC146880 is upregulated in NSCLC and is associated with poor prognosis of the disease.The A allele in rs140618127 SNP in lncRNA LOC146880 decreases NSCLC risk.LOC146880 offers microRNA miR-539-5p an alternative binding site, altering ENO1 phosphorylation with PI3K and Akt pathway's activation [147].6) As listed in Table 6, researchers found lncRNA MALAT1 SNPs rs619586, rs664589, and rs1194338 are associated with CRC risk through binding of various TFs [148].rs67085638 in lncRNA CCAT1 increases risk of CRC, while rs7013433 is related to CRC late clinical stage [149].On the other hand, rs2470151 (CT/TT genotype) in lncRNA RP11-108K3.2 could decrease the risk of CRC [150].Linc-ROR SNP rs1942347 was associated with CRC large tumor size and mortality [151].rs2839698 in lncRNA H19 associated with increased CRC risk, changing promotor activity and H19 function [152].Moreover, H19 SNPs rs4930101, rs11042170, and rs27359703 were associated with increased risk of CRC [153].HOTTIP is an antisense lncRNA that is upregulated in different tumors including CRC.SNPs rs3807598, rs2067087, and rs17427960 in HOTTIP increase susceptibility to CRC, through affecting Transcription Factor Binding Sites (TFBSs) according to SNP function prediction [154]; however, rs1859168 regulates lncRNA gene expression [155].A positive association between rs55829688 SNP in GAS5 and CRC risk reduced GAS5 expression by altering the TF YY1 s affinity for GAS5 [156].It has been reported that SNP rs2632159 in lncRNA PCAT1 can elevate the risk of CRC [157].It has been demonstrated that lncRNA PUNISHER "AGAP2-AS1" has a role in inducing CRC cell proliferation, epithelial-tomesenchymal transition, and enhancement of CRC cells' chemoresistance to gemcitabine.PUNISHER is associated with elevated risk of CRC, tumor relapse, and short survival time, via rs12318065.This SNP could modify regulatory motifs such as MRG1, Sin3Ak-20 disc6, and HOXA9 1 that have been found to be linked to CRC, or affecting binding with the TFs POL2, ZNF263, and STAT1, associated with carcinogenesis [158].It has been demonstrated that lncRNA MAGI2-AS3 acts as a tumor suppressor in many cancers; however, it helps in CRC progression.An increased risk for CRC is due to SNP rs7783388 in lncRNA MAGI2-AS3, via influencing the binding ability of glucocorticoid receptor (GR) to the MAGI2-AS3 promoter [159].SNHG16 is a lncRNA located on human chromosome 17q25.1,upregulated in BC, bladder cancer, and CRC, where it affects the expression of genes associated with lipid metabolism.SNP rs7353 in lncRNA SNHG16 suppresses CRC, while rs8038 and rs15278 increase this risk [160].Via binding to miR-4658 and impairing the expression of lncRNA CCSlnc362 "RP11-362K14.5" in CRC cells [161], SNP rs1317082 can protect against CRC.LincRNA Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3) is considered as a tumor-suppressor in thyroid cancer and glioma [162].SNP rs944289 in PTCSC3 decreases CRC risk [163].rs1456315 in lncRNA prostate cancer non-coding RNA (PRNCR1) increases CRC risk [164].LncRNA MEG3 SNP rs7158663 elevates CRC risk [165].By losing binding of miR-128-3p to LAMC2-1:1, rs2147578 in lncRNALAMC2-1:1 increased CRC risk [166].SNP rs7958904 in lncRNA HOTAIR is associated with both CRC mortality and incidence [167].LncRNA UCA1 is upregulated in different types of cancer including CRC, BC, bladder cancer, NSCLC, esophageal cancer, and TSCC.SNP rs12982687 in lncRNA UCA1 was proved to affect UCA1's binding to miR-873-5p and HIF-1 signaling, resulting in a contribution to the progression of smoking-triggered CRC [168].SNPs rs6983267 at 8q24 and HULC rs7763881 may serve as genetic indicators of a propensity towards CRC and are correlated with CCAT2 and HULC expression, respectively [169].
TINCR lncRNA SNPs rs2288947, rs8105637 are associated with CRC progression and susceptibility.The G allele of SNP rs2288947 was associated with decreased CRC risk, while the A allele of SNP rs8105637 was associated with increased CRC risk.The mechanism involves five motifs, Nanog disc3, CTCF disc9, Rad21 disc10, SP1 disc3, and SMC3 disc3, which may be affected by rs2288947.rs8105637 affects TCF12 and PITX2 expression linked to carcinogenesis [170].ANRIL's SNP rs1537373 may enhance pancreatic cancer susceptibility through TFs binding and Cyclin-dependent kinase inhibitor 2B (CDKN2B) expression regulation [171].Moreover, another study reported SNP rs1412832 in ANRIL may increase PDAC risk.Several target genes are regulated by ANRIL, including CDKN2A and p16, which typically exhibits harmful somatic and germline mutations and dysregulation [172].SNPs rs4759314 and rs200349340 in HOTAIR lncRNA can increase pancreatic cancer susceptibility.The later SNP affects HOTAIR expression by interfering with binding with miR-29a [173].Furthermore, the rs7046076 variant in lncRNA structural maintenance of chromosomes 2 (lnc-SMC2-1) increases PDAC risk, interfering with the lncRNA's ability to bind to miR-1256 [174].Although LINC00673 is an oncogene in many cancer types including NSCLC, it is a tumor suppressor in Pancreatic cancer [175].Pancreatic cancer risk increased via creating a binding site for miR-1231 upon the occurrence of SNP rs11655237 in LINC00673, via limiting degradation of protein tyrosine phosphatase non-receptor type 11 (PTPN11) [176].On the other hand, Hu et al. have found that SNP rs1859168 in HOTTIP may reduce pancreatic cancer susceptibility by suppressing HOTTIP expression [177].8) SNP rs7958904 in HOTAIR, SNPs rs3931282, rs1134492, and rs10589312 in Plasmacytoma variant translocation 1 (PVT1) and SNP rs84557 in Epidermal growth factor receptor-Antisense RNA 1 (EGFR-AS1) have been linked to the occurrence and prognosis of HCC through affecting their binding to different effector miRs, as listed in Table 7 [178].HOTTIP SNPs rs2067087, rs17501292, and rs17427960 and rs4102217 in the MALAT1 lncRNA increased HCC susceptibility by the regulation of certain motifs that elevate the expression of these carcinogenic lncRNA [179].SNP rs2839698 in lncRNA-H19 can predict the risk and prognosis of HCC [180].LN metastasis and HCC's increased susceptibility were related to SNP rs9914618 in LINC00673 [181].Summary of Point 4 "LncRNAs SNPs in different cancer types and their mechanism of action": SNPs in lncRNAs can increase or decrease the risk of various cancer types such as BC, CRC, HCC, etc., through different mechanisms (summarized in Tables 4-8).For example, SNP rs920778 in HOTAIR increases the risk of BC, while SNP rs3200401 in MALAT1 decreases the risk of BC.These studies could help in the progress of cancer treatments.

Summary and Conclusions
One abundant class of lncRNAs is lincRNAs, which are involved in various important biological processes.Numerous lincRNAs have been proved to be related to cancer, either being oncogenic, increasing cancer risk, susceptibility, progression, and/or metastasis, or decreasing cancer risk, being tumor suppressors, through different mechanisms of TFs or E2F, signaling pathways, or sponging various miRs.Specifically, LINC00511 has a crucial role in various types of cancer.Different lncRNAs SNPs or particularly LINC00511 SNPs were associated with cancer risk/protection, through distinct pathways, that could be a potential target/hit for cancer treatment as presented in Figure 3. Implementing ncRNA measurements in blood liquid biopsy or tumor tissues will be a step toward ncRNA precision health and fulfilling both big pharma's intention as well as the Sustainable Development Goals' goal 3 (SDGs #3) (Better Health).
Strengths of the current review study: Our review article covered almost all lin-cRNAs and their role in various cancer types.LINC RNA constitute promising hit target(s) for the design of chemotherapy treatment for different types of cancer, a step toward ncRNA precision treatment.
Limitation: Pathways of some lincRNAs are still unknown or missing in different in silico/bioinformatic databases and this mandates further studies, in either clinical or in vitro experimental manners, to prove findings.
Future Prospective: More future studies are required to link lincRNAs SNPs variants and haplotypes in different types of cancer, to help pick cancer cases in an early-stage or low-grade, identifying the pre-treatment predictors of response to therapy, ensuring personalized earlier identification, improvement of patients' survival, complementing the epigenome project, implementing ncRNA measurements in liquid biopsy or tumor tissues, a step toward ncRNA precision.Our research group "Epigenetics studies in Cancer" came into the way, at the advanced biochemistry research lab (ABRL) at the Biochemistry Dept., Faculty of Pharmacy, Ain Shams University, second to extensively studied tumor-suppressor(s) and/or oncogenic gene(s), their SNPs, variants, and haplotypes [182][183][184][185][186][187] in different cancer types.
Sustainability: as an initiative for decoding carcinogenesis from a ncRNA perspective [188], our research group are currently measuring three LINC00511 SNPs variants haplotypes in BC, HCC, and CRC clinical cohorts.Second, their link to multidrug resistance, and/or ce-miRs [189].
Author Contributions: S.E. was responsible for data curation, original draft preparation, and rewriting, first figures and tables drafts.D.N. edited, rewrote, and reviewed the manuscript.E.F.S. edited, rewrote, and careful extensive manuscript reviewing.N.M.H. was responsible for conceptualization, supervision, in silico databases search, bioinformatics software mining, review editing, Implementing ncRNA measurements in blood liquid biopsy or tumor tissues will be a step toward ncRNA precision health and fulfilling both big pharma's intention as well as the Sustainable Development Goals' goal 3 (SDGs #3) (Better Health).
Strengths of the current review study: Our review article covered almost all lincRNAs and their role in various cancer types.LINC RNA constitute promising hit target(s) for the design of chemotherapy treatment for different types of cancer, a step toward ncRNA precision treatment.
Limitation: Pathways of some lincRNAs are still unknown or missing in different in silico/bioinformatic databases and this mandates further studies, in either clinical or in vitro experimental manners, to prove findings.Future Prospective: More future studies are required to link lincRNAs SNPs variants and haplotypes in different types of cancer, to help pick cancer cases in an early-stage or low-grade, identifying the pre-treatment predictors of response to therapy, ensuring personalized earlier identification, improvement of patients' survival, complementing the epigenome project, implementing ncRNA measurements in liquid biopsy or tumor tissues, a step toward ncRNA precision.Our research group "Epigenetics studies in Cancer" came into the way, at the advanced biochemistry research lab (ABRL) at the Biochemistry Dept., Faculty of Pharmacy, Ain Shams University, second to extensively studied tumorsuppressor(s) and/or oncogenic gene(s), their SNPs, variants, and haplotypes [182][183][184][185][186][187] in different cancer types.
Sustainability: as an initiative for decoding carcinogenesis from a ncRNA perspective [188], our research group are currently measuring three LINC00511 SNPs variants haplotypes in BC, HCC, and CRC clinical cohorts.Second, their link to multidrug resistance, and/or ce-miRs [189].

Figure 1 .
Figure 1.LincRNA role in chromatin remodeling: (a) cis-acting lincRNA influences the expression of genes on the same chromosome that are close to its transcriptional location.Contrarily, trans-acting lincRNA can regulate gene expression at distinct loci on a different chromosome, with the involvement of TFs.LincRNA role as competitive endogenous RNA (ceRNA); (b) lincRNA competes for miR and acts as micro-RNA sponge; consequently, miR will bind to lincRNA instead of binding to mRNA, leading to an increased mRNA expression after being free.[lincRNA: long intergenic non-coding RNA; ceRNA: competitive endogenous RNA; TF: transcription factor; miR: micro-RNA; mRNA: messenger ribonucleic acid].

Figure 1 .
Figure 1.LincRNA role in chromatin remodeling: (a) cis-acting lincRNA influences the expression of genes on the same chromosome that are close to its transcriptional location.Contrarily, transacting lincRNA can regulate gene expression at distinct loci on a different chromosome, with the involvement of TFs.LincRNA role as competitive endogenous RNA (ceRNA); (b) lincRNA competes for miR and acts as micro-RNA sponge; consequently, miR will bind to lincRNA instead of binding to mRNA, leading to an increased mRNA expression after being free.[lincRNA: long intergenic non-coding RNA; ceRNA: competitive endogenous RNA; TF: transcription factor; miR: micro-RNA; mRNA: messenger ribonucleic acid].
Different Cancer Types 3.1.LINC00511 In Silico Info (Accessed on 25 November 2022 and Revised on 31 March 2023)

Figure 2 .
Figure 2. Tissue gene expression graph for LINC00511 in some tissue sites.The expression graph of LINC00511 is represented in transcripts per million (TPM), as TPM is an accurate statistic used when calculating gene expression comparisons across samples.Here, Figure 2 represents the expression values of LINC00511 in non-diseased tissue sites samples collected from 1000 individuals for molecular assays.As shown, the highest expression of LINC00511 was found in the sun-exposed skin tissues from GTEx Analysis https://www.gtexportal.org/home/gene/LINC00511(accessed on 25 November 2022 and revised on 31 March 2023).

Figure 2 .
Figure 2. Tissue gene expression graph for LINC00511 in some tissue sites.The expression graph of LINC00511 is represented in transcripts per million (TPM), as TPM is an accurate statistic used when calculating gene expression comparisons across samples.Here, Figure 2 represents the expression values of LINC00511 in non-diseased tissue sites samples collected from 1000 individuals for molecular assays.As shown, the highest expression of LINC00511 was found in the sun-exposed skin tissues from GTEx Analysis https://www.gtexportal.org/home/gene/LINC00511(accessed on 25 November 2022 and revised on 31 March 2023).

4. 5 .
LncRNAs SNPs List in Hepatocellular Carcinoma, Their Role and Mechanism of Action (Table

Figure 3 .
Figure 3. LincRNAs different functions, abnormal expression, and SNPs association with various types of cancer (presented as the review conclusion summary and the graphical abstract.).Lin-cRNAs have different functions, such as having a role in chromatin remodeling and DNA damage repair, in addition to acting as ceRNA and protein scaffold.Abnormal expression of lincRNAs, for example LINC00511, and SNPs in lincRNAs are associated with various types of cancer such as BC, lung cancer, CRC, and other types of cancer.

Figure 3 .
Figure 3. LincRNAs different functions, abnormal expression, and SNPs association with various types of cancer (presented as the review conclusion summary and the graphical abstract.).LincRNAs have different functions, such as having a role in chromatin remodeling and DNA damage repair, in addition to acting as ceRNA and protein scaffold.Abnormal expression of lincRNAs, for example LINC00511, and SNPs in lincRNAs are associated with various types of cancer such as BC, lung cancer, CRC, and other types of cancer.

Table 2 .
LincRNAs list in different types of cancer, expression level if upregulated or downregulated, sponging-miR, mechanism(s) of action, role in cancer as oncogene or tumor suppressor.

Table 3 .
LINC00511 role in different types of cancer, expression level if upregulated or downregulated, sponging-miR, mechanism of action, role in cancer as oncogene or tumor suppressor.

Table 4 .
LncRNAs SNPs lists in Breast Cancer (BC), their mechanism of action and role in BC.

Table 5 .
LncRNAs SNPs list in lung cancer, their mechanism of action and role in lung cancer..3.LncRNAs SNPs List in Colorectal Cancer (CRC), Their Role and Mechanism of Action (Table 4

Table 6 .
LncRNA SNPs list in Colorectal Cancer (CRC), their mechanism of action and role in CRC.

Table 6 .
Cont. .4.LncRNAs SNPs List in Pancreatic Cancer, Their Role and Mechanism of Action (Table7) 4

Table 7 .
LncRNAs SNPs list in pancreatic cancer, their mechanism of action and role in pancreatic cancer.

Table 8 .
LncRNAs SNPs list in HCC, their mechanism of action and role in HCC.
tables and figures creation, and careful extensive manuscript rewriting, reviewing from submission till acceptance.All authors approved the authorship submitted.All authors have read and agreed to the published version of the manuscript.