A relatively well-understood multistep process enables mutation-bearing cells to form primary tumours, which later use the circulation system to colonize new locations and form metastases. However, in which way the emerging abundance of different non-coding RNAs supports tumour progression is poorly understood. Here, we review new lines of evidence linking long and short types of non-coding RNAs to signalling pathways activated in the course of cancer progression by growth factors and by the tumour micro-environment. Resolving the new dimension of non-coding RNAs in oncogenesis will probably translate to earlier detection of cancer and improved therapeutic strategies.

Introduction

While studying chemical carcinogenesis in the 1940s and examining the somatic mutation theory of cancer, Berenblum and Shubik [1] proposed a three-stage model of cancer development, namely initiation, promotion and latency/progression. Realizing the pivotal roles of mutations affecting oncogenes and tumour suppressor genes, Fearon and Vogelstein [2] proposed, 40 years later, a model attributing progression of colorectal cancer to stochastic accumulation of 4–5 mutations. In its new dress, cancer progression is viewed as the outcome of parallel and branched evolutionary accumulation of low-frequency driver mutations, which create intratumour genetic heterogeneity [3]. The multiplicity of different subclonal populations of cells provides escape mechanisms in the face of pharmacological stress and also establishes the basis for subclonal selection occurring at new sites of metastasis. Interestingly, tumours may follow both microevolution and macroevolution, meaning major shifts in evolutionary trajectories, such as non-gradual, saltatory leaps driven by chromosomal rearrangements or genome doublings.

The surprising discovery, in recent years, that up to 90% of the human genome is subjected to pervasive transcription, although only <2% of the total genome encodes protein-coding genes, has placed non-coding RNAs in the limelight. As a result, we now understand that analyses of the ∼7000 small RNAs, ∼15,800 long non-coding RNAs (lncRNAs) and a slightly smaller number of pseudogenes (according to GENCODE v25, [4]) significantly change our view of developmental biology, genetics, pathology and many other disciplines of medicine and the life sciences (see Table 1). Cancer initiation/progression is not an exception. In addition to transfer RNAs and ribosomal RNAs, which are involved in the translation of messenger RNAs, several classes of long and short non-coding RNAs (ncRNAs) are involved in cancer. The involvement of ncRNAs in cancer is not surprising since human miRNA genes are often located in cancer-associated genomic regions or in fragile sites [5]. Likewise, recurrent alterations in cancers are consistently found in the so-called gene deserts [6]. Examples include the 2-Mb-long segment that contains the lncRNA gene PVT1. Importantly, amplification of PVT1 appears to be required for high MYC protein levels in 8q24-amplified human cancer cells [7]. Another example of an alteration of copy number involving an oncogene and a nearby lncRNA is the recently annotated lncRNA gene called SAMMSON, which is consistently co-amplified with MITF, a melanoma-specific oncogene located at 3p [8].

Table 1
Classes and functions of ncRNAs.
RNA type Length (nucleotides) Localization Structure Function Mechanisms of action Comments 
miRNAs [101,10221–24 nt Cytoplasm Derived from transcripts that fold back to form distinctive hairpin structures. Mediate gene suppression by targeted mRNA degradation and translation repression. The mature miRNA is loaded into the miRISC complex, which is directed to mRNAs by sequence complementarity binding. Their mechanism involves (i) cleavage of the mRNA strand, (ii) destabilization of mRNAs by poly(A) tail shortening or (iii) reduced translation efficiency. 
lncRNAs [103>2004 nt Nucleus and cytoplasm Diverse structures, often polyadenylated. Secondary structures might be important. Regulating transcription of coding and non-coding RNAs. Directing chromatin remodelling proteins to target loci, cis/trans regulation of transcription, control of mRNA splicing and translation, and modulation of microRNA functions. The definition of lncRNAs includes antisense RNAs, long intervening RNAs, pseudogenes, enhancer RNA and more. 
 circRNAs [77,104Variable Mostly in the cytoplasm Covalently closed circles formed by back splicing. Unknown, but rare functions might include sequestration of miRNAs and proteins, and regulation of mRNA splicing and miRNA transport. Unknown, but might involve sequence complementarity binding. Significantly more stable than linear RNAs. In general, their abundance reflects the levels of the respective linear transcripts. 
Small nucleolar RNAs (snoRNA) [105Mostly 60–300 nt. Nucleolus H/ACA box subtype: hairpin-hinge-hairpin-tail structure.
C/D box subtype: stem-box structure. 
Play an essential role in RNA biogenesis and guide post-transcriptional modifications of ribosomal RNAs, transfer RNA and snRNAs. Bind RNAs and proteins.
H/ACA box snoRNAs: pseudouridylation of RNA.
C/D box snoRNAs: methylation of RNA. 
Mostly encoded within introns; many orphan snoRNAs exist; some snoRNAs might have unexpected binding partners. 
Piwi-interacting RNAs (piRNAs) [106,10726–31 nt Nucleus and cytoplasm No clear secondary structure motifs. Display a bias for a 5′ uridine and a 3′-end 2′-O-methylation. Epigenetic and post-transcriptional silencing of transposons during the development of the embryo and germ cells. They may be involved in maternally derived epigenetic effects. Interact with Piwi proteins of the Argonaute family. Have a role in RNA silencing via the formation of RISCs. Directing DNA methylation. piRNAs are found in clusters throughout the genome. The majority is antisense to transposon sequences, and act in the germ line. 
snRNAs [108,109∼150 nt Splicing speckles and Cajal bodies Exported through nuclear pores, form a 3′ stem-loop structure and undergo hypermethylation of the 5′ cap. Control spliceosomal activity by base pairing with the hnRNA. Might regulate telomere maintenance and undergo 2′-O-methylation and pseudouridylations. Assemble into ribonucleoproteins. Regulate processing of pre-messenger RNA in the nucleus. Transcribed by either RNA polymerase II or RNA polymerase III; snoRNAs are a subclass of snRNAs. 
eRNAs [110,11150–>2,000 nt Nucleus No clear secondary structure. Regulating transcription. There is still no consensus on the functional significance of eRNAs. Are thought to act as scaffolds that facilitate the bringing together of distal enhancers with promoters. Transcribed from enhancer regions. Subdivided into 1D (unidirectional) and 2D (bidirectional) eRNAs, which differ also in size and polyadenylation state. 
siRNAs [112,11320–25 nt with a 2 nt overhang at 3′ end Cytoplasm Endogenous, short (25 nt or less) double-stranded RNA fragments produced by Dicer. Mediate gene suppression of viral and endogenous transcripts. The siRNA guide strand directs RISC to perfectly complementary RNA targets, which are then degraded by the Piwi domain of the Ago protein. Protect from viruses. Secondary siRNAs exist in worms. Used as a tool to turn off target gene expression for therapy. 
RNA type Length (nucleotides) Localization Structure Function Mechanisms of action Comments 
miRNAs [101,10221–24 nt Cytoplasm Derived from transcripts that fold back to form distinctive hairpin structures. Mediate gene suppression by targeted mRNA degradation and translation repression. The mature miRNA is loaded into the miRISC complex, which is directed to mRNAs by sequence complementarity binding. Their mechanism involves (i) cleavage of the mRNA strand, (ii) destabilization of mRNAs by poly(A) tail shortening or (iii) reduced translation efficiency. 
lncRNAs [103>2004 nt Nucleus and cytoplasm Diverse structures, often polyadenylated. Secondary structures might be important. Regulating transcription of coding and non-coding RNAs. Directing chromatin remodelling proteins to target loci, cis/trans regulation of transcription, control of mRNA splicing and translation, and modulation of microRNA functions. The definition of lncRNAs includes antisense RNAs, long intervening RNAs, pseudogenes, enhancer RNA and more. 
 circRNAs [77,104Variable Mostly in the cytoplasm Covalently closed circles formed by back splicing. Unknown, but rare functions might include sequestration of miRNAs and proteins, and regulation of mRNA splicing and miRNA transport. Unknown, but might involve sequence complementarity binding. Significantly more stable than linear RNAs. In general, their abundance reflects the levels of the respective linear transcripts. 
Small nucleolar RNAs (snoRNA) [105Mostly 60–300 nt. Nucleolus H/ACA box subtype: hairpin-hinge-hairpin-tail structure.
C/D box subtype: stem-box structure. 
Play an essential role in RNA biogenesis and guide post-transcriptional modifications of ribosomal RNAs, transfer RNA and snRNAs. Bind RNAs and proteins.
H/ACA box snoRNAs: pseudouridylation of RNA.
C/D box snoRNAs: methylation of RNA. 
Mostly encoded within introns; many orphan snoRNAs exist; some snoRNAs might have unexpected binding partners. 
Piwi-interacting RNAs (piRNAs) [106,10726–31 nt Nucleus and cytoplasm No clear secondary structure motifs. Display a bias for a 5′ uridine and a 3′-end 2′-O-methylation. Epigenetic and post-transcriptional silencing of transposons during the development of the embryo and germ cells. They may be involved in maternally derived epigenetic effects. Interact with Piwi proteins of the Argonaute family. Have a role in RNA silencing via the formation of RISCs. Directing DNA methylation. piRNAs are found in clusters throughout the genome. The majority is antisense to transposon sequences, and act in the germ line. 
snRNAs [108,109∼150 nt Splicing speckles and Cajal bodies Exported through nuclear pores, form a 3′ stem-loop structure and undergo hypermethylation of the 5′ cap. Control spliceosomal activity by base pairing with the hnRNA. Might regulate telomere maintenance and undergo 2′-O-methylation and pseudouridylations. Assemble into ribonucleoproteins. Regulate processing of pre-messenger RNA in the nucleus. Transcribed by either RNA polymerase II or RNA polymerase III; snoRNAs are a subclass of snRNAs. 
eRNAs [110,11150–>2,000 nt Nucleus No clear secondary structure. Regulating transcription. There is still no consensus on the functional significance of eRNAs. Are thought to act as scaffolds that facilitate the bringing together of distal enhancers with promoters. Transcribed from enhancer regions. Subdivided into 1D (unidirectional) and 2D (bidirectional) eRNAs, which differ also in size and polyadenylation state. 
siRNAs [112,11320–25 nt with a 2 nt overhang at 3′ end Cytoplasm Endogenous, short (25 nt or less) double-stranded RNA fragments produced by Dicer. Mediate gene suppression of viral and endogenous transcripts. The siRNA guide strand directs RISC to perfectly complementary RNA targets, which are then degraded by the Piwi domain of the Ago protein. Protect from viruses. Secondary siRNAs exist in worms. Used as a tool to turn off target gene expression for therapy. 

The table lists the major classes of ncRNAs, along with their structural and functional features. In general, non-coding transcripts might be divided into two classes on the basis of their size. The long transcripts can reach 100 kb, and their functions are the most diverse. This class includes rRNAs, long or large intergenic ncRNAs, aRNAs, circRNAs and PROMPTs. Unlike the functions of lncRNAs, which remain unknown in the majority of cases, the small non-coding RNAs have been relatively well characterized. This class includes, in addition to tRNAs and 5S/5.8S rRNAs, miRNAs and siRNAs, which are implicated in RNA silencing; snoRNAs and snRNAs, which are implicated in covalent modification of rRNAs and in mRNA splicing, respectively; and Piwi-interacting RNAs and enhancer RNAs, which are involved in transposon repression and transcription regulation, respectively. Abbreviations: Ago, argonaute; aRNAs, antisense RNAs; circRNAs, circular RNAs; eRNAs, enhancer RNAs; hnRNA, heteronuclear RNA; lncRNAs, long non-coding RNAs; miRISC, microRNA-induced silencing complex; miRNAs, microRNAs; PROMPTs, promoter-associated long RNAs; RISC, RNA-induced silencing complex; rRNAs, ribosomal RNAs; siRNAs, small-interfering RNAs; snoRNAs, small nucleolar RNAs; snRNAs, small nuclear RNAs; ssRNA, single-strand RNA; tRNAs, transfer RNAs.

As will be expanded on below, recent studies uncovered the involvement of ncRNAs in various types of tumours and propose that different ncRNAs co-operate with oncogenic mutations, as well as with the tumour micro-environment and its messengers (i.e. various growth factors and cytokines) to advance cancer progression [9,10]. Of particular interest are genetic studies that utilize knockout models of ncRNAs and thus address the mechanisms by which ncRNAs contribute to tumorigenesis [1114]. Apart from the cell autonomous functions of ncRNAs, recent lines of evidence indicate that cells communicate with their neighbouring cells through the secretion of exosomes and their payload, including ncRNAs. Thus, ncRNA-loaded exosomes have been shown to be capable of altering the tumour stroma, affecting the development of the pre-metastatic niche and stimulating tumour angiogenesis [12]. Non-coding RNAs further influence the tumour micro-environment by regulating the ability of the tumour to attract cancer-associated fibroblasts [13] and cells of the immune system, which support tumour growth [14]. In this review, we describe the emerging roles of ncRNAs, especially lncRNAs, in cancer progression, with an emphasis on the tumour micro-environment, growth factors and signal transduction pathways. The reader is directed to another review dealing with the roles played by ncRNAs in cancer progression [10].

Involvement of ncRNAs in distinct stages of cancer progression

Tumour initiation

Most human tumours are initiated by oncogenic mutations induced by physical or chemical factors, but a small fraction is attributable to germ-line (inherited) mutations (see Figure 1). It is estimated that viral and other infections contribute to 15–20% of all human cancers, partly by inducing oncogenic mutations. Some ncRNAs can promote virus replication and allow escape from cytosolic surveillance. For example, the lncRNA HULC (hepatocellular carcinoma up-regulated long non-coding RNA) is up-regulated by the hepatitis B virus (HBV), which along with hepatitis C virus (HCV) accounts for 80% of liver cancer. In hepatocellular carcinoma, up-regulated HULC results in reduced expression of a tumour suppressor gene, the cyclin-dependent kinase inhibitor p18 [15]. HBV and HCV cause liver cancer because of massive inflammation and fibrosis. Chronic inflammation is characteristic to other diseases, including colorectal carcinoma (CRC), but daily use of aspirin (acetylsalicylic acid), a common anti-inflammatory medication, markedly reduces the risk of CRC. Guo et al. [16] have shown that aspirin can suppress tumour development through transcriptional induction of a specific lncRNA, OLA1P2 (obg-like ATPase 1 pseudogene 2), which blocks phosphorylated STAT3 (signal transducer and activator of transcription 3) signalling by directly binding and preventing homodimerization of STAT3. Similarly, specific microRNAs (miRNAs) target molecules involved in signalling pathways regulating inflammation, for instance, the nuclear factor κB (NF-κB) and the transforming growth factor β (TGF-β) pathways (reviewed in ref. [17]). Subtler mechanisms implicating ncRNAs in tumour initiation might involve altered miRNA-binding sites [18], defective miRNA biogenesis [19] and cancer predisposing mutations within miRNAs [20]. For example, the Let-7 miRNA binds with the 3′-untranslated region of KRAS, such that polymorphism of the site might predict survival time of CRC patients, but the results are still conflicting [18]. An inhibitor of Let-7 biogenesis, LIN28, is highly expressed in neuroblastoma, leading to diminished tumour suppression by the miRNA [19]. Similarly to the RAS–Let-7 pair, miR-31 directly targets transcripts corresponding to the androgen receptor (AR), but a mutation disrupting the miR-31-binding site in the AR gene might lead to overexpression of AR in prostate cancer [21]. Finally, the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a lncRNA up-regulated in metastatic carcinoma cells, is involved in both transcriptional and post-transcriptional regulation of gene expression [22]. OncodriveFML, a method that surveys patterns of somatic mutations in both coding and non-coding regions and across different tumours, uncovered high accumulation of somatic mutations within MALAT1, but their functional significance remains unclear [23].

Roles for ncRNAs in the stepwise progression of cancer.

Figure 1.
Roles for ncRNAs in the stepwise progression of cancer.

The process leading to malignancy might be instigated by a somatic mutation, chronic inflammation or viral infection, all conferring considerable survival and growth advantage to the initiated cell. Several ncRNAs assist cancer initiation [see step 1 and the indicated examples]. LncRNAs like ANRIL and miRNAs like miR-21 can act as oncogenes and support proliferation of initiated clones [step 2]. However, several other ncRNAs (e.g. MEG3 and Let-7) may act as tumour suppressors and inhibit subsequent steps of cancer progression. Invasion [step 3] refers to migration and penetration by cancer cells into neighbouring tissues. This process involves loss of epithelial polarity, acquisition of a motile, mesenchymal-like phenotype and secretion of proteases. Both lncRNAs (e.g. HOTAIR, HOTTIP, LIMT and others; [81,92]) and miRNAs (e.g. the miR-200 family and others; [93,94]) control this critical phase of tumour development by regulating EMT. Cancer cells enter (intravasation) lymphatic and blood vessels [step 4] and some survive the circulation stress [step 5]. Extravasation [step 6] refers to their exit and colonization of distant organs [step 7]. Formation of micro-metastases is inhibited by ncRNAs, like miR-126, which inhibits recruitment of stromal cells into the tumour micro-environment, and miR-205, which decreases the expression of oncogenic prospero homeobox1 (PROX1) [95]. Micro-metastases usually display sensitivity to chemotherapy and radiotherapy. Notably, up-regulation of several lncRNAs, for example HOTAIR, LINP1, lncRNA-ATB and GAS5 [96], is associated with resistance to chemo-, radio-, immune- and endocrine therapy, respectively. Several miRNAs, such as miR-95 and others [97100], modulate sensitivity to treatment. This propels outgrowth of resistant clones [step 8]. Angiogenesis is essential for the establishment of large primary and secondary tumours. LncRNAs like MALAT1 indirectly up-regulate the expression of angiogenic growth factors, such as the FGF2, and facilitate sprouting of existing vessels [step 9]. Additional ncRNAs, such as TUG1 and the miR-17–92 cluster, support angiogenesis. In the final phase, relatively large metastases populate a set of target organs characteristic of the primary tumour [step 10].

Figure 1.
Roles for ncRNAs in the stepwise progression of cancer.

The process leading to malignancy might be instigated by a somatic mutation, chronic inflammation or viral infection, all conferring considerable survival and growth advantage to the initiated cell. Several ncRNAs assist cancer initiation [see step 1 and the indicated examples]. LncRNAs like ANRIL and miRNAs like miR-21 can act as oncogenes and support proliferation of initiated clones [step 2]. However, several other ncRNAs (e.g. MEG3 and Let-7) may act as tumour suppressors and inhibit subsequent steps of cancer progression. Invasion [step 3] refers to migration and penetration by cancer cells into neighbouring tissues. This process involves loss of epithelial polarity, acquisition of a motile, mesenchymal-like phenotype and secretion of proteases. Both lncRNAs (e.g. HOTAIR, HOTTIP, LIMT and others; [81,92]) and miRNAs (e.g. the miR-200 family and others; [93,94]) control this critical phase of tumour development by regulating EMT. Cancer cells enter (intravasation) lymphatic and blood vessels [step 4] and some survive the circulation stress [step 5]. Extravasation [step 6] refers to their exit and colonization of distant organs [step 7]. Formation of micro-metastases is inhibited by ncRNAs, like miR-126, which inhibits recruitment of stromal cells into the tumour micro-environment, and miR-205, which decreases the expression of oncogenic prospero homeobox1 (PROX1) [95]. Micro-metastases usually display sensitivity to chemotherapy and radiotherapy. Notably, up-regulation of several lncRNAs, for example HOTAIR, LINP1, lncRNA-ATB and GAS5 [96], is associated with resistance to chemo-, radio-, immune- and endocrine therapy, respectively. Several miRNAs, such as miR-95 and others [97100], modulate sensitivity to treatment. This propels outgrowth of resistant clones [step 8]. Angiogenesis is essential for the establishment of large primary and secondary tumours. LncRNAs like MALAT1 indirectly up-regulate the expression of angiogenic growth factors, such as the FGF2, and facilitate sprouting of existing vessels [step 9]. Additional ncRNAs, such as TUG1 and the miR-17–92 cluster, support angiogenesis. In the final phase, relatively large metastases populate a set of target organs characteristic of the primary tumour [step 10].

Primary tumour growth

Following initiation, tumour growth depends on avoidance of both differentiation and cell death (apoptosis), rapid rates of cell proliferation and the establishment of a new vascular system (angiogenesis) within nascent tumours. Overexpression of a novel lncRNA, the mitosis-associated long intergenic non-coding RNA1, MA-linc1, accelerates cancer cell proliferation by regulating the G2/M phase of the cell cycle. This effect is mediated by cis repression of a cell cycle regulator, called Purα, which induces cell cycle arrest [24]. In an alternative mechanism, overexpression of the lncRNA-ANRIL (antisense ncRNA in the INK4 locus) down-regulates the expression of several tumour suppressor genes, namely p14, p15 and p16, by recruiting members of the polycomb repressive complexes PRC2 (the EZH2 subunit) and PRC1 (the CBX7 subunit), thereby promoting cell cycle progression in prostate and ovarian tumours [2528]. ANRIL also inhibits apoptosis by up-regulating expression of BCL2 [29], an important inhibitor of apoptosis. Another mechanism regulating BCL2 involves the nuclear lncRNA named lnc-ASNR (apoptosis-suppressing non-coding RNA) [30]. Interestingly, lnc-ASNR displays significant up-regulation in tumours and binds with the RNA-binding protein named AUF1 [ARE/poly (U)-binding/degradation factor 1], known to promote degradation of BCL2's mRNA. By inducing nuclear retention of AUF1, lnc-ASNR stabilizes BCL2 in the cytoplasm and decreases cell death. miRNAs also fulfil critical roles in initial phases of tumour development. For example, an important miRNA regulating cancer cell proliferation is miR-155, which suppresses the expression of RIPK1 (an apoptosis-inducing gene), which regulates the BCL6/cyclin D2 axis and targets FBXW7 (which encodes an adaptor of an E3 ubiquitin ligase complex that degrades several oncoproteins) [3133].

Tumour angiogenesis

During angiogenesis, quiescent endothelial cells lining the inner face of blood vessels start proliferating and form sprouting branches. The new branches provide oxygen and nutrients, as well as remove toxic metabolites, thereby facilitating tumour growth beyond the diffusion-limited size of a few millimetres. The miR-17–92 cluster (consisting of miR-17, miR-18a, miR-19a, miR-20a, miR-19b and miR-92a) plays a direct role in increasing tumour angiogenesis. These pro-angiogenic functions are mediated by repression of anti-angiogenic (e.g. TSP-1 and CTGF) and other molecules in tumour cells [34]. Furthermore, the vascular endothelial growth factor (VEGF) instigates a positive feedback loop by stimulating the ERK/ELK1 cascade, which propels transcriptional activation of the miR-17-92 cluster [35]. Similarly, transcriptional induction of MALAT1 under hypoxic conditions promotes angiogenesis, and manipulation of the abundance of MALAT1 indirectly regulates the expression of another angiogenic growth factor, the fibroblast growth factor 2 (FGF2) [36]. Yet another lncRNA, taurine up-regulated 1 (TUG1), induces angiogenesis in glioblastoma by down-regulating miR-299, a suppressor of VEGF-A expression [37].

Invasion and metastasis

Local cell movements and invasion into adjacent tissues, along with penetration through the vasculature, initiate dissemination of malignant cells. The transition from polarized epithelial cells to motile mesenchymal-like cells, which are often associated with degradation of the underlying basement membrane, is best described by the epithelial-to-mesenchymal transition (EMT) [38]. EMT and metastasis are suppressed by the miR-200 family, a group of miRNAs capable of down-regulating expression of the EMT-inducing transcription factors called ZEB1 and ZEB2 [39,40]. This regulatory switch is well controlled by growth factor signalling: for instance, EGF stimulation leads to down-regulation of miR-200s [41], whereas SPRY2, an inhibitor of receptor tyrosine kinase signals, up-regulates ZEB1 expression by repressing miR-200 [42]. In the last few years, we learned that several lncRNAs regulate EMT by acting as molecular sponges of the miR-200 family. Examples include HULC, which sponges miR-200a-3p in liver cancer [43], and miR-204 sponging by NEAT1 in nasopharyngeal carcinoma [44]. H19, an imprinted lncRNA, follows the same line and promotes metastasis of osteosarcomas through up-regulation of ZEB1 and ZEB2 [45]. Interestingly, expression of ZEB1 and ZEB2 is also regulated by the antisense transcripts ZEB1-AS1 and ZEB2-AS1, located in physical proximity to the ZEBs' coding genes [46,47]. Both non-coding transcripts influence up-regulation of the two ZEB proteins to facilitate EMT. It is increasingly becoming clear that metabolic reprograming plays a critical role in metastasis: metabolic reprograming is linked to the activation of oncogenes and/or suppression of tumour suppressor genes, which are further regulated by ncRNAs, especially miRNAs, that play important roles in the interplay between oncogenic processes and metabolic reprograming [48].

Resistance to cytotoxic stress

Chemotherapy and radiation therapy are the most common cytotoxic treatments of cancer. Over time, cancer cells might develop resistance to these and other forms of cytotoxic stress, by means of activating pro-survival pathways, for example by secreting survival factors, or by activating DNA damage repair mechanisms. The DNA damage response involves activation of p53-dependent signalling pathways, which have been shown to induce expression of the lncRNA DINO (damage-induced non-coding), which activates damage signalling and cell cycle arrest [49]. An additional p53-regulated lncRNA, LINP1, is overexpressed in triple-negative breast tumours. LINP1 enhances repair of DNA double-strand breaks by acting as a scaffold for Ku80 and DNA-PKcs, key non-homologous end joining (NHEJ) proteins [50], and its knockdown results in increased sensitivity to radiotherapy. Neat1 is another p53-regulated lncRNA whose knockdown increases the sensitivity of tumour cells to chemotherapy. Neat1 was shown to promote signalling by ATR (ATM- and RAD3-related) in response to replication stress and thus attenuate oncogene-dependent activation of p53 [11]. The lncRNA, called HOTAIR, activates a pro-survival pathway, WNT/β-catenin, in ovarian cancer, thereby conferring resistance to cisplatin [51]. Another mechanism employs the cell cycle machinery: p21 (WAF1), an inhibitor of cyclin-dependent kinases, causes cell cycle arrest after DNA damage, but HOTAIR down-regulates p21 expression, thereby instigating chemoresistance [52]. Interestingly, since 2000, several monoclonal antibodies against surface antigens are emerging as agents, which sensitize tumour cells to chemo- or radiotherapy. For example, trastuzumab, a humanized antibody targeting the HER2 oncoprotein, is used in combination with chemotherapy to treat breast and gastric cancer. Interestingly, the lncRNA, called lncRNA-ATB (activated by TGF-β), promotes resistance to trastuzumab by inducing EMT in breast cancer cells. Resistance is achieved due to competitive binding of lncRNA-ATB to miR-200c, which drives up-regulation of ZEB1 and induces EMT [53].

Growth factor signalling and ncRNAs controlling cancer progression

Growth factors are widely involved in the multiple step process that transforms an initiated cancer cell into a metastatic tumour containing a variety of branching clones. As part of the tumorigenic process, growth factors act as mitogens, survival factors, motility inducers or angiogenesis promoters [54]. Furthermore, oncogenic mutations are capable of generating constitutive growth factor signals, thus mimicking prolonged activation of specific steps of the growth factor signalling pathway [55]. Thus, productive signalling by growth factor receptors bearing tyrosine-specific kinase activity requires receptor dimerization, which stimulates the intrinsic kinase function [56] and, accordingly, certain oncogenic mutations stabilize receptor dimers or otherwise activate the enzymatic receptor's function. Similarly, downstream effectors of receptor tyrosine kinases are transiently activated following growth factor stimulation, but certain oncogenic mutations constantly activate effector molecules, such as RAS and RAF. A cross-talk between growth factor signalling and ncRNAs occupies an increasing space in the field of tumour progression. However, while the biological roles for miRNAs and their general mode of action in tumorigenesis are quite known [57], the mechanisms by which lncRNAs regulate growth factor signals and tumour progression are diverse and less understood. Below and in Figure 2, we focus on lncRNAs embedded within signal transduction networks and elaborate on the various signalling steps they harness in order to regulate tumour progression.

ncRNAs are embedded within growth factor signalling networks.

Figure 2.
ncRNAs are embedded within growth factor signalling networks.

Ligand binding to membrane receptors instigates a cascade of protein–protein, protein–RNA and RNA–RNA interactions, which regulate signals that reach the nucleus and mediate specific cellular outcomes. Several reported mechanisms enable miRNAs and lncRNAs to regulate the following aspects of signal transduction: (1) synthesis and secretion of ligands (e.g. lncRNA-ATB regulating secretion of IL-11 by binding to its mRNA and stabilizing it), (2) transcription of receptors (e.g. CAR10 regulating EGFR expression), (3) availability of receptor mRNAs (e.g. H19 regulating the insulin-like growth factor 1 receptor, IGFR1, by means of the miRNA let-7) and (4) receptor stabilization or destabilization (e.g. H19 and miR-675 regulating EGFR by means of CBL). LncRNAs further facilitate the recruitment of protein kinases to the receptors, thus enabling transduction of signals beyond the membrane (e.g. LINK-A regulating GPNMB and EGFR signalling via direct binding to BRK and LRRK2). Additionally, lncRNAs might regulate activation of key effectors of specific signalling pathways, such as the PI3K/AKT/PTEN pathway, in which PTEN abundance is positively regulated by two lncRNAs, MEG3 and the pseudogene PTENP1, which sponge specific inhibitory miRNAs. A widespread lncRNA-mediated modulation of miRNA function is further exemplified by the regulation of ZEB proteins by miRNAs of the miR-200 family. Three individual lncRNAs (MALAT1, lncRNA-ATB and linc-ROR) have been shown to alleviate the targeting of ZEB1 and ZEB2 by miRNAs of the miR-200 family, thus contributing to EMT and metastasis formation. ZEB2 is also positively regulated by an antisense lncRNA, ZEB2-AS1 (also named ZEB2NAT). Growth factor signals initiated at the plasma membrane reach the nucleus and modulate expression of many lncRNAs, including LIMT and HOTAIR, which oppositely regulate metastasis of breast cancer. In the case of LIMT, a decrease in levels of this lncRNA is preceded by a change in histone acetylation of the respective promoter/enhancer (H3K27Ac; denoted by a circle), which corresponds to reduced transcription.

Figure 2.
ncRNAs are embedded within growth factor signalling networks.

Ligand binding to membrane receptors instigates a cascade of protein–protein, protein–RNA and RNA–RNA interactions, which regulate signals that reach the nucleus and mediate specific cellular outcomes. Several reported mechanisms enable miRNAs and lncRNAs to regulate the following aspects of signal transduction: (1) synthesis and secretion of ligands (e.g. lncRNA-ATB regulating secretion of IL-11 by binding to its mRNA and stabilizing it), (2) transcription of receptors (e.g. CAR10 regulating EGFR expression), (3) availability of receptor mRNAs (e.g. H19 regulating the insulin-like growth factor 1 receptor, IGFR1, by means of the miRNA let-7) and (4) receptor stabilization or destabilization (e.g. H19 and miR-675 regulating EGFR by means of CBL). LncRNAs further facilitate the recruitment of protein kinases to the receptors, thus enabling transduction of signals beyond the membrane (e.g. LINK-A regulating GPNMB and EGFR signalling via direct binding to BRK and LRRK2). Additionally, lncRNAs might regulate activation of key effectors of specific signalling pathways, such as the PI3K/AKT/PTEN pathway, in which PTEN abundance is positively regulated by two lncRNAs, MEG3 and the pseudogene PTENP1, which sponge specific inhibitory miRNAs. A widespread lncRNA-mediated modulation of miRNA function is further exemplified by the regulation of ZEB proteins by miRNAs of the miR-200 family. Three individual lncRNAs (MALAT1, lncRNA-ATB and linc-ROR) have been shown to alleviate the targeting of ZEB1 and ZEB2 by miRNAs of the miR-200 family, thus contributing to EMT and metastasis formation. ZEB2 is also positively regulated by an antisense lncRNA, ZEB2-AS1 (also named ZEB2NAT). Growth factor signals initiated at the plasma membrane reach the nucleus and modulate expression of many lncRNAs, including LIMT and HOTAIR, which oppositely regulate metastasis of breast cancer. In the case of LIMT, a decrease in levels of this lncRNA is preceded by a change in histone acetylation of the respective promoter/enhancer (H3K27Ac; denoted by a circle), which corresponds to reduced transcription.

Regulation of receptor synthesis and degradation

An important element of all signalling pathways is availability of the membrane receptors, which is dictated by production rates and kinetics of degradation. CAR10, a lncRNA, up-regulates the transcription rate of the epidermal growth factor receptor (EGFR) by directly binding with a specific transcription factor, the Y-box-binding protein 1 (YB-1), and thus stabilizing it. Concordantly, knockdown of CAR10 inhibits cell proliferation in vitro and tumour growth in vivo by down-regulating EGFR signalling [58]. This mechanism is relevant to lung tumours, in which CAR10 is overexpressed. H19 is an additional lncRNA regulating receptor abundance. H19 acts as a molecular sponge that reduces bioavailability of let-7, a miRNA capable of reducing the abundance of the transcript encoding the insulin-like growth factor-1 receptor (IGFR1) [59]. This mechanism is relevant to the accelerated rates of proliferation often displayed by endometrial stromal cells. H19 is also involved in the regulation of receptor degradation in metastatic breast cancer cells. This lncRNA is post-transcriptionally processed to produce functional miR-675 molecules [60]. Vennin et al. [61] found that H19-derived miR-675 down-regulates CBL, an E3 ubiquitin–protein ligase that ubiquitinates EGFR and leads to subsequent receptor degradation in lysosomes [62].

Recruitment of downstream effectors

Once encountering a ligand growth factor, the respective receptor undergoes dimerization and autophosphorylation, which permits recruitment of cytoplasmic proteins essential for signal propagation. The most immediate interactions are those occurring between the receptor itself and intracellular effectors, such as non-receptor protein kinases. Breast tumour kinase (BRK) is such a putative oncoprotein that is absent from normal breast tissues, but exists in a large fraction of breast tumours [63]. A cytosolic lncRNA, called LINK-A, was recently found to facilitate recruitment of BRK to a complex formed by ligand-activated EGFR and another transmembrane glycoprotein, GPNMB [64]. Furthermore, the cytoplasmic interaction with LINK-A was found to be essential for recruitment of both BRK and a second kinase, LRRK2, by directly binding to these enzymes and enabling subsequent phosphorylation of hypoxia-inducible factor 1-α (HIF1α). Notably, phosphorylation of HIF1α, a transcription factor implicated in cancer progression [65], promotes metabolic reprogramming and tumorigenesis [64].

Regulation of key signalling pathways

Once activated, receptor tyrosine kinases simultaneously stimulate several signalling pathways, thereby accomplishing rapid effects on cellular structure, survival and metabolism. One important linear pathway of protein kinases comprises the phosphoinositide 3-kinase (PI3K), the downstream kinase AKT and PTEN (phosphatase and tensin homologue), which curtails signals [66]. This pathway is unique in that every major node is frequently mutated in a wide variety of solid tumours. PTEN is a tumour suppressor lipid phosphatase. By dephosphorylating a lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], PTEN negates the action of PI3K and restricts activation of AKT. Recently, it was shown that the lncRNA, called MEG3 (maternally expressed gene 3), modulates the PI3K/AKT/PTEN pathway by abolishing the inhibitory effects of miR-1297 on PTEN. The authors proposed that MEG3 competitively binds with miR-1297, thus increasing PTEN protein levels and restricting growth of testicular germ cell tumours [67]. Yet another RNA-based mechanism that positively controls PTEN expression is exerted by its pseudogene, namely PTENP1, which itself cannot be translated into a protein due to a missense mutation of its initiator methionine codon [68]. Interestingly, high homology exists between PTEN and PTENP1, which includes the existence of similar miRNA-binding sites on both transcripts. Accordingly, PTENP1 was shown to act as a decoy that binds with both miR-19b and miR-20a, thereby liberates PTEN molecules from inhibitory effects [68]. The miRNA sponging effects of PTENP1 and MEG3 exemplify a general RNA–RNA interaction mechanism in which RNA transcripts that contain miRNA-binding sites can regulate each other by competing specifically for shared miRNAs, thus acting as competing endogenous RNAs [69].

Regulation of transcription networks

Many signalling pathways stimulated by growth factors culminate in the nucleus, where they regulate transcriptional events. One of the best characterized pathways is the aforementioned EMT and its reciprocal process, mesenchymal-to-epithelial transition [20,39,40]. Highly polarized and quiescent epithelial tissues express high levels of E-cadherin, a cell–cell adhesion molecule, which is transcriptionally repressed by the zinc finger proteins SNAIL, ZEB1 and ZEB2. Expression of ZEB proteins is kept at low levels, partly due to targeting by members of the miR-200 family [39,40]. Upon activation of cells by growth factors, such as FGF, TGF-β or EGF, expression of these miRNAs is reduced, leading to increased abundance of ZEB1 and ZEB2, followed by down-regulation of E-cadherin. Subsequently, ZEB proteins specifically bind to sites on the promoters of miR-200 family members and repress their transcription, thus perpetuating the mesenchymal phenotype. Interestingly, the interplay between members of the miR-200 family and the transcripts encoding ZEBs is regulated by many lncRNAs, including MALAT1, lncRNA-ATB and linc-ROR (regulator of reprogramming). For instance, MALAT1 is induced by TGF-β in bladder cancer cells [70]. Mechanistically, MALAT1 was found to promote proliferation and metastasis of renal carcinoma cells through its sponging activity of miR-200 family members [71]. Similarly, linc-ROR, which is highly expressed in primary breast cancer specimens, positively controls metastasis by sponging miR-205, a regulator of ZEB1 and ZEB2 [72,73]. A similar sponging effect was reported for lncRNA-ATB, which regulates invasion and metastasis [74] by a dual mechanism involving (i) release of ZEBs' transcripts from targeting of miR-200 miRNAs and (ii) direct binding to and stabilization of the mRNA encoding interleukin 11 (IL-11), correlating to higher levels of secreted IL-11, which activates STAT3 signalling and contributes to the metastatic process.

Regulation of ncRNAs by signal transduction pathways

In addition to the above-described mechanisms allowing ncRNAs to regulate signal transduction pathways, several reciprocal routes enable growth factors of the WNT, TGF-β and EGF families to control ncRNAs involved in cancer progression. For example, growth factors of the EGF family can rapidly down-regulate a set of 23 miRNAs targeting a set of immediate early genes, such as FOS and JUN, as their target transcripts [75]. In line with roles as suppressors of growth factor signalling, the abundance of this subset of miRNAs is decreased in breast and brain tumours driven by EGFR signalling. Interestingly, another class of ncRNAs, the circular RNAs, show no alterations following stimulation of cells with EGF [76], although natural RNA circles might play a role in growth regulation by virtue of the ability of some circRNA molecules to act as efficient miRNA sponges [77,78]. Another example relates to the WNT family of growth factors. Aberrant WNT signalling has been observed in colorectal and in many more cancer types. Binding of WNT ligands with a receptor of the frizzled family results in the inactivation of a destruction complex and enables β-catenin to migrate to the nucleus, where it activates TCF and/or LEF transcription factors [79]. Recently, combined inhibition of EGFR and c-ABL, by clinically approved small molecule drugs, was shown to block accumulation of β-catenin in the nucleus and prevent its recruitment to the HOTAIR promoter in triple-negative breast cancer cells [80]. Forced expression of β-catenin was further shown to rescue expression of HOTAIR [80]. Alike WNT signalling, down-regulation of the lncRNA, called LIMT (long non-coding RNA inhibiting metastasis), was observed in mammary epithelial cells after stimulation with EGF [81]. Interestingly, down-regulation of LIMT required an active ERK pathway, and low expression of LIMT associates with poor survival of breast cancer patients. Furthermore, it was shown that knockdown of LIMT enhances metastasis in an animal model. Opposite to the effect of LIMT, knockdown of the lncRNA BANCR (BRAF-regulated lncRNA 1) yielded a reduction in migration of melanoma cells [82]. BANCR, which was originally identified as a lncRNA up-regulated in melanocytes carrying an active mutant of BRAF (V600E), has recently been shown to regulate migration in additional cell types [8385].

Concluding remarks

Till recent years, regulation of signalling networks in health and disease was attributed mainly to protein–protein interactions and to post-translational covalent modifications of proteins, such as phosphorylation and ubiquitination. However, the burgeoning new information documenting multiple functions of RNA–RNA, RNA–DNA and RNA–protein interactions portray a more complex picture. The examples we reviewed here exemplify how the direct and indirect involvement of ncRNAs in cell signalling pathways change the way we consider the escalating process underlying cancer progression. Future studies uncovering more oncogenic mutations within DNA sequences corresponding to non-coding RNAs will probably deepen our understanding. Stepwise accumulation of such mutations might complement the better understood mutations affecting protein-coding genes. Beyond new mutations, the challenge ahead entails primarily functional understanding, since the mechanisms of action of the vast majority of non-coding transcripts remain elusive. Resolving modes of action will allow us to start to define sets of lncRNAs sharing nucleotide sequences or other features, such as cellular functions and common structural motifs. Another challenge relates to the full contribution of RNA-loaded exosomes to cancer progression. Accumulating findings indicate the existence of miRNAs and lncRNAs in secreted exosomes (reviewed in ref. [86]), and report the ability of these ncRNAs to increase aggressiveness of tumours [87] or modulate response to chemotherapy [88, 89]. Furthermore, due to their proposed role as biomarkers of cancer [90], profiling of exosome-derived ncRNAs may be used as a diagnostic tool to replace biopsy profiling. In the long term, our ever-refined knowledge of the functions of ncRNAs will probably translate to the identification of biomarkers able to predict who are the patients who will benefit from a particular targeted therapy [91].

Abbreviations

     
  • AR

    androgen receptor

  •  
  • AS

    antisense transcripts

  •  
  • ASNR

    apoptosis-suppressing non-coding RNA

  •  
  • ATB

    activated by TGF-β

  •  
  • AUF1

    ARE/poly (U)-binding/degradation factor 1

  •  
  • BANCR

    BRAF-regulated lncRNA 1

  •  
  • BRK

    breast tumour kinase

  •  
  • CRC

    colorectal carcinoma

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • EMT

    epithelial-to-mesenchymal transition

  •  
  • FGF2

    fibroblast growth factor 2

  •  
  • HBV

    hepatitis B virus

  •  
  • HCV

    hepatitis C virus

  •  
  • HIF1α

    hypoxia-inducible factor 1-α

  •  
  • HULC

    hepatocellular carcinoma up-regulated long non-coding RNA

  •  
  • IGFR1

    insulin-like growth factor 1 receptor

  •  
  • IL-11

    interleukin 11

  •  
  • LIMT

    long non-coding RNA inhibiting metastasis

  •  
  • lncRNA

    long non-coding RNAs

  •  
  • MALAT1

    metastasis-associated lung adenocarcinoma transcript 1

  •  
  • MEG3

    maternally expressed gene 3

  •  
  • miRNAs

    microRNAs

  •  
  • ncRNAs

    non-coding RNAs

  •  
  • NHEJ

    non-homologous end joining

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PTEN

    phosphatase and tensin homologue

  •  
  • ROR

    regulator of reprogramming

  •  
  • STAT3

    signal transducer and activator of transcription 3

  •  
  • TUG1

    taurine up-regulated 1

  •  
  • VEGF

    vascular endothelial growth factor.

Acknowledgments

Our research was supported by the European Research Council, the Seventh Framework Program of the European Commission, the German-Israeli Project Cooperation (DIP), the Israel Cancer Research Fund and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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