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1. Introduction

The human genome project has demonstrated that <2% nucleic acid sequences are protein-coding. In 2002, Okazaki et al (1) first identified a class of longer transcripts by sequencing a mouse cDNA library, and termed them long non-coding RNAs (lncRNAs). Due to limitations in our understanding of gene regulation and expression, these non-coding RNAs were considered to be transcriptional noise until HOX transcript antisense RNA (HOTAIR) was identified. HOTAIR is a lncRNA located on the antisense strand of the HOXC gene cluster, which regulates the expression of the HOXD gene and the occurrence of H3K4me2 methylation modifications in certain gene regions, and silences expression at this site (2,3). Although lncRNAs do not encode proteins, they participate in important cellular physiological processes. Numerous studies have reported that lncRNAs are abnormally expressed in various types of tumor, and affect the occurrence and development of tumors through different signaling pathways. lncRNAs are generally defined as long-stranded RNAs with >200 nucleotides, but this is not absolute. For example, BC1 and snaR are <200 nucleotides in length (4). lncRNAs may also be classified according to location, object of action and functional mechanism (5). The progress in lncRNA research is associated with the progress in research technology. It is worth mentioning that RNA-sequencing technology, proposed by the Snyder team at Yale University, has low background noise and is able to detect single-base differences between similar genes or different transcripts caused by variable cleavage in the gene family, as well as low abundance transcripts (6). At present, next-generation sequencing technologies have provided the largest experimental evidence on lncRNA, with the advantages of high flux, short duration, high accuracy and abundant information.

lncRNAs participate in the regulation of various biological activities, including genomic imprinting, X-chromosome inactivation, chromosome modification and telomere biology. They are also associated with the occurrence and development of various human diseases, particularly with the occurrence and development of malignant tumors. Their long ribbon-like molecular structure interacts with multiple types of molecules, thus affecting cell biological activities. Signaling pathways participate in the transduction of cell signals through a series of enzymatic reactions, which are regulated by various types of molecules. lncRNA is an important regulator of signaling pathways, and regulates gene expression at a transcriptional, post-transcriptional and epigenetic level. This review focused on the function of lncRNA in several classical signaling pathways.

2. lncRNA and the p53 signaling pathway

The p53 gene was first reported in 1979 by Lane and Crawford (7), and >50% cancer types have been found to be related to mutations of the p53 gene. A tight and precise regulatory system regulates the activities of p53-associated signaling pathways to prevent abnormal changes in p53 levels from harming cells. lncRNA has gained increasing attention as an important regulator of p53 signaling.

The damage induced noncoding (lncRNA-DINO) is a DNA damage-activated transcriptional lncRNA involved in the lncRNA-directed biological DNA damage response. Numerous abnormal changes in the p53 pathway may increase the probability of tumorigenesis. DINO interacts with the p53 protein to promote its stability, which causes protein accumulation, activation of p53 target proteins and regulates a p53 auto-enhancement loop (Fig. 1). DINO is involved in p53-dependent gene expression, cell cycle arrest and apoptosis. In the absence of DNA damage, artificially upregulating DINO expression can effectively activate the DNA damage response pathway and cell cycle arrest. However, when artificially inhibiting the expression of DINO, the response of cells to p53 signaling is weakened. In mice, inactivation of the DINO gene or the promoter blocks the p53 pathway and improves acute radiation syndrome in vivo (8). Thus, DNA damage-induced lncRNAs form a feedback loop with homologous transcription factors to enhance cell signaling networks. A genome-wide transcriptome analysis of human diploid fibroblasts revealed that lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in regulating the expression of cell cycle-associated genes, and is required for G1/S and mitotic progression. Low expression of MALAT1 leads to the activation of p53 and its target genes, and cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 expression levels, indicating that p53 is a key downstream mediator of MALAT1. Furthermore, reduced expression of an oncogenic transcription factor, B-MYB, which is involved in G2/M progression, is expressed in MALAT1-depleted cells due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing (9). These findings reveal the mechanism by which lncRNA regulates cell proliferation.

Figure 1 A typical lncRNA feedback loop regulatory mechanism. After p53 recognizes and responds to DNA damage, it can interact with DINO to enhance stability, and transcriptional activation of downstream gene expression including DINO. The increase in DINO levels, in turn, binds and stabilizes the p53 protein, creating a positive feedback loop that cascades the damage signal within the nucleus, thereby regulating the p53 signaling pathway's response to DNA damage. +, upregulation; PANDA, p21-associated lncRNA DNA-damage activated; DINO, damage induced noncoding; CDKN1A, cyclin dependent kinase inhibitor 1A.

lncRNAs also regulate p53, subsequently affecting cell cycle progression, for example via lncRNA regulator of reprogramming (lncRNA-ROR). Unlike MDM2, which leads to p53 degradation through the ubiquitin-proteasome pathway, it directly inhibits p53 through interactions with heterogeneous nuclear ribonucleoprotein I (hnRNP I) at the translational level. ROR carries an hnRNP I binding domain that acts on the 5'-untranslated region of p53 mRNA to suppress the translation of p53, thereby inhibiting p53-mediated cell cycle arrest and apoptosis. The induction of p53 following treatment with doxorubicin increases ROR expression levels, and the ectopic expression of p53 induces ROR production, resulting in a ROR-p53 auto-regulatory feedback loop (10). Similarly to mRNA, the major transcriptional processes of lncRNA are regulated by various factors, including p53, NF-κB, Sox2, Oct4 and Nanog (11). For example, the transcriptional promoter region of ROR is directly affected by pluripotency factors, OCT4, SOX2 and KLF4 (12). lncRNA-p21 binding to hnRNP-K assists hnRNP-K to localize and inhibit p53-regulated genes, and is a p53-dependent transcriptional response inhibitor (13). Competing endogenous RNAs (ceRNAs) regulate gene expression through competitive binding of microRNA. By providing ceRNA or natural microRNA sponge-like functions, lncRNAs are important post-transcriptional regulators of gene expression, regulating microRNAs and competitively inhibiting important receptors involved in various cellular biological activities (14). For example, lncRNA-loc285194, growth-arrest specific 5 (GAS5) and HOTAIR appear to function as competitive endogenous RNAs participating in the inhibition of tumor development (15-17). GAS5 also has the ability to simulate DNA and compete with steroid receptors in cells, which regulates steroid-mediated transcriptional regulation, growth arrest and apoptosis (18). In human meningioma cells, lncRNA maternally expressed gene 3 (MEG3) stimulates p53-mediated transactivation and inhibits tumor proliferation by inducing apoptosis (19), which may be associated with its ability to downregulate MDM2 expression as demonstrated by Zhou et al (20). Certain natural antisense transcripts are important lncRNAs that may be paired with complementary RNAs to form sense-antisense double-stranded RNAs. This causes the degradation or translational inhibition of target mRNA. For example, lncRNA-Wrap53 is a natural antisense transcript of p53. The highly conserved Wrap53 has been demonstrated to regulate endogenous p53 mRNA levels and further induce p53 protein expression by targeting the 5'-untranslated region of p53 mRNA (21). p21-associated lncRNA DNA-damage activated (PANDA) is an lncRNA located ~5 kB upstream of the CDKN1A TSS gene, and is induced by specific DNA damage. PANDA is also a p53-associated regulatory lncRNA involved in cell cycle progression and apoptosis (22). The ectopic expression of lncRNA is involved in numerous disease processes, but the underlying molecular mechanism is not yet fully understood. Table I lists the lncRNAs that interact with the p53 pathway in various types of human cancer.

Table I lncRNAs interact with p53 signaling pathway in cancers.

Table I

lncRNAs interact with p53 signaling pathway in cancers.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Liu et al, 2013	LOC285194	Osteosarcoma	Inhibit tumor cell growth	Positive	(15)
Tano et al, 2017	MALAT1	Lung adenocarcinoma	Inhibit cell cycle arrest	Negative	(90)
Yang et al, 2016	ROR	Colorectal cancer	Decrease sensitivity to radiotherapy	Negative	(91)
Chen et al, 2016 Zhu et al, 2015	MEG3	Hepatoma	Inhibit proliferation and apoptosis	Positive	(92,95)
Li et al, 2016	MEG3	Glioma	Inhibit tumorigenesis	Positive	(93)
Lu et al, 2013	MEG3	Non-small cell lung cancer	Inhibit proliferation and apoptosis	Positive	(94)
Sun et al, 2016	MEG3	Breast cancer	Inhibit proliferation, metastasis and invasion	Positive	(96)
Zhang et al, 2014	TUG1	Non-small cell lung cancer	Inhibit tumorigenesis	Positive	(97)
Huang et al, 2015	UCA1	Breast cancer	Promote tumorigenesis	Negative	(98)
Zhai et al, 2016	HOTAIR	Non-small cell lung cancer	Promote proliferation and invasion	Negative	(99)
Su et al, 2017	PRAL	Lung cancer	Inhibit proliferation	Positive	(100)
Gong et al, 2014	LOC401317	Nasopharyngeal carcinoma	Inhibit proliferation	Positive	(101)
Zhai et al, 2015	ASLNC04080	Endometrial carcinoma	Promote proliferation and invasion	Negative	(102)
Thorenoor et al, 2016	ZFAS1	Colorectal cancer	Promote proliferation	Negative	(103)

3. lncRNA and the NF-κB signaling pathway

NF-κB is a widely expressed pleiotropic transcription factor. It is a heterotrimer composed of p50, p65 and IκB. The NF-κB signaling pathway is activated by a variety of extracellular stimuli, serving a central role in transcriptional regulation, and in the expression and regulation of various genes. It is a marker of cell activation, and mediates a variety of biological processes, including inflammation, cell proliferation and tumor metastasis. The NF-κB pathway is regulated by various lncRNAs.

lncRNA-Lethe was the first lncRNA identified to be involved in regulation of the NF-κB signaling pathway. In human 293 cells, Lethe is selectively induced by pro-inflammatory cytokines through the NF-κB pathway, and acts on RelA (the p65 subunit of NF-κB) to inhibit RelA-DNA binding and subsequently target gene activation (23). Lethe has an active role in regulating the NF-κB pathway and is involved in inflammation through a typical negative feedback mechanism. Activated NF-κB promotes the expression of Lethe, and Lethe directly inhibits this pathway by interacting with RelA, thereby reducing the production of various inflammatory proteins (23). A novel lncRNA, namely nuclear transcription factor NF-κB interacting lncRNA (NKILA), which participates in the inhibition of breast cancer metastasis through the NF-κB signaling pathway, was discovered by analyzing a large number of lncRNAs in human breast cancer (24). NF-κB upregulates the expression of NKILA by binding to the promoter of NKILA, and a large quantity of NKILA is able to bind to NF-κB/IκB to form a stable complex, thus directly masking the phosphorylation site of IκB to prevent IKK-mediated phosphorylation of IκB and activation of NF-κB. The negative feedback of NKILA and NF-κB serves a key role in preventing overactivation of the NF-κB pathway in inflammation-stimulated mammary epithelial cells. However, highly expressed microRNA-103/107 mediates the degradation of NKILA, which results in overactivation of the NF-κB pathway, thus contributing to cancer metastasis and poor patient outcome (24). As a key enzyme in prostaglandin synthesis, COX-2 serves an important role in the prognosis of tumors, particularly neoangiogenesis and tumor progression (25,26). lncRNA p50-associated COX-2 extragenic RNA (PACER), localized in the nucleus, binds directly to free p50, inhibits the formation of homodimers, promotes the formation of heterodimers, increases the transcription enhancement effect and increases the expression of COX-2 (27). Pearson et al (28) achieved results, which support these observations, whereby primary human osteoarthritic chondrocytes treated with IL-1β rapidly induced the formation of PACER, indicating that PACER expression is associated with COX2. In addition to PACER, the lncRNA cyclooxygenase 2 (COX2) locus near the COX2 gene is essential for the transcription of NF-κB-associated late inflammatory genes in endotoxin-treated mouse macrophages (29). In the nucleus, MALAT1 interacts with the P65-p50 heterodimer to inhibit downstream TNF/ IL-6 expression. Bioinformatics analysis has revealed that MALAT1 affects NF-κB/RelA activity in the epithelial-mesenchymal transition process (30). The abnormal expression of HOTAIR in ovarian cancer induces NF-κB activation by inhibiting Iκ-Bα in the DNA damage response. It also increases the expression of MMP-9 and IL-6, key target genes of NF-κB, and serves an important role in DNA damage response, cell senescence and chemotherapy resistance (31). In addition, certain lncRNAs regulate signaling pathways indirectly through signaling elements or associated upstream molecules in the NF-κB pathway. For example, MIR31HG is frequently deleted in glioblastoma, and significantly reduces the levels of micro (mi)RNA-31, while loss of miRNA-31 expression enhances NF-κB signaling by targeting TRADD, its upstream activator, and promotes tumor growth (32). C2dat1 promotes neural cell survival by enhancing CAMK2D expression and activating the NF-κB pathway (33). Expression of IL1β-eRNA, IL1β-RBT46, AS-IL1α, ANRIL, THRIL and IL7R is induced by the NF-κB signaling pathway, and regulates the expression of NF-κB-associated target genes (34-38). Table II lists the lncRNAs that interact with the NF-κB pathway in cancer.

Table II lncRNAs interact with NF-κB signaling pathway in cancers.

Table II

lncRNAs interact with NF-κB signaling pathway in cancers.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Rajbhandari et al, 2015	MIR31HG	Glioblastoma	Inhibit tumor growth	Negative	(32)
Chen et al, 2016	MEG3	Hepatoma	Inhibit cell apoptosis	Positive	(92)
Özeş et al, 2016	HOTAIR	Ovarian cancer	Promote cellular senescence and chemotherapy resistance	Positive	(31)
Li et al, 2017	HOTAIR	Colorectal cancer	Promote 5FU resistance	Positive	(104)
Liao et al, 2018	H19	Malignant melanoma	Promote the metastasis and invasion	Positive	(105)
Liu et al, 2015	NKILA	Breast cancer	Inhibit metastasis	Negative	(24)
Yang et al, 2018	NKILA	Laryngeal cancer	Inhibit proliferation and metastasis Enhance radiosensitivity	Negative	(106)
Bian et al, 2017	NKILA	Malignant melanoma	Inhibit invasion and metastasis	Negative	(107)
Huang et al, 2016	NKILA	Tongue squamouscell carcinoma	Inhibit migration and invasion	Negative	(108)
Ma et al, 2018	DANCR	Glioma	Promote cisplatin resistance	Positive	(109)

4. lncRNA and the Wnt signaling pathway

The Wnt gene was first named Int1, because its activation is dependent on the insertion of the mouse breast cancer-associated virus gene (39). Since then, a large number of studies have reported that Int1 serves an important role in the normal embryonic development of mice and is equivalent to the Wingless gene of drosophila. Therefore, combining Wingless with Int1 it was named Wnt. The Wnt signaling pathway is an evolutionarily highly conserved signaling system involved in important physiological processes, including embryonic development, tissue differentiation and cell homeostasis (40,41). Specific lncRNAs associated with the Wnt signaling pathway are discussed below.

Numerous lncRNAs target and affect the accumulation of β-catenin, a key molecule that acts on the Wnt pathway, thereby regulating the expression of Wnt target genes and the function of cancer cells (42,43). Numerous lncRNAs regulate target genes to promote tumorigenesis and development. In breast cancer, patients exhibiting high CCAT2 expression have a significantly poorer prognosis and lower overall survival rate compared with patients with low CCAT2 expression (44). A previous study on MCF-7 and MDA-MB-231 breast cancer cells demonstrated that the suppression of CCAT2 expression decreases the levels of β-catenin in the cytoplasm and nucleus, and reduces the expression of CCND1 and c-myc, which are classic downstream genes of the Wnt/β-catenin signaling pathway. These results indicate the possible role of CCAT2 in breast cancer (44). The abnormal expression of HOTAIR has been demonstrated in certain types of human cancer. In colorectal cancer, Wnt/0205-catenin signaling is inhibited by HOTAIR-knockdown and miR-203a-3p overexpression (45). The downregulation of HOTAIR expression is essential for reducing cell proliferation and chemoresistance via modulation of miR-203a-3p expression levels and the activity of the Wnt/0205-catenin signaling pathway (45). lncRNA-CRNDE is significantly overexpressed in renal cell carcinoma. Elevated CRNDE expression may regulate the PI3K/Akt/GSK3b signaling pathway, increase the level of β-catenin in the nucleus, and ultimately regulate the expression of the Wnt target gene to regulate the proliferation of renal cancer cells (46). lncRNA-TCF7 promotes the self-renewal and proliferation of hepatocellular carcinoma cells by activating the Wnt signaling pathway. It may be that TCF7 recruits SWI/SNF complexes to act on its own promoter to regulate expression and activate the Wnt pathway (47). Similarly, numerous studies have reported that lncRNAs inhibit tumorigenesis. In a large number of non-small cell lung cancer tissue samples, low expression of AK126698 often predicts larger tumor diameter and advanced tumor stage. Conversely, an increase in AK126698 expression targets Frizzled-8, one of the receptors acting of the Wnt/β-catenin signaling pathway, inhibiting the proliferation and metastasis of cancer cells and inducing apoptosis (48). The expression of lncRNA-CTD903 is significantly upregulated in human colorectal cancer and may be used as an independent prognostic factor for colorectal cancer. When CTD903 was knocked down in the RKO and SW480 cell lines, the invasion and metastasis of the tumor cells is increased, and epithelial-mesenchymal transition-like characteristics are exhibited (49). Further results demonstrated that downregulated CTD903 expression allows the Wnt/β-catenin signaling pathway to be more easily activated, increasing the expression of transcription factors, Twist and Snail, as well as the protein expression of the mesenchymal marker, Vimentin, and reducing that of the epithelial marker, ZO-1 (49). Chemotherapy resistance can result in poor prognosis. Furthermore, lncRNAs serve a role in cell resistance. The level of lncRNA-Meg3 is significantly lower in the cisplatin-resistant lung cancer cell line, A549/DDP, compared with that in the A549 cell line (50). Further results demonstrated that the upregulation of Meg3 expression in vitro increases the sensitivity of the A549/DDP lung cancer cell line to cisplatin. However, the sensitivity of A549 cells to cisplatin decreased following RNA interference downregulation of Meg3 expression. Researchers hypothesized that Meg3 mediates increased cell cycle arrest and apoptosis by regulating p53, β-catenin and survivin, resulting in increased sensitivity to chemotherapy (50). In osteosarcoma, HOTTIP induces tumor occurrence and resistance by activating the Wnt signaling pathway, which may be a potential target for the treatment of osteosarcoma (51). Table III lists the lncRNAs that interact with the Wnt signaling pathway and their general roles in cancer.

Table III lncRNAs that interact with the Wnt signaling pathway in cancer.

Table III

lncRNAs that interact with the Wnt signaling pathway in cancer.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Cai et al, 2015	CCAT2	Breast cancer	Promote cell growth and tumor formation	Positive	(44)
Shao et al, 2016	CRNDE	Renal cell carcinoma	Promote cell proliferation	Positive	(46)
Wang et al, 2015	TCF7	Hepatocellular carcinoma	Promote liver cancer stem cells self-renewal and tumor propagation	Positive	(47)
Fu et al, 2016	AK126698	Non-small cell lung cancer	Inhibit proliferation and migration	Negative	(48)
Yuan et al, 2016	CTD903	Colorectal cancer	Inhibit cancer invasion and migration	Negative	(49)
Xia et al, 2015	MEG3	Lung cancer	Enhance chemosensitivity	Negative	(50)
Rajbhandari et al, 2015	TUG1	Oral squamous cell carcinoma	Promote proliferation and metastasis	Positive	(110)
Fan et al, 2014	UCA1	Bladder cancer	Promote chemoresistance	Positive	(43)
Yang et al, 2016	UCA1	Oral squamous cell carcinoma	Promote proliferation and metastasis	Positive	(111)
Xiao et al, 2018	HOTAIR	Colorectal cancer	Promote cell proliferation and chemoresistance	Positive	(45)
Ge et al, 2013	HOTAIR	Esophageal squamous cell cancer	Promote metastasis and invasion	Positive	(112)
Wu et al, 2017	H19	Colorectal cancer	Promote methotrexate resistance	Positive	(113)
Cao et al, 2017	CCAT1	Epithelial ovarian cancer	Promote metastasis and poor prognosis	Positive	(114)
Li et al, 2015	HOTTIP	Osteosarcoma	Promote tumor occurrence	Positive	(51)
Fu et al, 2017	HOTTIP	Pancreatic cancer	Promote tumorigenesis	Positive	(115)
Yue et al, 2018	CYTOR	Colon cancer	Promote epithelial mesenchymal transformation and metastasis	Positive	(116)
Liu et al, 2016	LET	Lung adenocarcinoma	Inhibit tumor growth and epithelial mesenchymal transformation	Negative	(117)
Wang et al, 2017	PTCSC3	Papillary thyroid carcinoma	Inhibit proliferation and metastasis	Negative	(118)
Zhang et al, 2016	CASC11	Colorectal cancer	Promote proliferation and metastasis	Positive	(119)
Zhang et al, 2017	PCAT1	Extrahepatic cholangiocarcinoma	Promote tumorigenesis	Positive	(120)
Wang et al, 2018	LINC00968	Non-small cell lung cancer	Promote tumorigenesis	Positive	(121)

5. lncRNA and the Notch signaling pathway

The notch signaling pathway is a highly evolutionarily conserved cell signaling pathway. It mediates direct cell-cell contact and affects the normal morphogenesis of cells. It regulates differentiation of multipotent progenitor cells, apoptosis, cell proliferation and the formation of cell borders (52). lncRNA also interacts with the Notch signaling pathway and affects tumor progression.

It has been reported that the non-coding sequences that accompany the genes are often involved in the regulation of peripheral genes. In the human genome, lncRNA-NALT was identified at a distance of ~100 bases from the NOTCH1 gene. In T-cell acute lymphoblastic leukemia cells, increased expression of NALT significantly promotes cell proliferation. It may be that NALT activates transcription in the Notch pathway and regulatory elements in the nucleus (53). lncRNA-SNHG12 expression is significantly elevated in osteosarcoma tissues and cell lines, and predicts poor prognosis. A study of the biological function of SNHG12 in the 143B and U2OS cell lines revealed that the downregulation of SNHG12 inhibits cell proliferation by blocking the G0/G1 phase of the cell cycle, and reduces the potential for cell invasion and metastasis. SNHG12 sponges miR-195-5p in osteosarcoma cells, similarly to endogenously-competent RNA, to regulate Notch2 gene expression, thereby affecting signal transduction in the Notch pathway (54). In a study of CRC specimens, and matched adjacent normal tissues and CRC cell lines, the expression of FOXD2-AS1 was significantly increased in CRC tissues as well as in CRC cell lines, and downregulation of FOXD2-AS1 expression suppressed proliferation, invasion and migration in vitro. Further study examined associated markers of the epithelial-mesenchymal transition and Notch signaling pathways, and confirmed that the two pathways are inactivated in CRC cells following FOXD2-AS1-knockdown (55). When studying the expression profile of lncRNA-MEG3 and the two Notch pathway-associated molecules, Notch1 and Hes1, in human endometrial tissues and cell lines, Guo et al (56) reported that, compared with the normal control group, MEG3 expression is significantly downregulated in cancer tissue. However, the expression levels of Notch1 and Hes1 are significantly increased. Upregulation of MEG3 in tumor cells in vivo inhibits the growth of tumors by inhibiting the Notch pathway (56). The Notch pathway serves an important role in maintaining the pluripotency of glioma stem cells. The activation of Notch1 induces lncRNA-TUG1 expression in specific glioma cell lines. In the cytoplasm, TUG1 promotes cell self-renewal by decoying miR-145. In the nucleus, TUG1 binds YY1 by recruiting multi-comb complexes to allow site-specific H3K27 histones to methylate, thereby inhibiting gene mutation. In addition, intravenous administration of TSG1 with antisense oligonucleotides induces the differentiation of glioma stem cell lines in vivo, and effectively inhibits their proliferation (57). Table IV lists the lncRNAs that interact with the Notch pathway in cancer.

Table IV lncRNAs that interact with the Notch signaling pathway in cancer.

Table IV

lncRNAs that interact with the Notch signaling pathway in cancer.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Wang et al, 2015	NALT	Pediatric T cell acute lymphoblastic leukemia	Promote proliferation	Positive	(53)
Zhou et al, 2018	SNHG12	Osteosarcoma	Promote cell invasion and migration	Positive	(54)
Yang et al, 2018	FOXD2-AS1	Colorectal cancer	Promote cell proliferation and migration	Positive	(55)
Guo et al, 2016	MEG3	Endometrial carcinoma	Inhibit proliferation	Negative	(56)
Cai et al, 2017	HOTAIR	Pancreatic cancer	Promote tumor growth	Positive	(17)
Hang et al, 2015	AK022798	Gastric cancer	Promotes cisplatin-resistant	Positive	(122)
Lu et al, 2018	FAM83H-AS1	Colorectal carcinoma	Promote proliferation	Positive	(123)
Chen et al, 2017	00673	Hepatocellular carcinoma	Promote proliferation and metastasis	Positive	(124)

6. lncRNA and the PI3K/AKT signaling pathway

AKT, also known as protein kinase B, is an important crossover molecule in multiple signaling pathways and is activated by various substances, including hormones, growth factors, cytokines and intercellular matrix. The PI3K/AKT signaling pathway is involved in important physiological activities, including cell proliferation and survival, and is associated with cancer, diabetes, rheumatoid arthritis and other diseases (58,59). In recent years, the regulatory mechanism of lncRNAs in the PI3K/AKT pathway and the impact on diseases, have gradually been revealed.

Using a CRISPR/Cas9-based synergistic activation mediator system, Koirala et al (60) studied numerous lncRNAs that may affect AKT activity. They reported that lncRNA-AK023948 is a positive regulator of the AKT pathway. In malignant cells, upregulation of AK023948 and DHX9 expression promotes the activation of the AKT pathway. Furthermore, they may interact with ATP-dependent RNA helicase A (RHA/DHX9) and P58 to participate in the AKT pathway, and respond to growth factors or internal environmental stimuli, such as acid-alkali poisoning (60). It has been reported that the upregulation of lncRNA-AB073614 expression in ovarian cancer (61) and glioma (62,63) is associated with the occurrence and development of tumors. In vitro, the knockdown of AB073614 expression significantly inhibits the proliferation, differentiation, apoptosis, metastasis and invasion of colorectal cancer cells, and results in increased rates of apoptosis and G1 phase cell cycle arrest, while overexpression of AB073614 results in the opposite effects. The agonist (740Y-P) and an inhibitor (LY294002) of the PI3K/AKT signaling pathway were used to demonstrate the role of AB073614 in colorectal tumor cells (64). Using similar research methods, a team reported that PlncRNA-1 (65) and NEAT1 (66) act on the PI3K/AKT pathway, and participate in the proliferation and apoptosis of colorectal cancer cells. A study on 102 gastric cancer tissues and adjacent normal tissues indicated that the abnormal expression of lncRNA-UCA1 serves an important role in the development, metastasis and invasion of gastric cancer. In vitro and in vivo experiments demonstrated that the molecular mechanism of UCA1 regulation on the PI3K/AKT pathway occurs by regulating PI3K-Akt-mTOR signaling proteins and downstream molecules to influence the growth process of gastric cancer cells (67). MALAT1 regulates multiple signaling pathways. In breast and ovarian cancer, it was recently discovered that MALAT1 influences the epithelial-mesenchymal transition and regulates the tumorigenicity of cells by targeting the PI3K/AKT pathway (68,69). In bovine epithelial cells, lncRNA-H19 also affects the epithelial-mesenchymal transition via PI3K/AKT regulation (70). Table V lists the lncRNAs associated with the PI3K/AKT signaling pathway in cancer.

Table V lncRNAs that interact with the PI3K/AKT signaling pathway in cancer.

Table V

lncRNAs that interact with the PI3K/AKT signaling pathway in cancer.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Cheng et al, 2015	AB073614	Ovarian cancer	Promote tumorigenesis	Positive	(61)
Wang et al, 2017	AB073614	Colorectal cancer	Promote tumor growth	Positive	(64)
Song et al, 2017	PlncRNA-1	Colorectal carcinoma	Promote tumor growth	Positive	(65)
Peng et al, 2017	NEAT1	Colorectal cancer	Promote tumor growth	Positive	(66)
Zhang et al, 2017	MEG3	Glioma	Inhibit tumorigenesis	Negative	(125)
Li et al, 2018	UCA1	Osteosarcoma	Promote proliferation	Positive	(126)
Yun et al, 2016	TUG1	Osteosarcoma	Promote proliferation	Positive	(127)
Yan et al, 2016	HOTAIR	Gastric cancer	Promotes cisplatin resistance	Positive	(128)
Wang et al, 2017	HOTAIR	Chronic myeloid leukemia	Promote imatinib resistance	Positive	(129)
Jiang et al, 2017	DANCR	Osteosarcoma	Promote tumor progression	Positive	(130)
Yuan et al, 2018	HOTTIP	Papillary thyroid carcinoma	Promote proliferation	Positive	(131)
Xue et al, 2016	GAS5	Prostate cancer	Inhibit tumor growth	Negative	(132)
Huang et al, 2016	Xist	Breast cancer	Inhibit tumor growth	Negative	(133)
Lu et al, 2017	HULC	Chronic myeloid leukemia	Promote proliferation	Positive	(134)
Wang et al, 2017	HULC	Bladder cancer	Promote proliferation	Positive	(135)
He et al, 2017	NONHSAT062994	Colorectal cancer	Inhibit tumor growth	Negative	(136)
Han et al, 2018	p21	Osteosarcoma	Inhibit proliferation	Negative	(137)
Wang et al, 2018	AB209630	Pancreatic ductal adenocarcinoma	Inhibit gemcitabine resistance	Negative	(138)
Wang et al, 2017	MIR31HG	Non-small cell lung cancer	Promote gefitinib resistance	Positive	(139)
Chen et al, 2017	PTENP1	Breast cancer	Inhibit proliferation and metastasis	Negative	(140)

7. lncRNA and the MAPK signaling pathway

The MAPK pathway is a classical signaling pathway, and is involved in the regulation of cell proliferation, differentiation, transformation and apoptosis. The MAPK pathway is associated with the occurrence of various diseases, including inflammation and tumors, by phosphorylating nuclear transcription factors, cytoskeletal proteins, and enzymes. MAPK signaling primarily includes four pathways: ERK, JNK/SAPK, P38 and ERK5/BMK1. The ERK, JNK, P38 and ERK5/BMK1 pathways can be activated by different stimuli, and there is wide crosstalk between these pathways, resulting in mutual synergy or inhibition between them. As important regulatory genes, numerous lncRNAs have been identified to regulate the MAPK pathway.

An important role of the SNHG12-miR-181a-MAPK/Slug axis was described in multidrug resistance in non-small cell lung cancer cells. In non-small cell lung cancer cells, silencing of lncRNA-SNHG12 upregulates miR-181a expression, and inhibits MAPK1 and MAP2K1 expression. This is accompanied by decreased phosphorylation of MAPK1 and MAP2K1, and decreased Slug expression levels. Ultimately, lncRNA-SNHG12 inhibits the activation of the MAPK/Slug pathway and increases the drug sensitivity of tumor cells (71). Similarly, lncRNA-XIST acts via microRNA to influence the activation of pathways. XIST regulates MAPK1 by targeting miR-194-5p-like ceRNA and reducing its expression. Silenced XIST inhibits the proliferation of hepatoma cells and reduces their invasiveness (72). In previous in vitro and in vivo studies of gallbladder carcinoma, the knockdown of MALAT1 was demonstrated to reduce the phosphorylation of MEK1/2, ERK1/2, MAPK and JNK 1/2/3, resulting in significant inhibition of the ERK/MAPK pathway. The metastasis and invasiveness of cancer cells is also weakened simultaneously (73). In a cecal ligation and puncture (CLP) rat model, the expression levels of p38, MAPK and NF-κB protein were significantly higher in the CLP group compared with that in the sham group (74). Overexpression of MALAT1 alone significantly increases the levels of p38/MAPK and NF-κB. An elaborative study demonstrated that MALAT1 mediates the development of heart failure and the inflammatory response through the activation of p38/MAPK/NF-κB. Furthermore, in the inflammatory response to sepsis, p38/MAPK/NF-κB may be downstream of MALAT1 signaling (74). In neuro-genic hyperplasia of neuroblastoma-derived Neuro-2a cells, silencing of MALAT1 results in significant activation of the MAPK pathway, and abnormal activation of the peroxisome proliferator-activated receptor and the p53 pathway (75). Thus, the same lncRNA appears to exhibit different effects in different types of tumors. When lncRNA-BANCR is deleted in lung cancer cells, the proliferation and metastasis of cancer cells is increased. In addition, when the expression of BANCR is increased, the proliferation of lung cancer cells is inhibited, acting as a tumor suppressor gene (76). In in vivo and in vitro experiments on malignant melanoma, tumor growth is inhibited following BANCR-knockout. The underlying mechanism may involve the silencing of BANCR making it difficult to activate the MAPK pathway, and to inhibit important components of the pathway, ERK1/2 and JNK (77). Table VI lists the lncRNAs that interact with the MAPK pathway in cancer.

Table VI lncRNAs that interact with the MAPK signaling pathway in cancer.

Table VI

lncRNAs that interact with the MAPK signaling pathway in cancer.

Author, year	lncRNA	Associated disease	Function	Effect on pathway	(Refs.)
Wang et al, 2017	SNHG12	Non-small cell lung cancer	Promote multidrug resistance	Positive	(71)
Kong et al, 2017	Xist	Hepatocellular carcinoma	Promote proliferation, migration and invasion	Positive	(72)
Wu et al, 2014	MALAT1	Gallbladder cancer	Promote proliferation and metastasis	Positive	(73)
Liu et al, 2017	MALAT1	Retinoblastoma	Promote proliferation and metastasis	Positive	(143)
Jiang et al, 2015	BANCR	Lung carcinoma	Promotes proliferation and migration	Positive	(76)
Li et al, 2014	BANCR	Malignant melanoma	Promote proliferation	Positive	(77)
Huang et al, 2015	TUG1	Non-small cell lung cancer	Inhibit tumorigenesis	Negative	(98)
Chen et al, 2017	PTENP1	Breast cancer	Inhibit proliferation and metastasis	Negative	(140)
Li et al, 2018	HOTAIR	Cervical cancer	Promote metastasis and invasion	Positive	(141)
Gao et al, 2017	CCAT1	Medulloblastoma	Promote proliferation and metastasis	Positive	(142)
Huang et al, 2015	DBH-AS1	Hepatocellular carcinoma	Promote proliferation	Positive	(144)
Peng et al, 2017	RoR	Breast cancer	Promote estrogen-independent tumor growth	Positive	(145)
Wu et al, 2017	NEAT1	Non-small cell lung cancer	Promote tumorigenesis	Positive	(146)
Peng et al, 2016	CCHE1	Hepatocellular carcinoma	Promote carcinogenesis	Positive	(147)

8. Discussion

The regulatory roles of lncRNAs are diverse and complex, and the current understanding of them is limited. The ENCODE research project identified <10,000 lncRNAs in the human genome (78), but only ~100 lncRNAs are known to be biologically functional. This is not only due to limited research techniques, but also the nature of lncRNAs. The intracellular abundance of lncRNA is typically low, and the function between different species is not conserved. For example, the human HOTAIR gene has a transregulatory effect on the HOXD gene, but this function is not observed in mice (79). Previous studies have demonstrated that lncRNAs primarily act as signal transduction molecules, decoys, transcription factors and scaffolds, interacting with proteins, DNA, RNA or other molecules to participate in transcriptional regulation, post-transcriptional regulation and epigenetic regulation of genes. The transcriptional regulation and posttranscriptional regulation of lncRNAs have been detailed, but their regulatory role in epigenetics is also an important function, and lncRNA-Xist is an interesting example (80,81). lncRNA-Xist is able to extensively bind to the X-chromosome through an interaction with polycomb repressive complex 2, leading to the inactivation of the X-chromosome (82,83). Recently, the novel silencing effect of Xist on the X-chromosome identified by Chen et al (84) has been debated. In the experiments by Chen et al (84), it was demonstrated that Xist interacts with Lamin B Receptor (LBR), a nuclear inner membrane protein involved in the establishment of the three-dimensional structures of chromosomes by regulating the anchoring of chromatin in the nucleus. It was hypothesized that the combination of Xist and LBR triggers alterations to the three-dimensional structure of the X-chromosome and thus participates in the silencing of the X-chromosome. This hypothesis was validated by constructing stable cell lines, LBS-Xist and LBS-Xist-BoxB, associated with Xist and LBR (84). However, a study by Wang et al questioned these findings. According to the analysis of the original sequencing data, it was considered that the Xist-associated stable cell lines, LBS-Xist and LBS-Xist-BoxB, were unsuccessfully constructed, and the sequencing depth and data normalization were also problematic (85). In response, the original research team provided more detailed evidence to confirm the results of their own research (86). Similar disputes reflect that, although lncRNAs have been recognized as having important biological functions, our understanding remains far from thorough. However, rational academic controversy makes lncRNA-associated research more rigorous.

The lncRNA research surge began with HOTAIR, first reported in cell by Rinn et al, in 2007 (2). As the first lncRNA reported to have a transregulatory effect, it became a popular topic of research. However, researchers still question the role of HOTAIR in mouse development, and it is considered that it may not be as important as previous studies have described (87,88). Furthermore, enrichment of the H3K27me3 modification of HOTAIR-regulated HOXD sites is not as pronounced as originally thought (79), and reports directly indicate that HOTAIR-knockout mice exhibit no apparent phenotypic changes (89). With some controversy, the differential expression of lncRNAs in a variety of types of cancer and chronic diseases have been confirmed. Several of the complex molecular mechanisms of lncRNA interaction have also been revealed. lncRNA research has improved our understanding of cell biological regulatory network, which is a step towards understanding the molecular mechanisms involved in disease. Although lncRNAs are currently at an early stage of research as potential targets for the treatment of cancer, certain small molecule lncRNAs have entered clinical trials as targeted drugs. It is expected that the targeted treatment of lncRNAs will become clinically available, improve the quality of life and prolong the survival of patients.

Funding

This grant was supported by National Science Foundation Committee of China (grant no. 81502482 and 81672474), Zhejiang Provincial National Science Foundation Committee of China (grant no. LQ14H160017) and Zhejiang Provincial research projects of medical and healthy industries (grant nos. 2015KYB026, 2017KY193 and 2017KY210).

Availability of data and materials

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Authors' contributions

YS, JYZ and HHC consulted and preliminarily summarized the literature required for the manuscript. WS was the major contributor in writing the manuscript. ZFW contributed to the writing of the manuscript. DSH and JGZ approved the final version of the manuscript. All authors read and approved the final manuscript.

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Competing interests

The authors declare that they have no competing interests.

Acknowledgments

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References