LGR5

Gene Summary

Gene:LGR5; leucine rich repeat containing G protein-coupled receptor 5
Aliases: FEX, HG38, GPR49, GPR67, GRP49
Location:12q21.1
Summary:The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:leucine-rich repeat-containing G-protein coupled receptor 5
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: LGR5 (cancer-related)

Zhan T, Ambrosi G, Wandmacher AM, et al.
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer.
Nat Commun. 2019; 10(1):2197 [PubMed] Free Access to Full Article Related Publications
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.

Münch NS, Fang HY, Ingermann J, et al.
High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.
Gastroenterology. 2019; 157(2):492-506.e2 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.
METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.
RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.
CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.

Legge DN, Shephard AP, Collard TJ, et al.
BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells.
Dis Model Mech. 2019; 12(3) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin, it is perhaps surprising, given the importance of deregulated Wnt/β-catenin/T-cell factor (TCF) signalling in colorectal carcinogenesis, that the functional significance of this interaction is not known. Here, we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in CRC cell lines and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes

Rot S, Kaune T, Taubert H, et al.
Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients.
BMC Cancer. 2019; 19(1):155 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5-8) has yet to be thoroughly investigated.
METHODS: Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers.
RESULTS: An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5all mRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).
CONCLUSION: The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.

Gay DM, Ridgway RA, Müller M, et al.
Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.
Nat Commun. 2019; 10(1):723 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.

Pereira CV, Duarte M, Silva P, et al.
Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer.
Nutrients. 2019; 11(2) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of

Chen Z, Xue C
G-Protein-Coupled Receptor 5 (LGR5) Overexpression Activates β-Catenin Signaling in Breast Cancer Cells via Protein Kinase A.
Med Sci Monit Basic Res. 2019; 25:15-25 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND Targeting cancer stem cells (CSCs) in breast cancer (BrCa) may improve treatment outcome and patient prognosis. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a well-recognized adult stem cell and CRC marker, and previous reports have suggested the cancer-promoting role of LGR5 in breast cancer, but the mechanism remains unclear. MATERIAL AND METHODS Potential LGR5-associating genes were explored using STRING database, and LGR5 overexpression and knockdown was constructed in MCF-7 and MDA-MB-453 human BrCa cells, respectively. PKA catalytic subunit activation and PKA kinase activity in human BrCa cells was examined by Western blot and PKA kinase activity assay, respectively. Protein expression level or activation of β-catenin and GSK-3β in human BrCa cells was investigated by Western blot. Cell proliferation, colony formation, Transwell migration, cisplatin sensitivity, and in vivo tumor formation of human BrCa cells were examined. RESULTS LGR5 overexpression increased PKA activation and its kinase activity in human BrCa cells, which was decreased by LGR5 knockdown. LGR5 expression level or PKA kinase activity were correlated with β-catenin Ser 552 phosphorylation but inversely correlated with GSK-3β Ser9 phosphorylation in human BrCa cells in vitro. LGR5/PKA increased cell proliferation, colony formation, Transwell migration, and cisplatin resistance in vitro, as well as tumor formation in vivo, of human BrCa cells. CONCLUSIONS LGR5 activates the Wnt/β-catenin signaling pathway in human BrCa cells in vitro via PKA.

Saberi S, Piryaei A, Mirabzadeh E, et al.
Immunohistochemical Analysis of LGR5 and TROY Expression in Gastric Carcinogenesis Demonstrates an Inverse Trend
Iran Biomed J. 2019; 23(2):107-20 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Background: Two of the Wnt signaling pathway target genes, tumor necrosis factor receptor family member (TROY) and leucine-rich G-protein coupled receptor (LGR5), are involved in the generation and maintenance of gastrointestinal epithelium. A negative modulatory role has recently been assigned to TROY, in this pathway. Here, we have examined their simultaneous expression in gastric carcinogenesis.
Methods: Tumor and paired adjacent tissues of intestinal-type gastric cancer (GC) patients (n = 30) were evaluated for LGR5 and TROY expression by immunohistochemistry. The combination of the percentage of positively¬ stained cells and the intensity of staining was defined as the composite score and compared between groups. The obtained findings were re-evaluated in a mouse model.
Results: TROY expression in the tumor tissue was significantly lower than that of the adjacent tissue (2.5 ± 0.9 vs. 3.3 ± 0.9, p = 0.004), which was coincident with higher LGR5 expression (3.6 ± 1.1 vs. 2.7 ± 0.9, p = 0.001). This observation was prominent at stages II/III of GC, leading to a statistically significant mean difference of expression between these two molecules (p = 0.005). In the H. pylori infected-mouse model, this inverse expression was observed in transition from early (8-16 w) to late (26-50 w) time points, post treatment (p = 0.002).
Conclusion: Our data demonstrates an inverse trend between TROY down-regulation and LGR5 up-regulation in GC tumors, as well as in response to H. pylori infection in mice. These findings support a potential negative modulatory role for TROY on LGR5 expression.

Cardoso C, Serafim RB, Kawakami A, et al.
The lncRNA RMEL3 protects immortalized cells from serum withdrawal-induced growth arrest and promotes melanoma cell proliferation and tumor growth.
Pigment Cell Melanoma Res. 2019; 32(2):303-314 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
RMEL3 is a recently identified lncRNA associated with BRAFV600E mutation and melanoma cell survival. Here, we demonstrate strong and moderate RMEL3 upregulation in BRAF and NRAS mutant melanoma cells, respectively, compared to melanocytes. High expression is also more frequent in cutaneous than in acral/mucosal melanomas, and analysis of an ICGC melanoma dataset showed that mutations in RMEL3 locus are preponderantly C > T substitutions at dipyrimidine sites including CC > TT, typical of UV signature. RMEL3 mutation does not correlate with RMEL3 levels, but does with poor patient survival, in TCGA melanoma dataset. Accordingly, RMEL3 lncRNA levels were significantly reduced in BRAFV600E melanoma cells upon treatment with BRAF or MEK inhibitors, supporting the notion that BRAF-MEK-ERK pathway plays a role to activate RMEL3 gene transcription. RMEL3 overexpression, in immortalized fibroblasts and melanoma cells, increased proliferation and survival under serum starvation, clonogenic ability, and xenografted melanoma tumor growth. Although future studies will be needed to elucidate the mechanistic activities of RMEL3, our data demonstrate that its overexpression bypasses the need of mitogen activation to sustain proliferation/survival of non-transformed cells and suggest an oncogenic role for RMEL3.

Yang Y, Bhosle SR, Yu YH, et al.
Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells.
Molecules. 2018; 23(11) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from

Hua F, Shang S, Yang YW, et al.
TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis.
Gastroenterology. 2019; 156(3):708-721.e15 [PubMed] Related Publications
BACKGROUND & AIMS: Activation of Wnt signaling to β-catenin contributes to the development of colorectal cancer (CRC). Expression of tribbles pseudo-kinase 3 (TRIB3) is increased in some colorectal tumors and associated with poor outcome. We investigated whether increased TRIB3 expression promotes stem cell features of CRC cells and tumor progression by interacting with the Wnt signaling pathway.
METHODS: We performed studies with C57BL/6J-Apc
RESULTS: At 10 weeks of age, more than half the Apc
CONCLUSION: TRIB3 interacts with β-catenin and TCF4 in intestine cells to increase expression of genes associated with cancer stem cells. Knockdown of TRIB3 decreases colon neoplasia in mice, migration of CRC cells, and their growth as xenograft tumors in mice. Strategies to block TRIB3 activity might be developed for treatment of CRC.

Shi S, Chen X, Liu H, et al.
LGR5 acts as a target of miR-340-5p in the suppression of cell progression and drug resistance in breast cancer via Wnt/β-catenin pathway.
Gene. 2019; 683:47-53 [PubMed] Related Publications
Breast cancer is one of the most common malignant tumors among females. Recent studies demonstrated that microRNAs (miRNAs) played an important role in the regulation of tumor progression. In our present study, we firstly detected miR-340-5p expression in breast cancer cell lines and found lower expression of miR-340-5p in breast cancer cell lines (MCF-7, MDA-MB-231, BT-549, ZR-75-1) through qRT-PCR. Overexpressed miR-340-5p inhibited cell proliferation and drug resistance to docetaxel with enhanced cell apoptosis of breast cancer cells. Through bioinformatic prediction, we found that LGR5 was a potential target of miR-340-5p. LGR5 was highly expressed in breast cancer cells. Relative expression of LGR5 was negatively regulated by miR-340-5p. Knockdown of LGR5 also inhibited cell proliferation and drug resistance to docetaxel with enhanced cell apoptosis of breast cancer cells. Moreover, knockdown of LGR5 decreased the expression of β-catenin, c-myc, Survivin. The activation of Wnt/β-catenin pathway contracted the effects of LGR5 siRNA, indicating that LGR5 siRNA inhibited cell proliferation and drug resistance with induced apoptosis via suppressing Wnt/β-catenin signaling pathway in breast cancer. Taken together, our study demonstrated that overexpressed miR-340-5p inhibited cell proliferation and drug resistance with increased apoptosis of breast cancer cells through down-regulating LGR5 expression via Wnt/β-catenin pathway. The miR-340-5p/LGR5 axis may provide a new perspective for treatment for breast cancer.

Zhang J, Zhang C, Sang L, et al.
FOXF2 inhibits proliferation, migration, and invasion of Hela cells by regulating Wnt signaling pathway.
Biosci Rep. 2018; 38(5) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
This article was aimed to study the FOXF2 effects on cervical cancer. Tumor tissues and adjacent tissues of 41 cervical cancer patients were collected. Human endometrial epithelial cells (hEEC) and Hela cells were cultured. FOXF2 expression vector and its empty vector were transfected into Hela cells, and named as pcDNA 3.1-FOXF2 group and Vector group, respectively. Hela cells without any treatment were set as Blank group. qRT-PCR was used to detect mRNA expression. Nude mouse xenograft assay was performed to test Hela cells proliferation ability

Zhu P, Wu J, Wang Y, et al.
LncGata6 maintains stemness of intestinal stem cells and promotes intestinal tumorigenesis.
Nat Cell Biol. 2018; 20(10):1134-1144 [PubMed] Related Publications
The intestinal epithelium harbours remarkable self-renewal capacity that is driven by Lgr5

Li H, Li F
Exosomes from BM-MSCs increase the population of CSCs via transfer of miR-142-3p.
Br J Cancer. 2018; 119(6):744-755 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
BACKGROUND: Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) are progenitor cells shown to migrate to the tumour and participate in the tumour microenvironment. BM-MSCs play important roles in tumour processes through the release of cytokines or exosomes; however, how BM-MSCs influence the stemness of CSCs in colon cancer cells remains poorly understood.
METHODS: We isolated exosomes from BM-MSCs and used these exosomes to treat colon cancer cells (HCT-116, HT-29 and SW-480). We compared stemness traits of colon CSCs by cell surface marker (CD133 and Lgr5) and functional assays, such as chemoresistance, colony formation, cell adhesion, invasion and tumour-formation assay. We performed a microRNA array to investigate the differences in exosomal microRNA expression between colon cancer cells, BM-MSCs and co-cultured cells and performed functional and molecular analysis of the gene targets.
RESULTS: In this study, we found that BM-MSC-derived exosomes contained distinct microRNAs, including miR-142-3p, which in turn increased the population of CSCs in colon cancer cells. Depriving miR-142-3p from BM-MSC-derived exosomes clearly decreased the population of colon CSCs. Mechanistically, Numb was found to be the target gene of miR-142-3p, and miR-142-3p promoted the Notch signalling pathway by downregulating Numb.
CONCLUSIONS: Our findings indicate that BM-MSC-derived exosomes promote colon cancer stem cell-like traits via miR-142-3p.

Cheng CC, Liao PN, Ho AS, et al.
STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening.
J Biomed Sci. 2018; 25(1):60 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
BACKGROUND: Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes.
METHODS: In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs.
RESULTS: RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades.
CONCLUSIONS: We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.

Milosevic M, Lazarevic M, Toljic B, et al.
Characterization of stem-like cancer cells in basal cell carcinoma and its surgical margins.
Exp Dermatol. 2018; 27(10):1160-1165 [PubMed] Related Publications
BACKGROUND: Understanding the pathogenesis of basal cell carcinoma (BCC) and identifying the cells responsible for propagation and recurrence are crucial for the development of new treatment strategies. The aim of this study was to characterize the cells isolated from BCC and its margin.
METHODS: Primary cultures were established from 10 BCCs, their respective close resection margins (3 mm) and 10 control tissues. Stem cell markers analysis was carried out by real-time PCR and/or flow cytometry. Spheroid formation and MTT assays were also performed.
RESULTS: Real-time PCR showed a higher expression of embryonic (Oct4, Sox2 and Nanog) and mesenchymal (CD44 and CD73) stem cell markers in tumors compared to margins and controls (P < 0.05). Bmi-1 and GPR49 were also upregulated in tumors in comparison with margins. Both tumor and margin cells, but not normal, had the capacity to form spheroids. During passages, the number of spheres increased, while the diameter decreased. Tumor cells showed higher chemo-resistance compared to margin and control cells.
CONCLUSIONS: Basal cell carcinomas expressed stem cell markers, pointing to the existence of a cancer cell side population with stemness characteristics. Margin also appeared to harbour a small number of cancer-initiating cells.

Jing N, Huang T, Guo H, et al.
LncRNA CASC15 promotes colon cancer cell proliferation and metastasis by regulating the miR‑4310/LGR5/Wnt/β‑catenin signaling pathway.
Mol Med Rep. 2018; 18(2):2269-2276 [PubMed] Related Publications
Previous studies have indicated that overexpression of long noncoding RNA cancer susceptibility 15 (CASC15) may promote tumor development and progression in gastric cancer and hepatocellular carcinoma. However, the function of CASC15 in colon cancer remains unknown. In the present study, the expression of CASC15 was upregulated in colon cancer tissues and its expression was correlated with clinical Tumor‑Node‑Metastasis stage and tumor metastasis. In addition, knockdown of CASC15 significantly inhibited the proliferation, migration and invasion of colon cancer cells in vitro and in vivo. Following mechanistic experiments, CASC15 was observed to act as a sponge to suppress microRNA (miR)‑4310 that targeted LGR5. Through the inhibition of miR‑4310, CASC15 promoted leucine‑rich repeat‑containing G‑protein coupled receptor 5 (LGR5) expression and consequently activated the Wnt/β‑catenin signaling pathway. The results revealed that the inhibition of the Wnt/β‑catenin signaling pathway in CASC15‑overexpressing colon cancer cells suppressed cellular proliferation, migration and invasion. Collectively, these results demonstrated that CASC15 promoted colon cancer growth and metastasis through the activation of the Wnt/β‑catenin signaling pathway in a miR‑4310/LGR5 dependent manner. Thus, the present study suggested that CASC15 may be a therapeutic target for colon cancer treatment.

Wang Y, Lin X, Fu X, et al.
Long non-coding RNA BANCR regulates cancer stem cell markers in papillary thyroid cancer via the RAF/MEK/ERK signaling pathway.
Oncol Rep. 2018; 40(2):859-866 [PubMed] Related Publications
Thyroid cancer is one of the most common malignant tumors of the endocrine system. Among all thyroid cancers, papillary thyroid carcinoma (PTC) is the most common type. The BRAF-activated non-coding RNA (BANCR) is a 693-bp nucleotide transcript which was first identified in melanoma. However, the role of BANCR in the development of thyroid cancer remains unclear. Therefore, the present study investigated the potential involvement of BANCR in the development of thyroid cancer in vitro using patient tissue samples and a panel of thyroid cancer cell lines, and in vivo using a xenograft mouse model. We observed that BANCR was expressed at a higher level in human thyroid tumor tissues than that noted in the adjacent normal tissues. The expression level of BANCR differed between cultured thyroid cancer cell lines; BANCR expression was lower in the BCPAP cell line than that observed in the CAL-62, WRO and FTC-133 cell lines. Western blot analysis and flow cytometry revealed that overexpression of BANCR in the BCPAP cell line resulted in increased expression of the cancer stem cell markers, LGR5 and EpCAM. Single-clone formation experiments showed that upregulated expression of BANCR in the BCPAP cell line promoted an increase in the number of clones formed. Similarly, in microsphere formation experiments, overexpression of BANCR resulted in increased number and size of microspheres compared with the control cell line. Western blotting experiments showed that BANCR overexpression in BCPAP upregulated the expression of phosphorylated c-Raf, MEK1/2 and ERK1/2. Inhibition of c-Raf via U0126 decreased the expression of LGR5 and EpCAM, as well as phosphorylated levels of c-Raf, MEK1/2 and ERK1/2 in the BCPAP cells, compared to levels in the DMSO controls. In the xenograft mouse model, BANCR overexpression in the thyroid cancer cells significantly increased tumor growth. Taken together, these results suggest that BANCR plays a role in PTC development by regulating the expression of cancer stem cell markers LGR5 and EpCAM via the c-Raf/MEK/ERK signaling pathway. Therefore, BANCR may be used as a novel prognostic marker for PTC.

Piao L, Yang Z, Jin J, et al.
B7H4 is associated with stemness and cancer progression in esophageal squamous cell carcinoma.
Hum Pathol. 2018; 80:152-162 [PubMed] Related Publications
B7H4 is overexpressed in human cancers and often correlates with poor clinical outcome. There is a lack of data on the role of B7H4 as a cancer stem cell (CSC) regulator in esophageal squamous cell carcinoma (ESCC) and its expression levels compared to other stemness genes in ESCC. In this study, we have assessed the expression of B7H4 and cancer stemness proteins in 156 paraffin-embedded ESCC tissue samples using immunohistochemistry as well as in ESCC cell lines using Western blotting and immunofluorescence imaging. The correlation of B7H4 expression with clinicopathological parameters, cell cycle regulating genes, and PI3K/Akt/NF-κB signaling genes was investigated. The expression of B7H4 in ESCC tissue was correlated with the primary tumor (pT) stage, stromal activity, and the expression of CD68 and HIF-1α. However, B7H4 expression was negatively associated with CD8+ T cell infiltration in ESCC tissues. Moreover, B7H4 was found to be strongly linked to prognostic factors leading to poor clinical outcome. B7H4-expressing cancer cells also expressed known cancer stemness proteins (Sox9, LSD1, Oct4, and LGR5). Moreover, B7H4, Sox9, LSD1, Oct4, and LGR5 were highly expressed in more poorly differentiated ESCC cell lines. Notably, B7H4 expression was positively associated with the expression of cell cycle regulators such as cyclin D1, p27, and PI3K/Akt/NFκB signaling proteins. B7H4 could be a novel cancer stem cell marker for the prognostic evaluation of ESCC patients as well as a potential therapeutic target against ESCC.

Tanaka K, Ikeda N, Miyashita K, et al.
DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene.
Cancer Sci. 2018; 109(8):2479-2489 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
DDX1, a member of the DEAD box RNA helicase family, plays a critical role in testicular tumors. However, it remains to be clarified whether DDX1 is involved in other types of malignant tumors such as colorectal cancer. We disrupted the DDX1 gene in a human colorectal cancer cell line LoVo using the CRISPR/Cas9-mediated gene-targeting system. DDX1-KO LoVo cells exhibited a much slower growth rate, produced fewer colonies in soft agar medium, and generated smaller solid tumors in nude mice than parental LoVo cells. Such phenotypes of the DDX1-KO cells were mostly reversed by exogenous expression of DDX1. These results indicate that DDX1 is required for tumorigenicity of colorectal cancer cells. In the DDX1-KO cells, the cancer stem cell marker genes LGR5, CD133, ALDH1 and SOX2 were markedly suppressed. Among them, expression of LGR5, which is essential for tumorigenicity of colorectal cancer cells, was restored in the DDX1-transfected DDX1-KO cells. Consistently, the DDX1-KO cells lost sphere-forming capacity in a DDX1-dependent fashion. Reporter and chromatin immunoprecipitation assays revealed that DDX1 directly bound to the -1837 to -1662 region of the enhancer/promoter region of the human LGR5 gene and enhanced its transcription in LoVo cells. Repression of LGR5 by DDX1 knockdown was observed in 2 other human colorectal cancer cell lines, Colo320 and SW837. These results suggest that LGR5 is a critical effector of DDX1 in colorectal cancer cells. The DDX1-LGR5 axis could be a new drug target for this type of malignant cancer.

Morgan RG, Mortensson E, Williams AC
Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?
Br J Cancer. 2018; 118(11):1410-1418 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
Leucine-rich repeat-containing G-protein coupled receptor (LGR5 or GPR49) potentiates canonical Wnt/β-catenin signalling and is a marker of normal stem cells in several tissues, including the intestine. Consistent with stem cell potential, single isolated LGR5

Katoh M
Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review).
Int J Mol Med. 2018; 42(2):713-725 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
β‑catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E‑cadherin/CDH1, N‑cadherin/CDH2, VE‑cadherin/CDH5 and α‑catenins), transmembrane‑type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain‑of‑function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss‑of‑function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β‑catenin target genes. β‑catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β‑catenin and NF‑κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β‑catenin‑targeted therapeutics are functionally classified into β‑catenin inhibitors targeting upstream regulators (AZ1366, ETC‑159, G007‑LK, GNF6231, ipafricept, NVP‑TNKS656, rosmantuzumab, vantictumab, WNT‑C59, WNT974 and XAV939), β‑catenin inhibitors targeting protein‑protein interactions (CGP049090, CWP232228, E7386, ICG‑001, LF3 and PRI‑724), β‑catenin inhibitors targeting epigenetic regulators (PKF118‑310), β‑catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β‑catenin inhibitors targeting transmembrane‑type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first‑line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β‑catenin inhibitors may be applicable for the prevention of organ fibrosis, second‑line HCC prevention and treating β‑catenin‑driven cancer. The multi‑layered prevention and treatment strategy of β‑catenin‑related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

Azhdarinia A, Voss J, Ghosh SC, et al.
Evaluation of Anti-LGR5 Antibodies by ImmunoPET for Imaging Colorectal Tumors and Development of Antibody-Drug Conjugates.
Mol Pharm. 2018; 15(6):2448-2454 [PubMed] Related Publications
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is highly expressed in colorectal tumors and marks colon cancer stem cells that drive tumor growth and metastasis. Recently, we showed that LGR5 is a promising target for antibody-drug conjugate (ADC) therapy. However, it is important to identify LGR5-positive tumors that would respond to ADC treatment. Prior to drug conjugation, we evaluated two different anti-LGR5 monoclonal antibodies (mAbs), 8F2 and 9G5, using

Cao J, Li C, Wei X, et al.
Selective Targeting and Eradication of LGR5
Mol Cancer Ther. 2018; 17(7):1475-1485 [PubMed] Related Publications
Cancer stem cells (CSC) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression, and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study, we aimed at the Wnt signaling characteristic of CSCs and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway coreceptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a patient-derived xenograft tumor model where LGR5

Ma X, Wang B, Wang X, et al.
NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells.
PLoS One. 2018; 13(4):e0192436 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
BACKGROUND: Accumulating evidence demonstrated that NANOG1, the key transcription factor for embryonic stem cells, is associated with human cancers. NANOGP8, one of the pseudogenes in NANOG gene family, contains an intact open reading frame and also said to be expressed in cancer tissues. Therefore, a systematic study is greatly needed to address the following questions: among NANOG1 and NANOGP8, which gene is the main contributor for NANOG expression in cancer cells and which one is the key regulator responsible for stemness, epithelial-mesenchymal transition (EMT), metastasis, chemoresistance and other malignant phenotypes. Here we try to explore these issues with gastric adenocarcinoma cell lines in vitro using variety of molecular and cellular techniques.
METHODS: Special primers were designed to distinguish PCR products from NANOG1 and NANOGP8. Sphere-forming cells were cultured with serum-free and selective medium. A stable cell line was established with infection of lentivirus containing NANOGP8. qPCR was performed to measure NANOGP8 expression and its association with stemness, EMT and CSC markers in adherent cells and sphere-forming cells. Western blot analysis was deployed to confirm results of the transcript analysis. Experiments of cell proliferation, migration, invasion, clonogenic assay, sphere cell growth assays, cell cycle analysis, β-catenin accumulation and translocation in nucleus, and drug resistance were conducted to measure the impact of NANOGP8 on malignant statuses of gastric cancer cells. Immunofluorescence staining was used to analyze cell subpopulations with different markers.
RESULTS: NANOGP8 is mainly responsible for NANOG expression in sphere-forming (stem cell-like) cells derived from gastric cancer cell lines regardless their differentiation status. Ectopic expression of NANOGP8 significantly up-regulates stemness transcription factors, EMT inducers, and cancer stem cell markers (CSC) including Lgr5. NANOGP8 also promotes expression of the signature genes vimentin and N-caderin for mesenchymal cells and down-regulates the signature gene E-caderin for epithelial cells whereby confer the cells with mesenchymal cell phenotype. In NANOGP8 over-expressed adherent and sphere-forming cells, Lgr5+ cells are significantly increased. Ectopic expression of NANOGP8 endows gastric cells with enhanced proliferation, migration, invasion, sphere-forming and clonogenic capacity, and chemoresistance. NANOGP8 expression also enhances β-catenin accumulation in nucleus and strengthens Wnt signal transduction.
CONCLUSION: NANOGP8 is the main regulator of gastric cancer stem cells. It is closely associated with EMT, stemness, and CSC marker as well as Wnt signal pathway. NANOGP8 is correlated with cell proliferation, migration, invasion, clonogenic capacity, β-catenin accumulation in nucleus, and chemoresistance in gastric cancer. NANOGP8 is a promising molecular target for clinical intervention of gastric cancer.

Jian Y, Wang M, Zhang Y, et al.
Jade family PHD finger 3 (JADE3) increases cancer stem cell-like properties and tumorigenicity in colon cancer.
Cancer Lett. 2018; 428:1-11 [PubMed] Related Publications
Jade family PHD finger 3 (JADE3) plays a role in inducing histone acetylation during transcription, and is involved in the progression of several human cancers; however, its role in colon cancer remains unclear. Herein, we found that JADE3 was markedly upregulated in colon cancer tissues and significantly correlated with cancer progression, and predicted shorter patient survival. Further, JADE3 was expressed much higher in colon cancer cell lines that are enriched with a stem-like signature. Overexpression of JADE3 increased, while silencing JADE3 reduced cancer stem cell-like traits in colon cancer cells in vitro and in vivo. Importantly, silencing of JADE3 strongly impaired the tumor initiating capacity of colon cancer cells in vivo. Furthermore, JADE3 interacted with the promoters of colon stem cell marker LGR5 and activated its transcription, by increasing the occupancy of p300 acetyltransferase and histone acetylation on the promoters. Finally, we found that JADE3 expression was substantially induced by Wnt/β-catenin signaling. These findings suggest an oncogenic role of JADE3 by regulating cancer stem cell-like traits in the colon cancer, and therefore JADE3 might be a potential therapeutic target for the treatment of colon cancer.

Leng Z, Xia Q, Chen J, et al.
Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer.
Cell Physiol Biochem. 2018; 46(2):860-872 [PubMed] Related Publications
BACKGROUND/AIMS: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer.
METHODS: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR.
RESULTS: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations.
CONCLUSION: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

Hou MF, Chen PM, Chu PY
LGR5 overexpression confers poor relapse-free survival in breast cancer patients.
BMC Cancer. 2018; 18(1):219 [PubMed] Article available free on PMC after 11/09/2019 Related Publications
BACKGROUND: Cancer stem cells (CSCs) are believed to promote the malignant transformation of breast cancer via multiple signaling pathways, including the Wnt/β-catenin pathway. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been identified as a CSC-associated Wnt-regulated target gene, but its clinical significance in the context of breast cancer remains elusive. Therefore, the purpose of this study was to investigate the clinical significance of the LGR5-β-catenin axis in breast cancer.
METHODS: Breast cancer tissue blocks from 126 patients were used to construct a tissue microarray (TMA). Histopathological and clinical data including age; tumor size; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) level; tumor grade; lymph node (LN) status; and survival were obtained from the cancer registry database and patients' medical records. Tissue on the breast TMA was scored for LGR5 and β-catenin expression using semi-quantitative immunohistochemical (IHC) staining. We also analyzed LGR5 expression in cellular datasets available through ONCOMINE, a web-based cancer microarray database.
RESULTS: Immunohistochemical staining revealed that 58 tumors (46%) exhibited high LGR5 expression, whereas 56 tumors (47%) displayed high β-catenin expression. High levels of LGR5 expression were significantly associated with tumor size (p = 0.002), LN metastasis status (p = 0.044), and triple-negative breast cancer (p = 0.029), consistent with our findings from the ONCOMINE database. In addition, we also found that β-catenin -expressing breast cancers were positive correlated with HER2 overexpression. Finally, with respect to clinical outcomes, patients with high levels of LGR5-β-catenin axis expression exhibited poorer relapse-free survival (RFS) compared to patients with low levels of LGR5-β-catenin axis expression (p = 0.027).
CONCLUSION: LGR5 overexpression was significantly associated with high T stage and LN metastasis status. High LGR5 expression was also associated with reduced RFS, indicating that LGR5 may represent a promising prognostic marker for breast cancer patients.

Dame MK, Attili D, McClintock SD, et al.
Identification, isolation and characterization of human LGR5-positive colon adenoma cells.
Development. 2018; 145(6) [PubMed] Article available free on PMC after 11/09/2019 Related Publications
The intestine is maintained by stem cells located at the base of crypts and distinguished by the expression of LGR5. Genetically engineered mouse models have provided a wealth of information about intestinal stem cells, whereas less is known about human intestinal stem cells owing to difficulty detecting and isolating these cells. We established an organoid repository from patient-derived adenomas, adenocarcinomas and normal colon, which we analyzed for variants in 71 colorectal cancer (CRC)-associated genes. Normal and neoplastic colon tissue organoids were analyzed by immunohistochemistry and fluorescent-activated cell sorting for LGR5. LGR5-positive cells were isolated from four adenoma organoid lines and were subjected to RNA sequencing. We found that LGR5 expression in the epithelium and stroma was associated with tumor stage, and by integrating functional experiments with LGR5-sorted cell RNA sequencing data from adenoma and normal organoids, we found correlations between LGR5 and CRC-specific genes, including dickkopf WNT signaling pathway inhibitor 4 (

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