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Research progress of circular RNA related to Wnt/β-catenin signaling pathway in lung cancer

 The incidence and mortality of lung cancer rank first among malignant tumors [1]. Lung cancer can be divided into two categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Among them, NSCLC mainly includes large cell carcinoma, squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma. Studies have shown that the survival rate of lung cancer patients is closely related to the stage. As the disease progresses, the 5-year survival rate gradually decreases from 82% in stage IA to 6% in stage IV [2]. Therefore, it is very important to study the molecular mechanism of lung cancer occurrence and development, search for lung cancer biomarkers and explore new therapeutic targets. Circular RNA (circRNA) is a type of closed circular non-coding RNA with a length of at least a few hundred nucleotides and no 5 and 3 ends. Its abnormal expression can pass through the Wnt/β-catenin signaling pathway A variety of signaling pathways included in the regulation of lung cancer cell proliferation, migration, apoptosis and other capabilities [3]. Regarding the interaction between circRNA and Wnt/β-catenin signaling pathway to regulate target genes is a hot spot in basic research on lung cancer in recent years, but there is still a lack of generalization. This article reviews the effects of circRNA related to the Wnt/β-catenin signaling pathway on lung cancer, with a view to finding new biomarkers and potential therapies for the diagnosis of lung cancer.


1. The biological function of circRNA


circRNA is a kind of closed loop RNA molecule ubiquitous in the transcriptome. Due to the lack of 5 and 3 ends, they are not easily degraded by RNase and are therefore more stable than linear RNA. According to the source, circRNA is divided into exon circRNA (ecircRNA), intron circRNA (ciRNA), exon and intron combination circRNA (EIcircRNA) [4]. As a widely expressed non-coding RNA, circRNA mainly has the following four functions: ① Acting as a microRNA (miRNA) sponge, most of ecircRNA contains miRNA response elements, which can be used as miRNA sponge to effectively adsorb miRNAs and prevent them from interacting with target mRNA, and regulate mRNA expression and protein translation [5]. ②Regulate gene transcription. circRNA has been proven to regulate the transcription of parental genes. For example, EIcircRNA, which is mainly located in the nucleus, promotes the transcription of parental genes through the interaction of complementary sequences with U1 small ribonucleoprotein bodies (snRNP) [4]. ③CircRNA can be combined with RNA binding protein (RBP) to control gene expression. For example, circular blind muscle protein (circMBL) and its flanking intron contain a conservative MBL binding site, which specifically binds to MBL. When MBL is overexpressed At the same time, by competing with the mRNA linear shearing, the production of circMBL is promoted to reduce the production of self-related mRNA. circMBL can combine with excess MBL to reduce the level of MBL in the cell [6]. ④Encoding protein. Studies have shown that some circRNAs with internal ribosome entry sites (IRES) can participate in protein translation, and circ-ZNF609 with IRES during the differentiation process of mouse and human myoblasts contains initiation codons and The open reading frame of the stop codon can be translated to produce proteins to control the proliferation of myoblasts [7].


2. The expression and significance of circRNA in lung cancer


1. Early diagnosis value


The abnormal expression of circRNA in lung cancer can provide new research directions for early clinical diagnosis of lung cancer. According to reports, in the peripheral blood of NSCLC cancer tissues, NSCLC cell lines, gefitinib-resistant cell lines, and chemotherapy-resistant NSCLC patients, the expression of hsa_circRNA_012515 is significantly increased, and its expression is related to the stage of the disease. Compared with stage Ⅰ/Ⅱ NSCLC patients, the expression of hsa_circRNA_012515 in stage Ⅲ/Ⅳ was significantly up-regulated. In addition, the area under the diagnostic receiver operating characteristic (ROC) curve is 0.89, confirming that the expression of hsa_circRNA_012515 is related to overall survival and progression-free survival, suggesting that hsa_circRNA_012515 has good clinical significance and can be used for early screening of NSCLC[ 8].


2. Therapeutic value


At present, the targeted therapy of cancer is the research focus of many scholars. Studies have shown that circRNA can participate in the occurrence and development of lung cancer by affecting various life processes of lung cancer cells, and is expected to become a target for molecular therapy of lung cancer. The study of Li et al. [9] showed that the expression of hsa_circ_0087862 increased in NSCLC cancer tissues and was related to poor prognosis. Down-regulation of hsa_circ_0087862 significantly reduced the viability, migration and invasion capabilities of NSCLC cells, and induced cell apoptosis. In vivo and in vitro studies have confirmed that overexpression of hsa_circ_0087862 promotes the progress of NSCLC; functional assays indicate that hsa_circ_0087862 may upregulate Ras-related proteins by targeting miR-1253 ( Rab-3D) is expressed and exerts its carcinogenic effect in NSCLC. Therefore, hsa_circ_0087862 is expected to become a target for the treatment of NSCLC in the future. Xu et al. [10] used microarray technology to reveal that the overexpression of hsa_circ_0000326 is related to the tumor stage, lymph node metastasis and tumor differentiation of human lung adenocarcinoma, which indicates that hsa_circ_0000326 may be a potential therapeutic target for patients with lung adenocarcinoma.


3. Prognostic evaluation value


Some circRNAs are related to the poor prognosis of lung cancer patients, and it is expected that the treatment plan may be adjusted to extend the survival time of patients. For example, regulating transforming growth factor-β (TGF-β) can affect the prognosis of lung cancer patients. TGF-β can not only inhibit tumor progression caused by precancerous cells, but also promote tumor spread [11]. Huang et al. [12] observed that circRNA epithelial splicing regulatory protein-1 (circESRP1) enhanced the drug sensitivity of SCLC cells by inhibiting the TGF-β pathway, and compared with the parental chemosensitive cells, the expression of circESRP1 in chemotherapy-resistant cells Down-regulation, in xenograft models derived from patients with acquired chemotherapy resistance, further confirmed that high expression of circESRP1 and TGF-β/Smad pathway inhibition can increase tumor sensitivity to chemotherapy and improve prognosis. Research suggests that circESRP1 can be used in the treatment of SCLC patients resistant to chemotherapy, and is expected to become a prognostic biomarker and potential therapeutic target for NSCLC patients.


3. Wnt/β-catenin signaling pathway and lung cancer


The Wnt gene was discovered in a mouse breast cancer model by Nusse et al. in 1982, and was named the INT1 gene at that time. Wnt protein is a secreted glycolipoprotein, which is necessary for the specificity of cell death, cell proliferation, and control of asymmetric cell division. The Wnt signaling pathway is divided into the classic β-catenin-dependent pathway and the non-classical β-catenin-independent pathway [13]. The classic Wnt signaling pathway is the Wnt/β-catenin signaling pathway. In the physiology of the lung, there have been many studies on Wnt signaling, and most of them focus on the β-catenin-dependent pathway.


1. Wnt/β-catenin signaling pathway


In the classical pathway lacking Wnt, the β-catenin destruction complex is assembled by axis inhibitor protein (AXIN), colorectal adenoma polyp protein (APC), casein kinase 1α (CK1α) and glycogen synthase 3β (GSK3β), By phosphorylation of β-catenin serine and threonine sites, β-catenin is targeted for ubiquitination and degradation. When Wnt is present, the Wnt protein will bind to the frizzled receptor (FZD) on the target cell membrane, forming a receptor complex between Wnt, FZD, LDL receptor-related protein (LRP), disheveled protein (DVL) and AXIN. In this active complex, DVL phosphorylates and ultimately inhibits GSK3β, which leads to an increase in non-phosphorylated β-catenin, which stops proteasome hydrolysis and destroys β-catenin, which then accumulates in the cytoplasm and transfers to the nucleus. The increase of β-catenin in the nucleus can enhance its interaction with T cell factor (TCF)/lymphoid enhancer factor (LEF) or other transcription factor co-regulators, such as target genes c-myc, cyclin D1 (cyclinD1), etc. Play a transcriptional activation role [13].


2. Wnt/β-catenin signaling pathway and lung cancer progression


Tumor drug resistance and epithelial-mesenchymal transition (EMT) are the keys to tumor invasion and metastasis. Recent studies have shown that this is closely related to the existence of cancer stem cells. Wnt/β-catenin signaling pathway can promote NSCLC to have cancer stem cell-like characteristics and EMT phenotype. Liu et al. [14] reported that Oct4/Nanog ectopic co-expression makes NSCLC cells have cancer stem cell characteristics, including self-renewal, drug resistance, EMT, and high tumorigenicity. Further studies have shown that Oct4/Nanog may be caused by Wnt/β-catenin. Signaling pathways are activated to regulate drug resistance and EMT changes, and silencing β-catenin counteracts this effect. In addition, changes in the components of the Wnt/β-catenin signaling pathway can affect the progression of lung malignant tumors. For example, Xu et al. [15] found that changes in the expression of Wnt1 and β-catenin in NSCLC are markers of poor prognosis.


Negative regulators of Wnt pathway can show significant anti-tumor effects on lung cancer cells by inhibiting canonical Wnt pathway, suggesting the potential of Wnt/β-catenin signaling pathway related molecules in the treatment of lung cancer. Its negative regulators include Wnt inhibitory factor 1 (WIF1), secreted frizzled-related protein (sFRP) family and members of Dickkopf (DKK) family.



 

WIF1 is a secretory antagonist of Wnt signaling. A study by Hsieh et al. (1999) showed that WIF1 recognizes and binds to Wnt protein outside the cell. Luo et al. [16] showed that WIF1 may induce autophagy in NSCLC cells through the PI3K/Akt/mTOR pathway, and then reduce the expression levels of DVL-2 and downstream molecules β-catenin, further inhibit Wnt signal transduction, thereby regulating NSCLC cells Proliferation and apoptosis. In addition, combined transfection with a gene vector overexpressing WIF1 and an autophagy agonist can effectively enhance the inhibitory effect of WIF1 on NSCLC cells, which may become a new strategy for the treatment of NSCLC.


The sFRP family is the main antagonist of the Wnt pathway, which can regulate the Wnt/β-catenin signaling pathway by competing with the FZD receptor for extracellular Wnt ligands. The study by Schlensog et al. [17] clarified that the expression of sFRP3 in lung adenocarcinoma cells was significantly reduced, and the level of DNA methylation of sFRP3 was increased. The study also confirmed that sFRP3 may block the Wnt1-FZD receptor interaction by binding to Wnt1, further reducing the expression of Wnt target genes and inhibiting cell proliferation in a Wnt1-dependent manner.


DKK3 is one of the most typical antagonists of canonical Wnt signaling. Yue et al. (2008) reported that due to the hypermethylation of the DKK3 promoter, the expression of DKK3 in lung cancer tissues was significantly reduced compared with normal tissues. Its reactivation can induce cell cycle arrest and apoptosis, delay cell growth, reduce the invasion ability of cancer cells, and enhance the sensitivity of cisplatin-resistant cell lines to cisplatin. This may be due to β-catenin and matrix metalloproteinases. -7 (MMP-7), survivin, c-myc and cyclinD1 decreased expression [18].


The impact of circRNA related to Wnt/β-catenin signaling pathway on lung cancer


circRNA can regulate gene expression through molecular interactions related to the Wnt/β-catenin signaling pathway, affect the transcription process, and promote cancer progression. Related studies on lung cancer have shown that a variety of circRNAs can regulate the biological process of lung cancer by targeting miRNAs and interacting with the Wnt/β-catenin signaling pathway. Gao et al. [19] reported that high expression of circ-SOX4 can promote the activity of Wnt pathway, while low expression of circ-SOX4 inhibits the activity of Wnt pathway. At the same time, the study further revealed that circ-SOX4 can promote the development of lung adenocarcinoma by targeting the miR-1270/polymorphic adenoma gene-like protein 2 (PLAGL2) axis and stimulating the Wnt pathway.


E3 ubiquitin protein ligase (ITCH) mainly inhibits the Wnt/β-catenin signaling pathway in cancer by degrading phosphorylated DVL-2. Wan et al. [20] reported that compared with adjacent tissues, the expression of circ-ITCH in lung cancer tissues was significantly reduced, and was related to advanced TNM staging. In addition, circ-ITCH could inhibit the proliferation of A549 and NIC-H460 cells. Further experiments It shows that circ-ITCH can act as a sponge for oncogenic miRNA-7 and miRNA-214, up-regulate ITCH and inhibit the activation of Wnt/β-catenin signaling pathway. Tian et al. [21] reported that overexpression of hsa_circ_0043256 can inhibit the proliferation of NSCLC cells and induce apoptosis, while the knockdown of hsa_circ_0043256 is the opposite. hsa_circ_0043256 can also be used as a sponge of miR-1252 to upregulate Wnt/β-catenin signaling pathway inhibitor ITCH. The above studies suggest that circ-ITCH and hsa_circ_0043256 can inhibit the Wnt/β-catenin signaling pathway by promoting the expression of ITCH in lung cancer.


Gao et al. [22] reported that hsa_circ_0007059 can be combined with


miRNA-378 reduced the expression levels of Wnt3a and β-catenin in lung cancer cells A549 and H1975, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway cascade. The study of Li et al. [23] found that hsa_circ_0058124 is highly expressed in lung cancer tissues.


hsa_circ_0058124 silencing can inhibit lung cancer cell viability, clone formation, migration and invasion, while promoting apoptosis, and inhibit the expression of β-catenin in the Wnt/β-catenin signaling pathway. miRNA-1297 inhibitors can eliminate this inhibitory effect, indicating hsa_circ_0058124 may be combined with miRNA-1297 to affect the Wnt/β-catenin signaling pathway to play a carcinogenic effect.


 

Studies have shown that Silent Information Regulator 1 (SIRT1) can promote the activation of Wnt/β-catenin signaling pathway [24]. miR-135a-5p binds to the 3-untranslated region of SIRT1 and reduces its expression. circ_001946 up-regulates SIRT1 expression in a miRNA-135a-5p-dependent manner and activates the Wnt/β-catenin signaling pathway in A549 and H1299 lung cancer cell lines. Promote the proliferation of lung cancer cells [25]. DKK1 is an inhibitor of the Wnt/β-catenin signaling pathway, which can relieve the interaction between LRP5/6 and FZD and inhibit this pathway. Yao et al. [26] showed that circ_0006427 inhibits lung adenocarcinoma cell proliferation, migration, invasion and EMT progression through sponge adsorption of miRNA-6783-3p, and at the same time up-regulates the expression level of DKK1 to inactivate the Wnt/β-catenin signaling pathway, suggesting circ_0006427 It can regulate the miRNA-6783-3p/DKK1 axis and Wnt/β-catenin signaling pathway to prevent the progression of lung adenocarcinoma.


In addition to circRNA-miRNA regulation, circRNA regulates Wnt/β-catenin signaling pathway and cancer development by directly regulating gene transcription, protein translation and other mechanisms. The high expression of circ_001569 up-regulates the expression of TCF4, Wnt1 and β-catenin, thereby activating the Wnt/β-catenin signaling pathway and enhancing the proliferation of A549 and H1299 cells [27]. hsa_circ_000984 activates Wnt/β-catenin and promotes the invasion, proliferation, migration and EMT of NSCLC cells [28]. Lv et al. [29] found that forkhead box protein M1 (FOXM1) is up-regulated in lung adenocarcinoma, and its transcription activates the expression of circ_0039411 (also known as circ-MMP-2) from MMP-2, which is β -Known downstream target of catenin. It is proved that FOXM1 can assist the nuclear translocation of β-catenin to promote the initiation of downstream genes. In addition, after knocking down the expression of circ_0039411, FOXM1 hinders the growth and metastasis of lung adenocarcinoma in vivo and in vitro, and it is verified by RIP analysis that circ_0039411 can recruit insulin-like Growth factor 2 mRNA binding protein 3 (IGF2BP3) enhances the stability of FOXM1 mRNA. It can be seen that circ-MMP-2 can regulate the Wnt/β-catenin signaling pathway through a complex positive feedback loop, which is a potential therapeutic target for lung cancer. Provides a new direction.


The related research of circRNA and Wnt/β-catenin signaling pathway in lung cancer is shown in Table 1, and the regulation mechanism is shown in Figure 1.


V. Conclusions and prospects


Lung cancer is the leading cause of cancer deaths worldwide. Although the diagnosis and treatment of lung cancer have made progress in recent years, the survival rate of lung cancer patients is still very low. Therefore, studying the regulatory mechanisms of lung cancer cells is essential for the development of new therapeutic targets. circRNA is a new field of cancer research and is involved in the important biological process of lung cancer. It has been confirmed that circRNA can regulate downstream targets closely related to tumorigenesis, metastasis, invasion, malignant transformation and signal transduction. Among the various signaling pathways that mediate the occurrence of lung cancer, the complex dysregulation of the Wnt/β-catenin signaling pathway is one of the important factors in the occurrence of lung cancer, and may be involved in controlling or partially controlling the occurrence and progression of lung cancer. In lung cancer, circRNA interacts with the Wnt/β-catenin signaling pathway, which may act as a "sponge" of miRNA or key molecules that regulate this pathway, such as Wnt, FZD and β-catenin. Wnt/β-catenin signaling pathway-related circRNA may become a new biomarker, a new therapeutic target for blocking or eradicating lung cancer. Therefore, further exploration of the specific mechanism of this interaction will bring a more effective plan for the clinical diagnosis and treatment of lung cancer in the future.

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