Gene Summary

Gene:SMO; smoothened, frizzled class receptor
Aliases: Gx, CRJS, SMOH, FZD11
Summary:The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:smoothened homolog
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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

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

Latest Publications: SMO (cancer-related)

Zhu R, Gires O, Zhu L, et al.
TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling.
Nat Commun. 2019; 10(1):2863 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness.

Cao Y, Zhu W, Chen W, et al.
Prognostic Value of BIRC5 in Lung Adenocarcinoma Lacking EGFR, KRAS, and ALK Mutations by Integrated Bioinformatics Analysis.
Dis Markers. 2019; 2019:5451290 [PubMed] Free Access to Full Article Related Publications
Objective: This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas).
Methods: The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis.
Results: A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all
Conclusion: Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

Tang X, Huang X, Wang D, et al.
Identifying gene modules of thyroid cancer associated with pathological stage by weighted gene co-expression network analysis.
Gene. 2019; 704:142-148 [PubMed] Related Publications
Thyroid cancer is the most common type of endocrine tumor. The TNM classification remains a standard for treatment determination and predicting prognosis in thyroid cancer. The genes modules associated with the progression of papillary thyroid carcinoma (PTC) were not clear. We applied a weighted gene co-expression network analysis (WGCNA) and differential expression analysis to systematically identified co-expressed gene modules and hub genes associated with PTC progression based on The Cancer Genome Atlas (TCGA) PTC transcriptome sequencing data. An independent validation cohort, GSE27155, was used to evaluate the preservation of gene modules. We identified two co-expressed genes modules associated with progression of PTC. Enrichment analysis indicated that the two modules were enriched in angiogenesis and extracellular matrix organization. DCN, COL1A1, COL1A2, COL5A2 and COL3A1 were hub genes in the co-expressed network. We systematically identified co-expressed gene modules and hub genes associated with PTC progression for the first time, which provided insights into the mechanisms underlying PTC progression and some potential targets for the treatment of PTC.

Tang D, Wu Q, Yuan Z, et al.
Identification of key pathways and gene changes in primary pancreatic stellate cells after cross-talk with pancreatic cancer cells (BXPC-3) using bioinformatics analysis.
Neoplasma. 2019; 2019(3):446-458 [PubMed] Related Publications
It is well known that as the king of cancer, pancreatic ductal adenocarcinoma (PDAC) has relatively malignant biological behavior and poor prognosis. The interaction between pancreatic stellate cells and PDAC cells promotes the development of PDAC. The aim of this study was to describe gene characteristics in pancreatic stellate cell (PSCs) after cross-talked with BXPC-3 and unravel their underlying mechanisms. The expression profiling analysis of genes in PSCs was completed after co-cultured with primary BXPC-3 for 48h. The Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis and gene ontology (GO) analysis were performed, and the differentially expressed genes (DEGs) were identified by Agilent GeneSpring GX program. In total, 1804 DEGs were filtered out in PSCs, including 958 up-regulated genes and 846 downregulated genes. GO analysis showed that the up-regulated DEGs were significantly enriched in biological processes (BP) such as defense response, immune system process and immune response; the down-regulated DEGs were significantly enriched in biological regulation and cytoskeleton organization. KEGG pathway analysis showed that 28 pathways were upregulated and 5 were downregulated. By constructing PPI network, we selected out 10 key genes (IL6,IL8, IL1B, BCL2, CCL2, CSF2, KIT, ICAM1, PTPRC and IGF1) and significant enriched pathways. In conclusion, the current study suggests that the filtered DEGs contribute to our understanding of the molecular mechanisms underlying the interaction between PSCs and pancreatic cancer cells, and might be used as molecular targets to further the study the role of tumor microenvironment in the progression of PDAC.

Aman NA, Doukoure B, Koffi KD, et al.
Immunohistochemical Evaluation of Ki-67 and Comparison with Clinicopathologic Factors in Breast Carcinomas
Asian Pac J Cancer Prev. 2019; 20(1):73-79 [PubMed] Free Access to Full Article Related Publications
Background: Patients primarily received tamoxifen based on their menopausal status due to the lack of immunohistochemistry. A recent study has shown that hormonal receptors were not correlated with menopausal status, and thus, indicating that they present limited therapeutic and prognostic significance in breast cancer management. This study aimed to evaluate Ki-67 value and analyze its association with clinicopathologic parameters in breast cancer patients. Methods: The formalin-fixed paraffin-embedded breast tissue blocks of 125 patients with primary breast carcinomas were subjected to immunohistochemical analysis using Ventana Benchmark® GX automated immunostainer. Analysis of variance and Chi-2 test were used to examine the relationship between Ki-67 and clinicopathologic variables. Results: The mean age of 125 patients included in the study was 47.7 years. The average score of Ki-67 was 56.0%. 84.8% of patients showed Ki-67 ≥ 14%. Mean scores of Ki-67 were correlated with grade (p = 0.006), PR (p = 0.026), histological type, ER, combined ER/RP, and molecular subtype (p < 0.001). Ki-67 was independent of HER2 (p = 0.402) and menopausal status (p = 0.471). The frequency of Ki-67 according to St Gallen 2011 was associated with histological type (p = 0.005), grade (p = 0.005), ER (p < 0.001), combined ER/PR (p = 0.004), and molecular subtype (p = 0.004). There was no significant relationship between the distribution of Ki-67 and the age of the patients (p = 0.859), menopausal status (p = 0.979), PR (p = 0.149), and HER2 (p = 0.597). Conclusion: Ki-67 is useful for treatment decisions in primary breast cancer patients. The high value of Ki-67 was associated with adverse clinicopathologic factors. The increased Ki-67 value should be carefully investigated in triple negative patients.

Zhang M, Tan S, Yu D, et al.
Triptonide inhibits lung cancer cell tumorigenicity by selectively attenuating the Shh-Gli1 signaling pathway.
Toxicol Appl Pharmacol. 2019; 365:1-8 [PubMed] Related Publications
Lung cancer is a leading lethal disease with a 5-year survival rate of only 16%. Inadequate potent anti-cancer drugs appear to be a bottleneck in the treatment of lung cancer; hence, how to develop effective anti-lung cancer therapeutics is an urgent problem. In this study, we aim to explore a novel compound with potent anti-lung cancer effect and study its anti-cancer mechanisms. We found that triptonide at very low concentrations of 5-10 nM caused a marked suppression of cell proliferation and colony formation of lung cancer cells. More interestingly, triptonide also robustly inhibited the lung cancer cell formation of tumor spheres, and reduced the stemness and tumorigenicity of the sphere-forming cells. In vivo studies showed that administration of triptonide significantly inhibited the tumor growth with low toxicity. Molecular mechanistic studies revealed that triptonide significantly decreased expression of the Gli1 at both mRNA and protein levels by repressing Gli1 gene promoter activity. Additionally, triptonide reduced the levels of cancer stem cell key signaling protein sonic hedgehog (Shh), but increased the amount of Ptch1, a protein binding to SMO to diminish the Shh signal transduction, thus inhibition of the Shh-Gli1 signaling pathway. Together, our findings show that triptonide effectively inhibits lung cancer cell growth, stemness, and tumorigenicity, and support the notion that triptonide is a new Shh-Gli1 signaling inhibitor and a novel anti-lung cancer drug candidate for further developing effective lung cancer therapeutics.

You Z, Sun L, Yan X, et al.
Clinicopathologic study on a rare variant of ameloblastoma with basal cell features.
Oral Dis. 2019; 25(3):788-795 [PubMed] Related Publications
OBJECTIVES: To investigate the clinical features, pathologic manifestations, and biologic behaviors of a variant of ameloblastoma with basal cell features (AM-BC).
MATERIALS AND METHODS: Following retrospective review of the clinical and pathological data of six cases of AM-BC, we described their histological and immunohistochemical (IHC) features and discussed the biologic behaviors, prognoses, pathogenesis, and clinical relevance of AM-BC. Direct sequencing of polymerase chain reaction products was also performed in all cases.
RESULTS: The six cases of AM-BC involved four women and two men, aged 22-82 years. Four lesions occurred in the maxilla and two in the mandible. Histologically, the basal cells tended to be arranged as unequally sized follicles, strands, or cords of odontogenic epithelium in the connective tissue stroma. Little or no stellate reticulum was present in the central portion of the nest. Expression of CKs was consistent with other histological variants of ameloblastoma (AM), but AM-BC had significantly higher p53 and Ki-67 (p < 0.05) labeling indices than other histological variants of AM. Two patients had BRAF gene mutations.
CONCLUSION: Ameloblastoma with basal cell features is a very rare variant of AM. Our study showed the differences and relationships that exist between AM-BC and other variants of AM, which could enhance understanding of AM-BC.

Yin WC, Satkunendran T, Mo R, et al.
Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma.
Dev Cell. 2019; 48(2):167-183.e5 [PubMed] Related Publications
SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB (∼60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis.

Antonucci L, Di Magno L, D'Amico D, et al.
Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation.
Int J Oncol. 2019; 54(2):505-514 [PubMed] Free Access to Full Article Related Publications
The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen‑activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy.

Qin T, Li B, Feng X, et al.
Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity.
J Exp Clin Cancer Res. 2018; 37(1):287 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear.
METHODS: The distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1.
RESULTS: Bioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway.
CONCLUSIONS: These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.

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] Free Access to Full Article 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

Jia Y, Gu D, Wan J, et al.
The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer.
Oncogene. 2019; 38(10):1764-1777 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.

Venur VA, Santagata S, Galanis E, Brastianos PK
New molecular targets in meningiomas: the present and the future.
Curr Opin Neurol. 2018; 31(6):740-746 [PubMed] Related Publications
PURPOSE OF REVIEW: Meningiomas, the most common primary brain tumor, have historically been managed with surgery and radiation. Traditional chemotherapy has not been effective. Fortunately, recent advances in genetic sequencing have led to an improved understanding of the molecular drivers in meningioma. This article aims to discuss the diagnostic and therapeutic implications of recently discovered genetic alterations in meningiomas.
RECENT FINDINGS: Many of the recently discovered genetic alterations correlate with distinct clinical phenotypes. SMO, AKT and PIK3CA mutations are enriched in the anterior skull base. KLF4 mutations are specific for secretory histology, and BAP1 alterations are common in progressive rhabdoid meningiomas. Alterations in TERT, DMD and BAP1 correlate with poor clinical outcomes. Importantly, the discovery of clinically actionable alterations in a number of genes, including SMO, AKT1 and PIK3CA, has opened up novel potential avenues for therapeutic management of meningiomas. Overexpression of PD-L1 in higher grade meningiomas also provides preclinical support for the investigation of checkpoint blockade.
SUMMARY: The discovery of genetic alterations has improved our understanding of the natural history and classification of meningiomas. Clinical trials with several novel agents targeting driver mutations are currently accruing patients and they can lead to better treatment strategies.

Biehs B, Dijkgraaf GJP, Piskol R, et al.
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition.
Nature. 2018; 562(7727):429-433 [PubMed] Related Publications
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)

Chen X, Zhou Z, Hannan R, et al.
Reliable gene mutation prediction in clear cell renal cell carcinoma through multi-classifier multi-objective radiogenomics model.
Phys Med Biol. 2018; 63(21):215008 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
Genetic studies have identified associations between gene mutations and clear cell renal cell carcinoma (ccRCC). Since the complete gene mutational landscape cannot be characterized through biopsy and sequencing assays for each patient, non-invasive tools are needed to determine the mutation status for tumors. Radiogenomics may be an attractive alternative tool to identify disease genomics by analyzing amounts of features extracted from medical images. Most current radiogenomics predictive models are built based on a single classifier and trained through a single objective. However, since many classifiers are available, selecting an optimal model is challenging. On the other hand, a single objective may not be a good measure to guide model training. We proposed a new multi-classifier multi-objective (MCMO) radiogenomics predictive model. To obtain more reliable prediction results, similarity-based sensitivity and specificity were defined and considered as the two objective functions simultaneously during training. To take advantage of different classifiers, the evidential reasoning (ER) approach was used for fusing the output of each classifier. Additionally, a new similarity-based multi-objective optimization algorithm (SMO) was developed for training the MCMO to predict ccRCC related gene mutations (VHL, PBRM1 and BAP1) using quantitative CT features. Using the proposed MCMO model, we achieved a predictive area under the receiver operating characteristic curve (AUC) over 0.85 for VHL, PBRM1 and BAP1 genes with balanced sensitivity and specificity. Furthermore, MCMO outperformed all the individual classifiers, and yielded more reliable results than other optimization algorithms and commonly used fusion strategies.

Esposito MR, Binatti A, Pantile M, et al.
Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients' survival and indicate proteins targetable at onset of disease.
Int J Cancer. 2018; 143(10):2525-2536 [PubMed] Related Publications
Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways.

Yang B, Miao S, Li Y
SCUBE2 inhibits the proliferation, migration and invasion of human non-small cell lung cancer cells through regulation of the sonic hedgehog signaling pathway.
Gene. 2018; 672:143-149 [PubMed] Related Publications
Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. Recently, it was found to play an important role in tumor development. However, the role of SCUBE2 in non-small cell lung cancer (NSCLC) has never been revealed. Here, we explored the roles and mechanism of SCUBE2 in the progression of NSCLC. Our result showed that SCUBE2 was expressed in low levels in NSCLC cell lines. In addition, overexpression of SCUBE2 significantly inhibited the proliferation, migration and invasion of NSCLC cells. Further mechanistic analysis showed that SCUBE2 overexpression efficiently inhibited the protein expression of Shh, Smo, and Gli1 in NSCLC cells. Moreover, experiments with recombinant sonic hedgehog protein rh-Shh dramatically dampened the decrease in cell proliferation, invasion, and migration triggered by SCUBE2. Taken together, these results suggest that overexpression of SCUBE2 inhibits NSCLC cell proliferation and invasion through suppressing the Sonic hedgehog signaling pathway. Thus, SCUBE2 may be a potential therapeutic target for NSCLC.

Veenstra VL, Dingjan I, Waasdorp C, et al.
Patched-2 functions to limit Patched-1 deficient skin cancer growth.
Cell Oncol (Dordr). 2018; 41(4):427-437 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
PURPOSE: Basal cell carcinoma (BCC) is one of the most common skin cancers, and is typically driven by an aberrantly activated Hedgehog (Hh) pathway. The Hh pathway is regulated by interactions between the Patched-1 (Ptch1) and Smoothened (Smo) receptors. Smo is an activating receptor and is subject to inhibition by Ptch1. Following ligand binding to Ptch1, its inhibitory action is relieved and pathway activation occurs. This receptor interaction is pivotal to restraining uncontrolled cellular growth. Both receptors have been found to be frequently mutated in BCCs. Ptch2 is a Ptch1 paralog that exhibits overlapping functions in both normal development and tissue homeostasis. As yet, its contribution to cancer growth is poorly defined. Here we set out to assess how Ptch2 inhibits BCC growth.
METHODS: We used several in vitro readouts for transcriptional and chemotactic Hh signaling in BCC-derived ASZ001 cells, and a novel xenograft model to assess in vivo BCC tumor growth. Gene editing by TALEN was used to untangle the different Ptch2-dependent responses to its ligand sonic hedgehog (Shh).
RESULTS: We first defined the signaling competence of Ptch2 in Ptch1-deficient ASZ001 cells in vitro, and found that Ptch2 ligand binding drives their migration rather than eliciting a transcriptional response. We found that subsequent targeting of Ptch2 abrogated the chemotaxic effect. Next, we tested the contribution of Ptch2 to in vivo tumor growth using a xenograft model and found that reduced Ptch function results in increased tumor growth, but that selective pressure appatently acts against complete Ptch2 ablation.
CONCLUSIONS: We conclude that like Ptch1, Ptch2 exerts a tumor-suppressive function in BCC cells, and that after targeting of both paralogs, ligand-independent activation of the Hh pathway contributes to tumor growth.

Gupta S, Mani NR, Carvajal-Hausdorf DE, et al.
Macrodissection prior to closed system RT-qPCR is not necessary for estrogen receptor and HER2 concordance with IHC/FISH in breast cancer.
Lab Invest. 2018; 98(8):1076-1083 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
An on-demand, closed RT-qPCR, the GeneXpert (GX) system, has the potential to provide biomarker information in low-resourced settings and elsewhere. We used this system with a research use only version of the Breast Cancer STRAT4 cartridge that measures the mRNA expression levels of ERBB2, ESR1, PGR, and MKi67. Here we evaluated the impact of non-macrodissected (non m-d) versus macrodissected (m-d) samples using STRAT4 on formalin-fixed, paraffin-embedded (FFPE) core needle biopsies. Two cohorts were assessed: (1) 60 FFPE infiltrating ductal carcinoma (IDCA) cases and (2) 20 FFPE IDCA cases with ductal carcinoma in situ (DCIS) with a range of HER2 expression as determined by clinical immunohistochemistry and fluorescence in situ hybridization (IHC/FISH). We observed about half of the core needle biopsy area as invasive tumor in both IDCA (mean = 51.5%) and IDCA with DCIS (mean = 53.5%) cohorts, but also found the mRNA levels were independent of tumor area. We found excellent agreement of the mRNA transcript level between the paired samples, m-d versus non m-d, for ERBB2, ESR1, PGR, and MKi67 for both the IDCA and IDCA with DCIS cohorts. No significant difference (P > 0.99) was observed when we compared the mRNA transcript level between the paired samples m-d versus non m-d. In addition, we noted a significant concordance (P < 0.001) between RT-qPCR and IHC/FISH for HER2-positivity, ER-positivity, and PR-positivity, independent of specimen dissection. These data suggest that mRNA expression for ERBB2, ESR, and PGR is sufficiently low in surrounding tissue cells such that macrodissection is not required for assessment of key breast cancer mRNA markers and is independent of the amount of input tumor. This approach may be valuable in settings lacking pathology expertise or using specimen types, such as fine-needle aspirates, where it may be challenging to separate non-tumor from tumor tissue.

Everson RG, Hashimoto Y, Freeman JL, et al.
Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design.
J Neurooncol. 2018; 139(2):469-478 [PubMed] Related Publications
INTRODUCTION: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents.
METHODS: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status.
RESULTS: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%).
CONCLUSION: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

Teichman J, Dodbiba L, Thai H, et al.
Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma.
PLoS One. 2018; 13(5):e0194809 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors.
METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling.
RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model.
CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

Guo L, Zhou Y, Chen Y, et al.
LncRNA ASAP1-IT1 positively modulates the development of cholangiocarcinoma via hedgehog signaling pathway.
Biomed Pharmacother. 2018; 103:167-173 [PubMed] Related Publications
Over the past decades, lncRNAs have attracted more and more attentions of researchers. It has been verified that lncRNAs can modulate multiple biological behaviors in various human cancers. LncRNA ASAP1-IT1 has been certified to be a tumor facilitator in several malignant tumors. This study aims to investigate the effects of dysregulated ASAP1-IT1 on biological processes of Cholangiocarcinoma. The high expression level of ASAP1-IT1 was tested in Cholangiocarcinoma tissues and cells with qRT-PCR. Upregulation of ASAP1-IT predicted the unfavorable prognosis for Cholangiocarcinoma patients. Next, ASAP1-IT1 was knocked down in cancerous cells for loss-of function assay. MTT, colony formation and transwell and western bot assays were performed to demonstrate the specific impacts of ASAP1-IT1 on proliferation, migration and EMT progression of Cholangiocarcinoma. Cells. As a results, the Cholangiocarcinoma progression was inhibited. Hedgehog signaling pathway has been discovered to be a treatment target in Cholangiocarcinoma. In this study, the interaction between ASAP1-IT1 and hedgehog pathway was specifically investigated. Smo and Gli1, two hedgehog-related proteins were examined in Cholangiocarcinoma cells. The results of qRT-PCR and western blot assay suggested that ASAP1-IT1 could positively modulate Smo and Gli1 in Cholangiocarcinoma. Finally, rescue assays were carried out to prove that ASAP1-IT1 could improve Cholangiocarcinoma progression and development via hedgehog signaling pathway.

Tan IL, Wojcinski A, Rallapalli H, et al.
Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation.
Proc Natl Acad Sci U S A. 2018; 115(13):3392-3397 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (

Rahman MM, Hazan A, Selway JL, et al.
A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors.
Cancer Res. 2018; 78(10):2577-2588 [PubMed] Related Publications
Small-molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients respond poorly. In this study, we report the results of investigations on PTCH1 signaling in the HH pathway that suggest why most patients with BCC respond poorly to SMO inhibitors. In immortalized human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, although siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacologic inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localization of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localization signal [N(o)LS]. Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistologic analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumors. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology and highlights a novel nuclear mechanism of SMO-GLI1 signaling that is unresponsive to SMO inhibitors.

Li N, Truong S, Nouri M, et al.
Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3.
Oncogene. 2018; 37(17):2313-2325 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
Hedgehog (Hh) is an oncogenic signaling pathway that regulates the activity of Gli transcription factors. Canonical Hh is a Smoothened- (Smo-) driven process that alters the post-translational processing of Gli2/Gli3 proteins. Though evidence supports a role for Gli action in prostate cancer (PCa) cell growth and progression, there is little indication that Smo is involved. Here we describe a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors (ARs) to Gli3. Androgens stimulated reporter expression from a Gli-dependent promoter in a variety of AR + PCa cells and this activity was suppressed by an anti-androgen, Enz, or by AR knockdown. Androgens also upregulated expression of endogenous Gli-dependent genes. This activity was associated with increased intranuclear binding of Gli3 to AR that was antagonized by Enz. Fine mapping of the AR binding domain on Gli2 showed that AR recognizes the Gli protein processing domain (PPD) in the C-terminus. Mutations in the arginine-/serine repeat elements of the Gli2 PPD involved in phosphorylation and ubiquitinylation blocked the binding to AR. β-TrCP, a ubiquitin ligase that recognizes the Gli PPD, competed with AR for binding to this site. AR binding to Gli3 suppressed its proteolytic processing to the Gli3 repressor form (Gli3R) whereas AR knockdown increased Gli3R. Both full-length and truncated ARs were able to activate Gli transcription. Finally, we found that an ARbinding decoy polypeptide derived from the Gli2 C-terminus can compete with Gli3 for binding to AR. Exogenous overexpression of this decoy suppressed Gli transcriptional activity in PCa cells. Collectively, this work identifies a novel pathway for non-canonical activation of Hh signaling in PCa cells and identifies a means for interference that may have clinical relevance for PCa patients.

Whitson RJ, Lee A, Urman NM, et al.
Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas.
Nat Med. 2018; 24(3):271-281 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

Riaz SK, Khan JS, Shah STA, et al.
Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer.
Cell Commun Signal. 2018; 16(1):3 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
BACKGROUND: Dysregulation of hedgehog pathway is observed in numerous cancers. Relevance of hedgehog pathway genes in cancer cohort and inhibition of its downstream effector (GLI1) towards metastasis in cell lines are explored in the study.
METHOD: One hundred fifty fresh tumours of breast cancer patients were collected for the study. Based on differential expression, panel of 6 key regulators of the pathway (SHH, DHH, IHH, PTCH1, SMO and GLI1) in microarray datasets were identified. Expressional profiles of aforementioned genes were later correlated with clinico-pathological parameters in Pakistani breast cancer cohort at transcript and protein levels. In addition, GLI1 over expressing breast cancer cell lines (MDA-MB-231 and MCF-7) were treated with GANT61 to explore its probable effects on metastasis.
RESULT: SHH, DHH, PTCH1 and GLI1 were significantly over-expressed in tumours as compared with respective normal mammary tissues. A significant correlation of SHH, DHH and GLI1 expression with advanced tumour size, stages, grades, nodal involvement and distant metastasis was observed (p < 0.05). Over-expression of SHH, DHH and GLI1 was significantly related with patients having early onset and pre-menopausal status. Of note, hedgehog pathway was frequently up regulated in luminal B and triple negative breast cancer affected women. In addition, positive correlations were observed among aforementioned members of pathway and Ki67 (r-value: 0.63-0.78) emphasizing their role towards disease progression. Exposure of GANT61 (inhibitor for GLI1) significantly restricted cell proliferation, reduced cell motility and invasion.
CONCLUSION: Role of activated hedgehog pathway in breast cancer metastasis provides a novel target for cancer therapy against aggressive cancer subtypes.

Ishiwata T, Iwasawa S, Ebata T, et al.
Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung.
Oncol Rep. 2018; 39(3):1148-1154 [PubMed] Related Publications
Large cell neuroendocrine carcinoma (LCNEC) of the lung is a highly aggressive tumor without established standard treatment. The Hedgehog (Hh) signal, which is critical in embryogenesis, is known to play important roles in maintaining a malignant phenotype in various cancers. The present study explored the possibility of targeting the Hh signal in the treatment of LCNEC by suppressing Hh downstream molecules, Smoothened (Smo) and GLI family zinc finger 1/2 (Gli1/2), in 3 human LCNEC cell lines. Smo inhibitor, BMS-833923, and Gli inhibitor, GANT61, downregulated Gli1 and 2, resulting in the suppression of the cell viability of the 3 cell lines as assessed using an MTT assay. The downregulation of Gli1 and/or Gli2 using siRNA for each gene also led to cell growth inhibition in the 3 cell lines. The downregulation of Gli1/2 made the cells more sensitive to cisplatin, resulting in increased apoptosis. These findings suggest that the Hh signaling pathway may be a candidate target for the treatment of LCNEC of the lung.

Shao X, Kuai X, Pang Z, et al.
Correlation of Gli1 and HER2 expression in gastric cancer: Identification of novel target.
Sci Rep. 2018; 8(1):397 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
HER2 becomes the standard of care for guiding adjuvant treatment of gastric cancer with trastuzumab in recent years. However, the usage of this target agent is still limited because of the resistance to trastuzumab or the negative expression of HER2 in tumor tissues. The Gli1 and HER2 both play an important role in the pathogenesis of gastric cancer. However, the correlation of them is still unclear. Here we found Gli1 and HER2 are highly expressed in gastric cancer tissues, and they are positively related. Next, we found Gli1 positive patients live a shorter survival time no matter HER2 positive or negative. Furthermore, univariate and multivariate analysis revealed that venous invasion, HER2 expression, Gli1 expression were independent prognostic factors for the survival time in gastric cancer. In addition, suppressing the expression level of Gli1 can decrease the cell viability and migration ability in cells and subcutaneous tumors. Finally, we found that HER2 may regulate Gli1 by Akt-mTOR-p70S6K pathway. Inhibit of HER2 and SMO have synergistic effect on reduction of cell viability. In conclusion, Gli1 is a favorable prognostic indicator in gastric cancer. As a novel target, Gli1 worth further study, especially in Her2-targeted therapy-resistant cancers.

Youssef O, Sarhadi V, Ehsan H, et al.
Gene mutations in stool from gastric and colorectal neoplasia patients by next-generation sequencing.
World J Gastroenterol. 2017; 23(47):8291-8299 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
AIM: To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms.
METHODS: Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP
RESULTS: NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in
CONCLUSION: Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.

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