Crosstalk between long non‐coding RNAs and Wnt/β‐catenin signalling in cancer

Abstract Long non‐coding RNAs (lncRNAs) are non‐protein‐coding transcripts in the human genome which perform crucial functions in diverse biological processes. The abnormal expression of some lncRNAs has been found in tumorigenesis, development and therapy resistance of cancers. They may act as oncogenes or tumour suppressors and can be used as diagnostic or prognostic markers, prompting their therapeutic potentials in cancer treatments. Studies have indicated that many lncRNAs are involved in the regulation of several signal pathways, including Wnt/β‐catenin signalling pathway, which has been reported to play a significant role in regulating embryogenesis, cell proliferation and controlling tumour biology. Emerging evidences have suggested that lncRNAs can interact with several components of the Wnt/β‐catenin signalling pathway to regulate the expression of Wnt target genes in cancer. Moreover, the expression of lncRNAs can also be influenced by the pathway. Nevertheless, Wnt/β‐catenin signalling pathway‐related lncRNAs and their interactions in cancer are not systematically analysed before. Considering these, this review emphasized the associations between lncRNAs and Wnt/β‐catenin signalling pathway in cancer initiation, progression and their therapeutic influence. We also provided an overview on characteristics of lncRNAs and Wnt/β‐catenin signalling pathway and discussed their functions in tumour biology. Finally, targeting lncRNAs or/and molecules associated with the Wnt/β‐catenin signalling pathway may be a feasible therapeutic method in the future.

Results from the latest GENCODE have indicated that there are only approximately 2% of the human genome are protein-coding genes, whereas the vast majority of the human genome is made up of non-coding RNAs (ncRNAs). 2 In the past decades, lots of ncRNAs have been found, such as ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA) and microRNA (miRNA) as well as long non-coding RNA (lncRNA). Aberrations within the non-coding genome are major decisive factors contributed to human diseases. 3 Among these non-protein-coding transcripts, lncRNAs, defined as longer than 200 nucleotides with little or no protein-coding ability, have emerged as essential regulators in diverse biological processes. [4][5][6] They can interplay with DNA, RNA and proteins to regulate the target gene expression. They can also influence several signalling pathways including Wnt/b-catenin signalling pathway, which is a common pathway involved in embryogenesis, development and homoeostasis of tissues. Aberrant regulation of the pathway is associated with human diseases. 7,8 The comprehensive interrelationship of lncRNAs and Wnt/bcatenin signalling pathway has appeared as a significant tumorigenic signalling network in various cancers. In this review, we summarized some lncRNAs which are associated with Wnt/b-catenin signalling pathway to describe their interactions and underlying mechanisms in cancer formation, development and response to treatments.

| CHARACTERISTICS OF LNCRNAS AND THEIR FUNCTIONS IN CANCER
LncRNAs represent a novel heterogeneous group of ncRNAs that usually exhibit cell-type-specific expression manner. 9 The genomic locations of lncRNAs can be classified into intragenic, bidirectional and intergenic on the basis of their relationship to adjacent proteincoding transcripts. 10 They are initially transcribed through pathways similar to that of protein-coding genes. And their transcription is mediated via RNA polymerase II. 11,12 Evidences have already indicated that lncRNAs can regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels. 13 For example, lncRNA CCAT2, which is up-regulated in colorectal cancer (CRC), can enhance tumour invasion and metastasis by regulating c-Myc transcription and activate the Wnt signalling pathway. 14 LncRNA CCAT1 can promote the progression of gastric carcinoma depending on the post-transcriptional activity of c-Myc. 15 Functionally, lncRNAs are not the "transcriptional junk" any more. They play an important role in normal cellular proliferation and differentiation. 16 They are predominantly localized in the nucleus or cytoplasm, and their function is location-specific. 17 In nucleus, lncRNAs are involved in chromatin remodelling, transcriptional regulation and RNA processing, while cytoplasmic lncRNAs can modulate mRNA stability, splicing or translation regulation, interact with special proteins and influence cellular signalling cascades. 18 Studies have shown that dysregulated expression of lncRNAs leads to diverse human diseases. [19][20][21] At present, masses of lncRNAs are known to be associated with the initiation and progression of cancer.
They can function as oncogenes or tumour suppresses. 22 Many lncRNAs have a tissue and cancer type-specific expression pattern and have already been shown to be useful as diagnostic and prognostic markers. [23][24][25] More recently, emerging evidences have revealed an important role of lncRNAs in tumour drug resistance as well. 26 These findings strongly suggest that they could become potential therapeutic targets in cancer treatments.

PATHWAY AND ITS ROLE IN CANCER
Wnt signalling pathway is an evolutionarily highly conserved pathway which controls critical biological processes including embryonic development, normal homoeostasis of adult tissues and cell fate. 27,28 It mainly contains three diverse signalling pathways: Wnt/b-catenin signalling pathway (canonical pathway), Wnt/Ca 2+ pathway and Wnt/planar cell polarity (PCP) pathway. Among them, Wnt/b-catenin signalling pathway (Wnt pathway for short) has obtained particular attentions due to its versatile functions in cells. In this section, we will provide an overview of the molecular mechanism of Wnt pathway.
The primary components of Wnt pathway are as follows: Wnt ligands, Frizzled receptors, LRP5/6 co-receptors (low density lipoprotein receptor-related protein 5/6), Dsh (Dishevelled), b-catenin and TCF/LEF (T-cell factor/lymphoid enhancer factor) as well as one "degradation complex" composed of APC (adenomatous polyposis coli), axin (the scaffolding protein) and two kinases: CK1a (casein kinase 1a) and GSK-3b (glycogen synthase kinase 3b). Wnt ligand and b-catenin play a vital role in this pathway. In the absence of Wnt ligand, the signalling cascade is repressed. Cytoplasmic b-catenin is phosphorylated and kept in low levels via proteasomemediated destruction, which is controlled by the "degradation complex". As a result, the translocation into nucleus is inhibited. However, when Wnt ligand binding to receptors at the surface of target cells, a chain of events is initiated that disrupt the degradation com- proliferation. The dysregulation of b-catenin and APC has also been found in sporadic colon cancer and some other kinds of tumours. 37 In addition, Wnt pathway could function as a significant anticancer target in cancer treatments. 38,39

| THE INTERACTIONS BETWEEN LNCRNAS AND WN T/b -CATENIN SIGNALLING PATHWAY
The Wnt pathway has been recognized as a pivotal pathway participated in the regulation of cell proliferation, tumorigenesis and progression as well as chemoresistance in various cancers. [40][41][42] Dysregulation of the multifunctional protein b-catenin, which is a crucial signalling effector in the pathway, contributes to aberrant activation of Wnt pathway. 43 Accumulating evidence demonstrated that lncRNAs could regulate several signal pathways via interacting with specific proteins. 44,45 More recently, numerous lncRNAs have been found to target key molecules associated with Wnt pathway and affect the accumulation of b-catenin. Then, modulating Wnt target genes expression and cancer cell functions. 46,47 For example, lncRNA CCAT2 was found to promote breast tumour progression by influencing the activity of b-catenin, and thus, activating the Wnt pathway. 48 These findings suggest that they may have close relationships with each other in cancer. Here, we enumerated some Wnt pathway-related lncRNAs to explore their reciprocities in tumorigenesis and progression, drug resistance and radiosensitivity of cancers (Table 1). Their probable regulatory network was depicted in a schematic diagram ( Figure 2). We also provided a perspective that a better understanding of the interactions between Wnt pathways and these lncRNAs may devise efficient strategies against tumour treatments.

| LncRNAs and Wnt/b-catenin pathway in tumorigenesis and tumour progression
As is known to all, the ability to propagate continuously is one of the primary characters of cancer, and the process contains various

| LncRNAs and Wnt/b-catenin pathway in therapeutical resistance
Chemotherapy is one of the major treatment methods of tumours.
Nevertheless, chemoresistance remains an obvious obstacle against satisfactory treatment outcomes. 57  And the decline of HOTAIR could enhance the expression of WIF-1, which leads to the suppression of Wnt pathway. As a consequence, decreased the proliferation, promoted the apoptosis and enhanced the radiosensitivity of PDAC cells after radiation. 75 In another report, Wang et al found that long intergenic non-coding RNA-p21 (lincRNA-p21) increases the sensitivity of radiotherapy for CRC through targeting Wnt pathway. In mechanism, the X-ray treatment up-regulates the expression of lincRNA-p21 which could directly inhibit the stability and/or translation of b-catenin. As a result, the activity of Wnt pathway is suppressed. Moreover, proapoptotic protein Noxa is elevated by lincRNA-p21. In the end, promoted cell apoptosis and enhanced the radiosensitivity for CRC. 76 Collectively, these studies have revealed a potent interrelationship between lncRNAs and Wnt pathway in drug resistance and in radiotherapy of various cancers. Based on these findings, it is expected that further researches are needed to clarify molecular mechanisms between lncRNAs and Wnt pathway, which may act as candidates to develop novel strategies to reverse the chemoresistance and increase radiosensitivity of cancer.

| The clinical applications of lncRNAs and Wnt/ b-catenin pathway
Detection of the specific biomarkers of tumour is one of effective methods for the early diagnosis of tumours. LncRNAs apparently exhibit a tissue-specific expression and can be measured non-invasively, raising the possibility that they may serve as promising biomarkers and therapeutic targets in cancer. 77 Several studies have reported that recognition of particular lncRNAs as biomarkers may be useful in improving the diagnostic and prognosis prediction of tumours. 24

| CONCLUSION S AND PE RSPECTIVE
LncRNAs are a class of non-protein-coding RNAs, which play important roles in diverse biological processes. 86 promote an efficient therapeutic strategy into a reality by targeting lncRNAs and/or Wnt pathway in cancer.

ACKNOWLEDGEMENT
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81372742 and 81372741).

CONF LICT OF I NTEREST
The authors declare that we have no conflict of interest.