Long non-coding RNAs (lncRNAs), also known as competing endogenous RNAs (ceRNAs) [27], 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]. According to GENCODE, more than 56,000 lncRNA transcripts in almost 19,000 genes have been identified in humans [30]. Recent evidence suggests that lncRNAs are implicated in several cancer progression mechanisms including proliferation [31,32], differentiation [33,34], autophagy [35,36], epithelial–mesenchymal transition (EMT) [37], invasion [38,39,40], and metastasis [41,42]. LncRNAs are often found as modulators of signaling cascades at the epigenetic, transcriptional, posttranscriptional, translational, or posttranslational levels [43]. 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]. 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].

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]. Additionally, covalently closed circular RNAs (circRNAs) are produced by the back splicing of exons, requiring spliceosomal machinery for their biogenesis [47].

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]. Some lncRNAs function as signals to regulate the initiation, elongation, or termination of actions by transcription factors [51]. Other lncRNAs function as decoys by binding to transcription protein complexes to deviate from their target DNA [50]. 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].

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]; similarly, lncRNA H19 overexpression prevented glucose-induced endMT in human retinal endothelial cells [54]. 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]; Ye et al. [56] 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]. 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]; 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], 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]. For instance, lncRNA HOXC-AS3 was found to mediate the oncogenesis of gastric cancer by the activation of abnormal histone modification [61]; in a similar fashion, Su et al. [62] 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]. 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 YAP^S127 phosphorylation [64].

3. Linc-ROR in Disease