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Role of the lncRNA/Wnt signaling pathway in digestive system cancer: a literature review

European Journal of Medical Research volume 29, Article number: 447 (2024) Cite this article

Abstract

The long noncoding RNA (lncRNA)/Wingless (Wnt) axis is often dysregulated in digestive system tumors impacting critical cellular processes. Abnormal expression of specific Wnt-related lncRNAs such as LINC01606 (promotes motility), SLCO4A1-AS1 (promotes motility), and SH3BP5-AS1 (induces chemoresistance), plays a crucial role in these malignancies. These lncRNAs are promising targets for cancer diagnosis and therapy, offering new treatment perspectives. The lncRNAs, NEF and GASL1, differentially expressed in plasma show diagnostic potential for esophageal squamous cell carcinoma and gastric cancer, respectively. Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

Background

Digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, constitute a significant proportion of global cancer incidence and mortality, imposing a substantial burden on global public health [1]. These tumors often remain undetected until advanced stages, leading to diminished prognosis and survival rates. Despite extensive research, the pathogenesis of most digestive system cancers remains poorly understood, and viable treatment options are limited. This presents a formidable challenge in developing targeted therapies.

Long noncoding RNA (lncRNA), devoid of protein-coding potential, can interact with microRNA (miRNA) or RNA-binding proteins, influencing the biological activity of downstream signaling pathways [2,3,4,5]. Thanks to RNA sequencing technology and bioinformatics tools, lncRNAs were found to be involved in cellular processes such as cell proliferation, transcriptional regulation, and signal transduction [6,7,8,9]. Recent findings have shown that long noncoding RNAs (lncRNAs) exhibit various expression patterns and have multiple functions. As a result, they play a crucial role in ongoing biomedical research. Recently, research on lncRNAs has expanded to include digestive system tumors. Abnormal lncRNA expression in these tumors is associated with crucial oncogenic processes, including uncontrolled cell proliferation, enhanced invasion, and increased metastatic potential [10, 11].lncRNAs affect tumor development by regulating gene expression and signal pathways [12,13,14]. Notably, lncRNAs’ involvement in the Wingless (Wnt)/β-catenin signaling pathway, which regulates normal physiological processes, has been identified as a significant factor in the progression of various digestive system cancers [15, 16]. Certain lncRNAs such as lncRNA GASL1, lncRNA MEG3, and NEF, can interact with genes linked to the Wnt pathway and modulate the transmission and activity of Wnt signals in digestive system tumors [17,18,19]. This regulatory effect may be achieved through various mechanisms. LncRNAs can act as miRNA sponges, which modulates the targeted regulation of Wnt pathway-related genes. For instance, lncRNA PART1 functions as a competitive endogenous RNA (ceRNA) in colorectal cancer, sequestering miR-150-5p and miR-520 h, resulting in the upregulated expression of CTNNB1 and the activation of the Wnt/β-catenin pathway [20]. Dysregulation of these mechanisms may lead to abnormal Wnt pathway activation, contributing to the development of digestive system tumors. This review focuses on understanding the roles and molecular mechanisms of long noncoding RNAs (lncRNAs) associated with the Wnt pathway in digestive system tumors. By gaining deeper insights into these mechanisms, we aim to identify potential lncRNA targets for therapeutic intervention.

lncRNA and Wnt signaling pathway

Significance of the Wnt pathway

The Wingless (Wnt) gene was first identified through random mutagenesis screening of fruit flies (Drosophila melanogaster) [21, 22]. Mutations in the Wnt gene inhibited wing development and created abnormal larval segmentation in fruit flies. The Wnt protein, forms a complex with Frizzled receptors and the low-density-lipoprotein receptor-related protein (LRP) to regulate β-catenin activity within cells, which influences processes such as cell proliferation, differentiation, and directional migration [23,24,25,26]. The Wnt signaling pathway comprises two distinct intracellular signaling pathways: the canonical and noncanonical Wnt pathway. The noncanonical Wnt pathway includes, Ca2+ pathway, and planar cell polarity (PCP) pathway [27, 28].

In the canonical Wnt pathway, Wnt signals primarily activate the Frizzled receptor-LDL receptor-related proteins (LRPs) complex [29, 30]. Wnt ligand binding leads to the stabilization and nuclear translocation of β-catenin [31]. In the absence of Wnt signaling, glycogen synthase kinase 3beta (GSK3beta) and other kinases phosphorylate β-catenin, marking it degradation, thus maintaining a low basal level of β-catenin in the cytoplasm [32, 33]. When the Wnt ligand binds to the Frizzled receptor and LRP complex, the complex undergoes a conformational change, ultimately activating the Frizzled receptor. This triggers a cascade of signaling events, including the inhibition of GSK3β phosphorylation and the release of Axin, which results in the accumulation of unphosphorylated and stable β-catenin in the cytoplasm. Stabilized β-catenin translocate into the nucleus and interacts and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors [34, 35]. This, in turn, promotes the expression of specific genes involved in regulating cell proliferation, differentiation, and survival.

Dysregulation of Wnt signaling in digestive system tumors

Aberrant Wnt signaling is a hallmark of many digestive system cancers, including colorectal cancer, gastric cancer, hepatocellular carcinoma (HCC), and pancreatic cancer [16, 36,37,38]. Mutations in key Wnt pathway components, such as β-catenin, and Axin, often lead to constitutive activation of Wnt signaling, resulting in uncontrolled cellular proliferation and survival, thereby contributing to tumorigenesis and cancer progression [16, 39, 40]. In colorectal cancer, mutations in the adenomatous polyposis coli (APC) gene are common, causing nuclear accumulation of β-catenin and subsequent activation of oncogenic Wnt target genes [41]. Similar mutations in β-catenin prevent its degradation, sustaining an activated Wnt signaling, which disrupts normal gastrointestinal homeostasis. These alterations in β-catenin and APC are commonly observed in gastric cancer [42]. Additionally, hypermethylation of Wnt antagonist genes like secreted frizzled-related protein (SFRP) and Dickkopf (DKK) reduces the inhibition of Wnt signaling [43, 44]. High levels of nuclear β-catenin in gastric cancer correlate with poor prognosis and advanced stages of the disease, suggesting a role in tumor aggressiveness and metastasis [45,46,47]. In HCC, prevalent mutations in CTNNB1 (encoding β-catenin) stabilize β-catenin, promoting transcription of genes that support cell proliferation and survival [48, 49]. Epigenetic alterations, such as promoter hypermethylation of Wnt suppressors, such as SFRP1 and DKK1, further contribute to enhanced Wnt signaling in HCC, which promotes, cell invasion, and tumor growth [50,51,52,53,54]. While mutations in Wnt pathway components are less common in pancreatic cancer, upregulation of Wnt ligands and receptors is frequently observed, which is sufficient to sustain Wnt signaling and contribute to cancer stem cell maintenance [55, 56]. Wnt signaling interacts with other pathways, such as Hedgehog and Notch, creating a complex network that drives pancreatic tumor growth and metastasis.

Comprehensive overview of lncRNAs

Initially considered transcriptional noise due to their lack of protein-coding potential [57, 58], long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression [59], thanks to advancements in high-throughput sequencing technologies. LncRNAs are RNA molecules, exceeding 200 nucleotides in length, characterized by their inability to code for proteins. They are classified based on their genomic location relative to protein-coding genes [60, 61]. The biogenesis of lncRNAs involves transcription by RNA polymerase II, including the addition of a 5' cap and polyadenylation at the 3' end, like messenger RNAs (mRNAs) [62, 63]. LncRNAs also undergo splicing, although the mechanisms can highly vary compared to mRNAs. These RNAs can be transcribed from various genomic loci, including intergenic regions, introns, and promoters of protein-coding genes. The primary categories include intergenic lncRNAs, intronic lncRNAs, sense lncRNAs, antisense lncRNAs, and bidirectional lncRNAs. Unlike mRNA, which carries the genetic code for protein synthesis, lncRNAs are involved in a diverse range of cellular processes [64]. By interacting with miRNAs, RNA-binding proteins, and other components of cellular machinery, lncRNAs regulate gene expression, eventually impacting various downstream signaling pathways [65,66,67]. The study of lncRNAs has provided significant insights into the complexities of gene regulation, revealing their crucial roles in cellular function and diseases, such as cancer, cardiovascular disorders, and neurological disorders [68,69,70]. In the context of cancer, lncRNAs can function as oncogenes or tumor suppressors, influencing various aspects of tumor biology. Understanding the roles of lncRNAs could lead to novel therapeutic strategies for treating these malignancies. LncRNAs affects the development of digestive system tumors by regulating gene expression and signal pathway activity. Abnormal expression of lncRNAs in these tumors is closely linked to key biological functions such as cell proliferation, invasion, and metastasis [71]. The expression levels of certain lncRNAs are either significantly upregulated or downregulated in digestive system tumor tissues, correlating with clinical features such as tumor grade, prognosis, and treatment response [72].

The crucial role of the lncRNA/Wnt axis in digestive system tumors

Dysregulation of the lncRNA/Wnt axis affects cell self-renewal and differentiation properties of cancer stem cells, as well as tumor cell proliferation, survival, and invasion. The lncRNA/Wnt axis also promotes epithelial–mesenchymal transition (EMT), tumor metastasis capabilities, and resistance to apoptosis. Additionally, lncRNAs modulate the expression of genes within the Wnt signaling pathway related to drug resistance, thereby reducing tumor sensitivity to chemotherapeutic agents. Consequently, extensive research is dedicated to targeting the lncRNA/Wnt axis to formulate effective therapeutic strategies for digestive system tumors. Understanding the lncRNA/Wnt axis dynamics can revolutionize patient management by identifying new therapeutic avenues for digestive system tumors.

Wnt pathway-associated lncRNAs in digestive system cancer

Esophageal cancer

Role of Wnt pathway-associated lncRNAs in promoting esophageal cancer

In esophageal squamous cell carcinoma (ESCC), the lncRNAs MYU, HERES, SNHG16, HOTAIR, and DGCR5 are notably upregulated (Fig. 1) [73,74,75,76,77]. These lncRNAs interact with the Wnt signaling pathway, playing significant roles in cancer progression. Overexpression of lncRNA MYU is linked to advanced clinicopathological features including higher histopathological grade, tumor invasion severity, lymph node metastasis, and advanced TNM stage in esophageal cancer patients (Table 1) [73]. Similarly, SNHG16 expression correlates with advanced tumor stage, lymph node metastasis, while HOTAIR expression is associated with higher histologic grade and nodal status in ESCC patients [75, 76]. Elevated DGCR5-S levels are connected to tumor recurrence, larger tumor size, lymph node metastasis, and advanced clinical stages in ESCC [78]. High expression levels of these lncRNAs (MYU, HERES, SNHG16, HOTAIR, and DGCR5-S) predict poorer prognosis, with HERES expression particularly reducing stage-free survival rates [73,74,75]. Functionally, lncRNA MYU and HERES promoted cell proliferation, migration, and invasion in ESCC cells, while HOTAIR specifically enhanced migration and invasion capabilities (Table 2) [73, 74, 76]. DGCR5-S promotes tumor aggression by encouraging macrophage infiltration, increasing cancer-associated fibroblasts, and stimulating angiogenesis [77]. Reducing lncRNA MYU expression leads to smaller tumors in nude mice and lower Ki-67 levels, indicating its role in tumor growth [73]. LncRNA MYU regulates the Wnt/β-catenin signaling pathway; its downregulation decreases the expression of key molecules like Wnt, β-catenin, and c-Myc, thereby attenuating oncogenic effects (Fig. 2) [73]. The Wnt/β-catenin pathway agonist CT99021 can counteract the oncogenic effects of lncRNA, such as tumor invasion [73]. HERES activates Wnt signaling through interaction with EZH2 through a G-quadruplex structure-like motif [74]. LncRNA MYU promotes cell invasion through the activation of the Wnt/β-catenin signaling pathway. HOTAIR exerts a direct inhibitory effect on WIF-1 expression by facilitating histone H3K27 methylation in the promoter region, consequently activating the Wnt/β-catenin signaling pathway [76]. DGCR5S increases metastatic potential by stimulating Wnt/β-catenin signaling through a splicing switch induced by Wnt3a, generating a shorter variant called DGCR5-S [79], which also promotes angiogenesis and macrophage infiltration. Targeting the Wnt/β-catenin signaling pathway effectively downregulates DGCR5-S expression, thereby suppressing ESCC progression [79].

Fig. 1
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Wnt pathway-associated lncRNAs in digestive system tumors

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Table 1 Expression and clinical characteristics of the lncRNA/Wnt axis in digestive system tumors
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Table 2 Function and mechanism of the lncRNA/Wnt axis in digestive system tumors
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Fig. 2
figure 2

lncRNAs exert a critical influence by modulating the Wnt pathway in esophageal cancer. On the one hand, molecules involved in the Wnt/β-catenin signaling pathway, including Wnt, β-catenin, and c-Myc, showed significantly downregulated expression following MYU downregulation. HERES triggers the Wnt signaling pathway by engaging EZH2 in esophageal cancer. HOTAIR inhibits WIF-1 to activate Wnt/β-catenin signaling through the PRC2 complex. Targeting Wnt/β-catenin signaling can downregulate DGCR5-S expression and suppress ESCC progression. On the other hand, MEG3 interacts with miR-4261, reducing DKK2 and blocking Wnt/β-cat signaling. NEF inhibits the onset of the cellular malignant phenotype by inactivating Wnt/β-cat signaling. The Wnt pathway-associated lncRNA GASL1 suppresses esophageal cancer progression by upregulating DKK1 expression

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Role of Wnt pathway-associated lncRNAs in suppressing esophageal cancer

In ESCC cell lines, the expression of lncRNAs GASL1, lncRNA MEG3, and NEF is downregulated [17,18,19]. MEG3 expression negatively correlates with tumor size, lymph node metastasis, and clinical stage in ESCC [18]. NEF upregulation in serum significantly associates with tumor size and distant metastasis [19]. Overexpression of GASL1, MEG3, and NEF suppresses cell proliferation, migration, and invasion in esophageal cancer [17,18,19]. GASL1 overexpression notably arrests ESCC cells in the G0/G1 phase while reducing the S phase cell population and inhibiting tumor growth in vivo [17]. Mechanistically, the inhibition of DKK1 enhances Wnt3a/β-catenin signaling, counteracting GASL1’s suppressive effects on cellular functions (Fig. 2) [17]. The interaction between DKK1 and GASL1 is critical in in modulating these biological processes [17]. MEG3 interacts with miR-4261, leading to the suppression of the Wnt/β signaling inhibitor, Dickkopf-2 (DKK2), and subsequent blockade of the Wnt/β-catenin signaling pathway [18]. Wnt activator administration does not significantly affect NEF, but a Wnt inhibitor effectively diminishes NEF's impact on key cellular processes [19]. These findings suggest that inhibiting Wnt signaling can counteract NEF dysregulation, underscoring its potential therapeutic significance [19].

Gastric cancer

Role of Wnt pathway-associated lncRNAs in promoting gastric cancer

The expression levels of SNHG11, lncRNA HOXC-AS1, ZEB2-AS1, H19, and LINC01226 are significantly elevated in gastric cancer tissues and cell lines [46, 80,81,82,83,84]. Elevated SNHG11 levels are associated with advanced stage or metastasis in gastric cancer patients, while H19 levels positively correlate with tumor grades [46, 83]. Patients with increased levels of SNHG11, H19, and LINC01226 have shorter overall survival (OS) [46]. Functionally, SNHG11, lncRNA HOXC-AS1, ZEB2-AS1, and LINC01226 promote cell proliferation and migration in gastric cancer [46, 81, 84, 85]. SNHG11 also enhances stemness in gastric cancer cell lines [46]. Knockdown of ZFAS1 increases sensitivity to cisplatin or paclitaxel, while [82] silencing H19 significantly reduces metastatic nodules in the lung and liver [83]. Downregulation of SNHG11 results in slower tumor growth and reduced levels of the stemness marker, CD133, in gastric cancer [46]. Mechanistically, SNHG11 and HOXC-AS1 enhance cell invasion by interacting with CUL4A and eIF4AIII, respectively, to activate the Wnt/β-catenin pathway [46]. SNHG11 also regulates autophagy independently of this mechanism [46]. HOXC-AS1 can enhance proliferation, promote EMT, and inhibit apoptosis through its interaction with eIF4AIII in the Wnt/β-catenin signaling pathway [85]. Knockdown of ZFAS1 suppresses cell motility and chemotherapeutic tolerance although these effects can be reversed by β-catenin overexpression [82]. H19 facilitates β-catenin translocation into the nucleus, activating the Wnt/β-catenin pathway and promoting cell motility and metastatic potential [86]. LINC01226 disrupts the STIP1-HSP90 complex, enhancing Wnt/β-catenin signaling and metastatic potential.

Role of Wnt pathway-associated lncRNAs in suppressing gastric cancer

LINC01133 expression is reduced in ESCC tissues and cell lines [87, 88], and its expression negatively correlates with tumor size, distant metastasis, and peritoneum dissemination in gastric cancer patients [87]. Patients with low LINC01133 expression have a significantly poorer prognosis [87]. Similarly, a decrease in serum GASL1 levels is observed, which negatively correlates with overall survival (OS) in gastric cancer patients [88]. Serum GASL1 levels may serve as a prognostic biomarker for gastric cancer. Functionally, LINC01133 and GASL1 inhibit cell proliferation [87, 88]. The LINC01133/miR-106a-3p/APC axis governs metastasis in gastric cancer cells in a Wnt-dependent manner [87]. The inhibitory effect of GASL1 overexpression on cell growth is diminished by treatment with a Wnt agonist, suggesting [88] that the Wnt agonist interacts with pathways downstream of GASL1. Further investigation is needed to elucidate these mechanisms and their potential therapeutic implications.

Liver cancer

Role of Wnt pathway-associated lncRNAs in promoting liver cancer

In liver cancer, the expression of lncRNAs, including PRR34-AS1, SNHG5, lncRNA-DAW, FOXD2-AS1, CTB-193M12.5, lncRNA-CR594175, and lncRNA-MUF is significantly upregulated. Among these, SNHG5 is notably correlated with clinical features such as tumor size, histologic grade, and TNM stage in HCC [89]. Additionally, lncRNA-CR594175 expression was higher in metastatic HCC than in primary HCC [90]. Elevated levels of SNHG5, FOXD2-AS1, and CTB-193M12.5 are linked to poorer prognosis [89, 91, 92]. Functionally, PRR34-AS1, SNHG5, lncRNA-DAW, FOXD2-AS1, CTB-193M12.5, and lncRNA-CR594175 enhance the cell proliferation in liver cancer [8, 90,91,92,93,94]. lncRNA-MUF promotes EMT, contributing to HCC progression, although its role in cell proliferation remains to be explored [95]. SNHG5 also augments the cancer stem cell (CSC)–like properties of HCC cells, indicated by a reduced expression of CSC markers (CD44, CD133, and ALDH1) and transcription factors (OCT4, SOX2, and NANOG) upon SNHG5 knockdown [8]. Mechanistically SNHG5 promotes HCC cell proliferation and CSC–like properties by modulating UPF1 and the Wnt/β-catenin pathway (Fig. 3). Treatment with XAV-939, an inhibitor of the Wnt/β-catenin pathway, impairs spheroid formation and reduces the number of spheroids in liver CSCs, suggesting its potential as a therapeutic agent for targeting CSCs self-renewal [8]. Furthermore, lncRNA-DAW enhances invasion by activating Wnt2 through EZH2 degradation [94]. FOXD2-AS1, upregulated by EGR1, drives HCC progression by silencing DKK1 and activating Wnt/β-catenin signaling [91]. CTB-193M12.5 promotes WNT10B transcription via epigenetic activation, further enhancing Wnt/β-catenin signaling [92]. Suppression of lncRNA-CR594175 inhibits HCC cell growth by restoring hsa-miR-142-3p’s regulation of CTNNB1 [90]. Additionally, lncRNA-MUF promotes metastasis by binding to Annexin A2 (ANXA2) and activating the Wnt/β-catenin signaling pathway [95].

Fig. 3
figure 3

Mechanisms of the lncRNA/Wnt axis in liver cancer. lncRNA PRR34-AS1 promotes the development of hepatocellular carcinoma (HCC). LncRNA PRR34-AS1 plays a pivotal role in hepatocellular carcinoma (HCC) development by modulating the miR-296-5p/E2F2/SOX12/Wnt/β-catenin axis. It achieves this by absorbing miR-296-5p and upregulating the expression of E2F2 and SOX12, both of which are critical for HCC progression. Additionally, SNHG5 regulates liver cancer progression by modulating UPF1 and the Wnt/β-catenin pathway. In liver cancer, lncRNA-DAW facilitates EZH2 degradation, leading to Wnt/β-catenin pathway activation. Furthermore, the upregulated expression of lncRNA FOXD2-AS1, induced by EGR1, drives HCC progression by silencing DKK1 and activating the Wnt/β-catenin signaling pathway. CTB-193M12.5 promotes WNT10B expression to facilitate HCC progression. Lastly, lncRNA-CR594175 enhances the Wnt pathway, promoting HCC cell growth by downregulating miR-142-3p. Additionally, lncRNA-MUF promotes HCC progression by binding to Annexin A2 (ANXA2) and activating the Wnt/β-catenin signaling pathway

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Role of Wnt pathway-associated lncRNAs in suppressing liver cancer

Conversely, lncRNAs KB-68A7.1 and lncRNA-NEF are significantly downregulated in liver cancer [96, 97]. Patients with lower lncRNA-NEF expression exhibit larger tumors, more aggressive clinical characteristics, and poorer survival outcomes. [96]. Overexpression of lncRNA-NEF inhibits EMT and cell migration, while in vivo studies show that lncRNA-NEF and KB-68A7.1 suppress HCC tumor growth and metastasis [96, 97]. Mechanistically, KB-68A7.1 exerts its tumor-suppressive effects by sequestering NSD1 in the cytoplasm, reducing WNT10B transcription and repressing Wnt/β-catenin signaling, and ultimately inhibiting tumor progression [96]. The reduced cellular proliferation and motility from KB-68A7.1 overexpression was reversed by ectopic WNT10B expression, while the Wnt/β-catenin signaling inhibitor ICG-001 counter the proliferation effects of KB-68A7.1 overexpression [96], highlighting its therapeutic potential. Additionally, lncRNA-NEF interacts with β-catenin, enhancing the association between GSK3β and β-catenin [97], thereby elucidating its role in HCC metastasis through the Wnt/β-catenin pathway.

Colorectal cancer

Role of Wnt pathway-associated lncRNAs in promoting colorectal cancer

Several Wnt pathway-related lncRNAs including STEAP3-AS1, MIR100HG, LEF1-AS1, PART1, LINC01606, H19, SLCO4A1-AS1, AC010789.1, CRNDE, and HOTAIR, are significantly upregulated in colorectal cancer [20, 98,99,100,101,102,103,104,105,106]. Cetuximab, a commonly used targeted therapy for colorectal cancer, often leads to drug resistance during treatment. Elevated levels of LINC01606 and AC010789 are positively associated with lymph node metastasis, and LINC01606 is also linked to distant metastasis [101, 104]. Patients with increased expression of STEAP3-AS1, LINC01606, H19, SLCO4A1-AS1, AC010789.1, CRNDE, and HOTAIR have a worse prognosis [98, 101,102,103,104,105,106]. Functionally, the overexpression of STEAP3-AS1, LEF1-AS1, PART1, LINC01606, H19, SLCO4A1-AS1, and AC010789.1 promotes cell proliferation, migration, and invasion in colorectal cancer cell lines [20, 100,101,102,103,104, 107]. Conversely, the downregulation of MIR100HG, CRNDE, and HOTAIR significantly lowers cetuximab resistance in colorectal cancer cells, in vitro and in vivo [99, 108]. Suppression of LEF1-AS1 inhibits tumor growth, as well as liver and lung metastasis in vivo [100]. Mechanistically, STEAP3-AS1 drives colorectal cancer progression by regulating the STEAP3/GSK3β/Wnt/β-catenin axis [98]. Downregulation of STEAP3-AS1 triggers cytoplasmic sequestration of β-catenin, which can be reversed by reintroducing STEAP3, thereby promoting invasion and metastasis [109]. MIR100HG interacts with hnRNPA2B1 to stabilize TCF7L2 mRNA, a crucial coactivator in Wnt/β-catenin signaling [108]. LEF1-AS1 promotes cell motility by increasing FUT8 expression and α1,6-fucosylation levels via the Wnt/β-catenin pathway [100]. PART1 acts as a ceRNA, sequestering miR-150-5p and miR-520 h, leading to upregulated expression of CTNNB1 and subsequent activation of the Wnt/β-catenin pathway, thereby promoting cell migration and invasion [20]. The H19/miR-29-3b/PGRN/Wnt signaling pathway promotes the onset of EMT in colorectal cancer [102]. SLCO4A1-AS1 interferes with the interaction between β-catenin and GSKβ, reducing β-catenin phosphorylation and enhancing stability in colorectal cancer cells [103]. CRNDE facilitates colorectal cancer cell proliferation and chemoresistance through the miR-181a-5p/Wnt/β-catenin axis [105].

Pancreatic cancer

Role of Wnt pathway-associated lncRNAs in promoting pancreatic cancer

In pancreatic cancer tissues and cell lines, the expression of PVT1, SH3BP5-AS1, LINC01614, OIP5-AS1, and FAM83H-AS1 is significantly upregulated (Fig. 1) [110,111,112,113,114]. Elevated levels of SH3BP5-AS1, LINC01614, and FAM83H-AS1 correlate with a worse prognosis [111, 112, 114]. Gemcitabine (GEM), a commonly used first-line chemotherapeutic drug for pancreatic cancer, faces challenges such as drug resistance and side effects. PVT1 has been shown to promote GEM resistance in pancreatic cancer cells, confirmed through in vivo studies [110]. Additionally, SH3BP5-AS1, LINC01614, OIP5-AS1, and FAM83H-AS1 enhance cell proliferation, migration, and invasion in pancreatic cancer cell lines [111,112,113,114]. Inhibition of LINC01614 significantly suppresses tumor growth in pancreatic cancer [112].

Mechanistically, PVT1 enhances gemcitabine resistance by activating the Wnt/β-catenin and autophagy pathways in pancreatic cancer, mediated via the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes [110]. SH3BP5-AS1 enhances CTBP1 expression, promoting gemcitabine resistance by activating the Wnt signaling pathway [111]. LINC01614 interacts with GSK-3β, disrupting its interaction with AXIN1, thereby upregulating β-catenin levels, which promotes cell migration and invasion [112]. OIP5-AS1 silences miR-320b, upregulating FOXM1expression, which activates the Wnt/β-catenin pathway and promotes invasive behavior [113]. FAM83H-AS1, by promoting FAM83H expression, reduces β-catenin ubiquitination, activating the Wnt/β-catenin pathway and facilitating pancreatic cancer progression [114].

Role of Wnt pathway-associated lncRNAs in suppressing pancreatic cancer

LINC01197 expression is significantly downregulated in pancreatic cancer tissues [115]. This reduced expression is strongly correlated with unfavorable disease-free prognosis and OS in pancreatic cancer patients [115]. Functionally, LINC01197 significantly inhibits the growth of pancreatic cancer in vitro and in vivo [115]. By interacting with LINC01197, FOXO1 disrupts the interaction between β-catenin and TCF4, inhibiting cell proliferation in pancreatic cancer [115].

Wnt pathway-associated lncRNAs as a biomarker

Advancements in technology have shed light on the role of the lncRNA/Wnt axis in tumorigenesis and disease development. lncRNAs hold potential as targets for diagnosing, prognosing, and treating digestive system tumors, with the lncRNA/Wnt axis showing great promise for clinical applications.

Wnt pathway-associated lncRNAs as a diagnostic biomarker

The expression of Wnt pathway-associated lncRNAs is significantly dysregulated in esophageal, gastric, liver, colorectal, and pancreatic cancers, making them potential biomarkers for diagnosing these digestive system tumors. Certain Wnt pathway-associated lncRNAs have shown promising diagnostic value in differentiating between digestive system tumor tissues and normal tissues. For instance, EWSAT1 expression levels significantly distinguish between ESCC patients and healthy controls, with an area under the curve (AUC) of 0.7174, indicating its diagnostic potential [116]. Similarly, LINC01606 expression can accurately discriminate patients with colorectal cancer from healthy controls, with an area under the receiver operating characteristic (ROC) of 0.725 [101]. SLCO4A1-AS1 has an AUC of 0.924, highlighting its excellent predictive value for colorectal cancer [103]. ROC analysis suggests thatSH3BP5-AS1 is a valuable prognostic biomarker for pancreatic cancer (AUC = 0.816) [111]. Although the differential expression of Wnt pathway-associated lncRNAs at the tissue level may present some challenges for clinical application, certain lncRNAs also show distinct levels in plasma. For example, in patients with ESCC, plasma level of the Wnt pathway-associated lncRNA, NEF, was significantly lower compared to healthy controls [19]. ROC analysis demonstrated that plasma NEF has significant diagnostic value for ESCC, with an AUC of 0.9042. Similarly, plasma levels of lncRNA GASL1 were significantly decreased in patients with gastric cancer compared to healthy controls, with an AUC of 0.8945 for differentiating gastric cancer patients from normal subjects [19, 88]. These findings suggest that plasma levels of Wnt pathway-associated lncRNAs hold potential clinical significance in diagnosing ESCC and gastric cancer. Further research is needed to validate these findings and explore the underlying mechanisms of these lncRNAs in tumor development.

Wnt pathway-associated lncRNAs as a prognostic biomarker

Identifying effective prognostic biomarkers during cancer treatment is crucial for predicting patient survival, guiding treatment selection, and monitoring treatment efficacy [117]. However, accurately predicting the prognosis of patients with digestive system tumors is challenging due to tumor heterogeneity, molecular variability, and various interfering factors. Multiple studies have highlighted the potential of Wnt pathway-associated lncRNAs as prognostic biomarkers in digestive system tumors. The expression of these lncRNAs is significantly associated with various prognostic characteristics in patients. Lower expression levels of certain lncRNAs are linked to a higher likelihood of disease recurrence or progression, leading to poorer disease-free survival. For example, HERES expression correlates with lower rates of stage-free survival in esophageal cancer [74]. Both univariate and multivariate analyses have shown that decreased expression of MEG3 independently predicts shorter disease-free survival and OS [18]. Similarly, downregulated GASL1 expression is associated with decreased postoperative survival time for gastric cancer [88]. Conversely, increased levels of LINC01226 are positively correlated with shorter progression-free survival or OS in gastric cancer patients [84]. These findings underscore the potential of Wnt pathway-related lncRNAs as valuable biomarkers for predicting patient outcomes in digestive system tumors. Exploring the intricate relationship between lncRNA expression and prognostic features may provide novel insights and identify potential therapeutic targets to enhance patient outcomes in digestive system cancers.

However, several challenges and limitations must be addressed before Wnt pathway-related lncRNAs can be effectively used in clinical practice. Tissue specificity, sensitivity, and reproducibility are major concerns. Differential expression of these lncRNAs at the tissue level complicates consistent and reliable sample collection across patient populations. Tumor heterogeneity and molecular variability further affect the reliability of lncRNAs as biomarkers. Standardized methodologies for detecting and quantifying Wnt pathway-related lncRNAs are crucial to overcoming these issues. While Wnt pathway-associated lncRNAs offer promising diagnostic and prognostic potential, further research and standardization are essential for their successful clinical application.

Targeting lncRNA/Wnt axis for therapy

Carcinogenesis involves the gradual accumulation of genetic and epigenetic alterations [118,119,120]. Studying tumor molecular mechanisms, which has been the research focus in recent years, enhances our understanding of cancer pathogenesis and informs targeted therapies. These alterations affect genes related to cell growth, DNA repair, and cell signaling pathways [121, 122]. For example, oncogene mutations or tumor suppressor gene dysregulation can lead to uncontrolled cell proliferation and tumor formation [123]. Targeted therapies aim to selectively modulate specific molecules or pathways involved in tumor growth and survival. Biomarker discovery plays a crucial role in treatment decisions. Some lncRNAs inhibit Wnt pathway activation, reducing proliferation and invasiveness, while others activate it, promoting tumor growth and metastasis. Wnt pathway-related lncRNAs provide new targets for tumor therapy and insights into cancer treatment. Researchers and clinical doctors can identify therapeutic targets and develop personalized strategies by understanding alterations in these lncRNAs. Discussing current strategies, such as using antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to knock down oncogenic lncRNAs, would be beneficial. Small molecule inhibitors targeting the Wnt signaling pathway, such as ICG-001 and PRI-724 disrupt the interaction between β-catenin and TCF/LEF transcription factors [8]. This inhibition reduces Wnt target gene expression and has shown efficacy in preclinical models. Ongoing clinical trials evaluate the safety and efficacy of these inhibitors in patients with various cancers, including digestive system tumors. Another promising approach involves CRISPR/Cas9 technology to edit lncRNA genes, potentially correcting mutations or dysregulations contributing to tumorigenesis. This precise genome-editing technique allows the investigation of specific lncRNA functions and the development of targeted cancer therapies.

Bridging preclinical and clinical research on the lncRNA/Wnt axis in digestive system cancers

Research on the interaction between the Wnt/β-catenin signaling pathway and lncRNAs in digestive system cancers primarily relies on cell and animal models. However, clinical validation is lacking. To demonstrate the translational relevance of these findings, more comprehensive clinical investigations are needed. Research using cell and animal models has revealed the crucial role of the Wnt/β-catenin signaling pathway in cancer progression. However, clinical validation in patient samples is necessary. For example, studies indicate that overactivation of the Wnt/β-catenin pathway in colorectal cancer, gastric cancer, and HCC is closely linked to cancer stem cell proliferation, EMT, chemoresistance, and metastasis [46, 83, 91, 103]. The lack of direct validation in human patients leaves the clinical applicability of these findings uncertain. To enhance the translational value, future research should prioritize conducting more studies with clinical samples to validate the interactions between the Wnt/β-catenin signaling pathway and lncRNAs in cancer progression. Additionally, initiating clinical trials to assess the efficacy and safety of therapies targeting the Wnt/β-catenin pathway and lncRNAs is essential. Undertaking multi-center studies to collect larger patient datasets will verify the generality and clinical relevance of these mechanisms across diverse populations.

Conclusions and future perspectives

The Wnt pathway plays a crucial in cell growth, differentiation, and development, by regulating the biological functions through protein interactions. Dysregulation of the Wnt pathway is linked to various digestive system cancers. LncRNAs, which are RNA molecules longer than 200 nucleotides can regulate gene expression through different pathways. In esophageal, gastric, liver, colorectal, and pancreatic cancers, the expression of Wnt pathway-associated lncRNAs is significantly altered, making them potential biomarkers for tumor diagnosis. Some of these lncRNAs have shown promise in distinguishing tumor tissues from normal tissues. Understanding Wnt pathway-related lncRNAs can help identify treatment targets and develop personalized cancer therapies. Specifically, Wnt pathway-related lncRNAs can affect the activity of the Wnt pathway through various mechanisms, thus regulating tumor growth, metastasis, and invasion. Therefore, Wnt pathway-related lncRNAs represent potential targets for cancer treatment. Wnt pathway inhibitors also offer therapeutic options for digestive system tumors. Understanding the changes in Wnt pathway-associated lncRNAs can help researchers and clinicians identify treatment targets and develop personalized cancer treatment strategies.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China

    Penghui Li

  2. Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Xiao Ma

  3. Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Di Huang

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  1. Penghui Li
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  3. Di Huang
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Penghui Li designed the work, Xiao Ma, and Di Huang wrote this manuscript, and made figures. All authors read and approved the final manuscript.

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Li, P., Ma, X. & Huang, D. Role of the lncRNA/Wnt signaling pathway in digestive system cancer: a literature review. Eur J Med Res 29, 447 (2024). https://doi.org/10.1186/s40001-024-02033-w

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European Journal of Medical Research

ISSN: 2047-783X

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