Gene Summary

Gene:SS18L1; SS18L1 subunit of BAF chromatin remodeling complex
Aliases: CREST, LP2261
Summary:This gene encodes a calcium-responsive transactivator which is an essential subunit of a neuron-specific chromatin-remodeling complex. The structure of this gene is similar to that of the SS18 gene. Mutations in this gene are involved in amyotrophic lateral sclerosis (ALS). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:calcium-responsive transactivator
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 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.

  • synovial sarcoma X breakpoint proteins
  • Binding Sites
  • Contig Mapping
  • Genes, Lethal
  • Chromosome 3
  • Neoplasm Proteins
  • Up-Regulation
  • Introns
  • Oncogene Fusion Proteins
  • Trans-Activators
  • SWI-SNF-B chromatin-remodeling complex
  • Phenotype
  • SS18
  • MED1
  • Cell Differentiation
  • Chromosome 20
  • Mediator Complex Subunit 1
  • Chromosome Mapping
  • Transcription Factors
  • Leg
  • Genes, Recessive
  • Evolution, Molecular
  • Proteins
  • Vertebrates
  • SS18L1
  • BCOR
  • Phylogeny
  • Pseudogenes
  • Molecular Sequence Data
  • Synovial Sarcoma
  • Chromosomal Proteins, Non-Histone
  • Repressor Proteins
  • Amino Acid Sequence
  • Alternative Splicing
  • Proto-Oncogene Proteins
  • Translocation
  • Base Sequence
  • CpG Islands
  • Knockout Mice
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: SS18L1 (cancer-related)

Kurahashi R, Kadomatsu T, Baba M, et al.
MicroRNA-204-5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma.
Cancer Sci. 2019; 110(6):1897-1908 [PubMed] Free Access to Full Article Related Publications
Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early-stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC-TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)-204-5p levels in urinary exosomes of 40-week-old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA-204-5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR-204-5p-containing exosomes. Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR-204-5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC-TFE3 fusion gene. These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.

Umapathy G, Mendoza-Garcia P, Hallberg B, Palmer RH
Targeting anaplastic lymphoma kinase in neuroblastoma.
APMIS. 2019; 127(5):288-302 [PubMed] Related Publications
Over the last decade, anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), has been identified as a fusion partner in a diverse variety of translocation events resulting in oncogenic signaling in many different cancer types. In tumors where the full-length ALK RTK itself is mutated, such as neuroblastoma, the picture regarding the role of ALK as an oncogenic driver is less clear. Neuroblastoma is a complex and heterogeneous tumor that arises from the neural crest derived peripheral nervous system. Although high-risk neuroblastoma is rare, it often relapses and becomes refractory to treatment. Thus, neuroblastoma accounts for 10-15% of all childhood cancer deaths. Since most cases are in children under the age of 2, understanding the role and regulation of ALK during neural crest development is an important goal in addressing neuroblastoma tumorigenesis. An impressive array of tyrosine kinase inhibitors (TKIs) that act to inhibit ALK have been FDA approved for use in ALK-driven cancers. ALK TKIs bind differently within the ATP-binding pocket of the ALK kinase domain and have been associated with different resistance mutations within ALK itself that arise in response to therapeutic use, particularly in ALK-fusion positive non-small cell lung cancer (NSCLC). This patient population has highlighted the importance of considering the relevant ALK TKI to be used for a given ALK mutant variant. In this review, we discuss ALK in neuroblastoma, as well as the use of ALK TKIs and other strategies to inhibit tumor growth. Current efforts combining novel approaches and increasing our understanding of the oncogenic role of ALK in neuroblastoma are aimed at improving the efficacy of ALK TKIs as precision medicine options in the clinic.

Sudo H, Tsuji AB, Sugyo A, et al.
Therapeutic efficacy evaluation of radioimmunotherapy with
Cancer Sci. 2019; 110(5):1653-1664 [PubMed] Free Access to Full Article Related Publications
Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is highly expressed in malignant mesothelioma. The rat-human chimeric antibody NZ-12 has high affinity for human podoplanin and antibody-dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with

Natarajan E
Black and Brown Oro-facial Mucocutaneous Neoplasms.
Head Neck Pathol. 2019; 13(1):56-70 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
Black and brown-colored mucocutaneous lesions present a differential diagnostic challenge, with malignant melanoma being the primary clinical concern. The vast majority of pigmented lesions in the head and neck region are the result of benign, reactive factors such as post-inflammatory melanosis. However, it is not uncommon to discover a range of muco-cutaneous black and brown neoplasms in the oro-facial area. The majority of black/brown pigmented neoplasms are melanocytic in origin; these are neoplasms of neural crest derivation. Melanocytic nevi are a diverse group of benign neoplasms that are the result of specific oncogenic mutations. They are common on cutaneous surfaces but can manifest in mucosal sites. Currently, nevi are classified based on clinical and histological criteria. The most common cutaneous and oral mucosal nevus is the acquired melanocytic nevus; nevi do not pose an increased risk for the development of malignant melanoma. Emerging information on specific genetic differences supports the notion of biologically distinct nevi. This article will review the classic clinical and microscopic features of nevi commonly found in the head and neck region, and discuss emerging concepts in nevus pathogenesis and taxonomy. Melanoma is a malignant melanocytic neoplasm and is a result of cumulative genetic deregulation. The etiology of malignant melanoma (MM) is multifactorial and includes underlying genetic susceptibility, UV radiation, skin-type, and race. The majority of MM occurs on cutaneous surfaces and less commonly on mucosal and extra-cutaneous visceral organs. Regardless of location, MM exhibits clinical-pathological features that relate to horizontal or vertical tumor spread. Cutaneous and mucosal MM typically present as asymmetrical, irregularly bordered, large (> 0.5 cm), heterogeneous brown-black lesions with foci of erythema, atrophy or ulceration. As with melanocytic nevi, advances in melanomagenesis research have revealed primary oncogenic BRAF and NRAS mutations associated with cutaneous MM. Unlike their cutaneous counterparts, mucosal melanomas exhibit primary oncogenic alterations in c-KIT and other genes. This article will discuss the role of specific primary oncogenic and secondary/tertiary genetic defects in differential clinical presentation, anatomic distribution, future classification changes, and targeted therapy of melanoma. The clinical and microscopic features of mucosal melanomas and a summary of management guidelines will be discussed. Additionally, this article will cover the salient features of melanocytic neuroectodermal tumor of infancy, a neoplastic entity that can involve the oro-facial region, and the clinical-pathological features of selected, commonly occurring pigmented ectodermally-derived neoplasms that are often part of the clinical differential diagnosis of black-brown pigmented lesions.

Monferrer E, Burgos-Panadero R, Blanquer-Maceiras M, et al.
High Oct4 expression: implications in the pathogenesis of neuroblastic tumours.
BMC Cancer. 2019; 19(1):1 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
BACKGROUND: Neuroblastic tumours (NBTs) are paediatric solid tumours derived from embryonic neural crest cells which harbour their own cancer stem cells (CSC). There is evidence indicating that CSC may be responsible for tumour progression, chemotherapy resistance and recurrence in NBTs. Oct4 is a transcription factor which plays a key role in mammal embryonic development and stem cell fate regulation. The aim of the study is to elucidate the clinical significance of Oct4 in NBTs.
METHODS: We studied Oct4 expression in 563 primary NBTs using digital image quantification. Chi-square test was applied to analyse the correlation between histopathology and the Oct4
RESULTS: We found that tumours with a high proportion of cells expressing Oct4 correlated statistically with undifferentiated and poorly differentiated neuroblastoma / nodular ganglioneuroblastoma, and that Oct4 expression was not present in ganglioneuroma (p < 0.05). Statistical analysis also indicated a relationship between high Oct4 expression levels, high-risk patients according to the International Neuroblastoma Risk Group pre-treatment classification parameters, larger blood vessels and low survival rates.
CONCLUSIONS: These results suggest that the Oct4 gene may regulate NBT pathogenic differentiation pathways, and should thus be considered as a target for knockdown when developing novel therapies for high-risk NBT patients.

Han TS, Voon DC, Oshima H, et al.
Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.
Gastroenterology. 2019; 156(4):1140-1155.e4 [PubMed] Related Publications
BACKGROUND & AIMS: Gastritis is associated with development of stomach cancer, but little is known about changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression in epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice.
METHODS: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b-knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan.
RESULTS: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130
CONCLUSIONS: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors.

Graf SA, Heppt MV, Wessely A, et al.
The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell invasion.
Pigment Cell Melanoma Res. 2019; 32(3):424-434 [PubMed] Related Publications
The transcription factor sex determining region Y-box 10 (SOX10) plays a key role in the development of melanocytes and glial cells from neural crest precursors. SOX10 is involved in melanoma initiation, proliferation, invasion, and survival. However, specific mediators which impart its oncogenic properties remain widely unknown. To identify target genes of SOX10, we performed RNA sequencing after ectopic expression of SOX10 in human melanoma cells. Among nine differentially regulated genes, peripheral myelin protein 2 (PMP2) was consistently upregulated in several cell lines. Direct regulation of PMP2 by SOX10 was shown by chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Moreover, a coregulation of PMP2 by SOX10 and early growth response 2 in melanoma cells was found. Phenotypical investigation demonstrated that PMP2 expression can increase melanoma cell invasion. As PMP2 protein was detected only in a subset of melanoma cell lines, it might contribute to melanoma heterogeneity.

Tabuchi Y, Hirohashi Y, Hashimoto S, et al.
Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma.
Exp Mol Pathol. 2019; 106:78-88 [PubMed] Related Publications
Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.

Peng EY, Shu Y, Wu Y, et al.
Presence and diagnostic value of circulating tsncRNA for ovarian tumor.
Mol Cancer. 2018; 17(1):163 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
tRNA-derived small non-coding RNAs (tsncRNAs), a class of newly defined small non-coding RNA, have been considered to be involved in various cellular biological processes through regulating gene expression at both transcriptional and post-transcriptional level. However, the presence of circulating tsncRNAs and their diagnostic potential is largely unclear. In this study, we investigate the serum-derived public transcriptome data from ovarian tumor patients and non-cancer controls, and find that circulating tsncRNAs cover a high proportion of total small RNA and are non-random degradation products in serum (ranging from 2.5-29.4%), which are enriched in several specific types of related tRNA (e.g., Gly-tRNA). Particularly, four tsncRNAs are differentially expressed in serum from cancer patients compared to those from healthy controls, and can predict abnormal cell proliferation with high accuracy. Our results reveal the ubiquitous presence of circulating tsncRNAs in serum, and diagnostic potential of specific tsncRNAs for ovarian tumor.

Gu Y, Lv F, Xue M, et al.
The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation.
J Exp Clin Cancer Res. 2018; 37(1):258 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
BACKGROUND: Neuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive.
METHODS: The correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro.
RESULTS: Based on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What's more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest.
CONCLUSION: Our findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB.

Honda K, Katzke VA, Hüsing A, et al.
CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation.
Int J Cancer. 2019; 144(8):1877-1887 [PubMed] Related Publications
Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

Takashima Y, Horisawa K, Udono M, et al.
Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors.
Cancer Sci. 2018; 109(11):3543-3553 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
Hepatocellular carcinoma (HCC) accounts for a large proportion of liver cancer cases and has an extremely poor prognosis. Therefore, novel innovative therapies for HCC are strongly desired. As gene therapy tools for HCC, 2 hepatic transcription factors (TF), HNF4A and HNF1A, have been used to suppress proliferation and to extinguish cancer-specific characteristics of target cells. However, our present data demonstrated that single transduction of HNF4A or HNF1A had only a limited effect on suppression of HCC cell proliferation. Thus, in this study, we examined whether combinations of TF could show more effective antitumor activity, and found that combinatorial transduction of 3 hepatic TF, HNF4A, HNF1A and FOXA3, suppressed HCC cell proliferation more stably than single transduction of these TF. The combinatorial transduction also suppressed cancer-specific phenotypes, such as anchorage-independent growth in culture and tumorigenicity after transplantation into mice. HCC cell lines transduced with the 3 TF did not recover their proliferative property after withdrawal of anticancer drugs, indicating that combinatorial expression of the 3 TF suppressed the growth of all cell subtypes within the HCC cell lines, including cancer stem-like cells. Transcriptome analyses revealed that the expression levels of a specific gene set involved in cell proliferation were only decreased in HCC cells overexpressing all 3 TF. Moreover, combined transduction of the 3 TF could facilitate hepatic differentiation of HCC cell lines. Our strategy for inducing stable inhibition and functional differentiation of tumor cells using a defined set of TF will become an effective therapeutic strategy for various types of cancers.

Dong P, Yu B, Pan L, et al.
Identification of Key Genes and Pathways in Triple-Negative Breast Cancer by Integrated Bioinformatics Analysis.
Biomed Res Int. 2018; 2018:2760918 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
Purpose: Triple-negative breast cancer refers to breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (Her2). This study aimed to identify the key pathways and genes and find the potential initiation and progression mechanism of triple-negative breast cancer (TNBC).
Methods: We downloaded the gene expression profiles of GSE76275 from Gene Expression Omnibus (GEO) datasets. This microarray Super-Series sets are composed of gene expression data from 265 samples which included 67 non-TNBC and 198 TNBC. Next, all the differentially expressed genes (DEGs) with p<0.01 and fold change ≥1.5 or ≤-1.5 were identified.
Result: 56 upregulated and 151 downregulated genes were listed and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis was performed. These significantly changed genes were mainly involved in the biological process termed prostate gland morphogenesis, inner ear morphogenesis, cell maturation, digestive tract morphogenesis, autonomic nervous system development, monovalent inorganic anion homeostasis, neural crest cell development, regulation of dendrite extension and glial cell proliferation, immune system process termed T cell differentiation, regulation of immune response, and macrophage activation. Genes are mainly involved in the KEGG pathway termed Oocyte meiosis. All DEGs underwent survival analysis using datasets from The Cancer Genome Atlas (TCGA) integrated by cBioPortal, of which amplification of SRY-related HMG-box 8 (SOX8), androgen receptor (AR), and Chromosome 9 Open Reading Frame 152 (C9orf152) were significantly negative while Nik Related Kinase (NRK) and RAS oncogene family 30 (RAB30) were positively correlated to the life expectancy (p<0.05).
Conclusions: In conclusion, these pathways and genes identified could help understanding the mechanism of development of TNBC. Besides, SOX8, AR, C9orf152, NRK and RAB30, and other key genes and pathways might be promising targets for the TNBC treatment.

Dravis C, Chung CY, Lytle NK, et al.
Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity.
Cancer Cell. 2018; 34(3):466-482.e6 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.

Ito S, Fujino Y, Ogata S, et al.
Involvement of an Orphan Transporter, SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells.
J Pharm Sci. 2018; 107(12):3163-3170 [PubMed] Related Publications
The SLC22A18 gene, which encodes an orphan transporter, is located at the 11p15.5 imprinted region, an important tumor suppressor gene region. However, the role of SLC22A18 in tumor suppression remains unclear. Here, we investigated the involvement of SLC22A18 in cell growth, invasion, and drug resistance of MCF7 human breast cancer cell line. Western blot analysis indicated that SLC22A18 is predominantly expressed at intracellular organelle membranes. Quantitative proteomics showed that knockdown of SLC22A18 significantly altered the expression of 578 (31.0%) of 1867 proteins identified, including proteins related to malignancy and poor prognosis of breast cancer. SLC22A18 knockdown (1) increased MCF7 cell growth concomitantly with a >7-fold increase of annexin A8 (involved in cell growth and migration; a predictor of poor prognosis), (2) induced spherical morphology of MCF7 cells concomitantly with a nearly 3-fold increase of CD44 (involved in regulation of malignant phenotypes), and (3) increased chemosensitivity to vinca alkaloids concomitantly with a >80% reduction of doublecortin-like kinase 1 (involved in regulation of microtubule polymerization). Our results suggest that SLC22A18 may act as a tumor suppressor by regulating the expression levels of cell growth-related proteins, and vinca alkaloids might show therapeutic efficacy against low-SLC22A18-expressing breast cancer.

Wu H, Larribère L, Sun Q, et al.
Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation.
Int J Cancer. 2018; 143(11):2962-2972 [PubMed] Related Publications
Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways during transformation determines the invasiveness of melanoma cells. In our study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in the invasion and the migration capacities of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified both an upregulation of FOXD1 in NC and melanoma cells, as well as a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired melanoma cell migration and invasion and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.

Vaes N, Schonkeren SL, Brosens E, et al.
A combined literature and in silico analysis enlightens the role of the NDRG family in the gut.
Biochim Biophys Acta Gen Subj. 2018; 1862(10):2140-2151 [PubMed] Related Publications
BACKGROUND: The N-Myc Downstream-Regulated Gene (NDRG) family comprises four members that function in cellular processes like proliferation and differentiation. While NDRG1 and NDRG2 are extensively studied, knowledge regarding NDRG3 and NDRG4, despite its recognition as a well-established early-detection marker for colorectal cancer (Cologuard®), is sparse.
SCOPE OF REVIEW: To summarize expression, biomarker potential and functional mechanisms of the NDRGs in the developing, mature and cancerous gut, we combine current literature and in silico analyses from the TCGA-database, GTEX Project, E14.5 mouse intestine and enteric neural crest cells, and an RNA-sequencing time-series of human embryonic colonic samples.
MAJOR CONCLUSIONS: This study reveals that all members display a differential expression pattern in the gut and that NDRG1, NDRG2 and NDRG4 (1) can serve as biomarker for colorectal cancer and (2) have tumor suppressive properties mainly affecting cell proliferation and epithelial-mesenchymal transition.
GENERAL SIGNIFICANCE: Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

Rambow F, Rogiers A, Marin-Bejar O, et al.
Toward Minimal Residual Disease-Directed Therapy in Melanoma.
Cell. 2018; 174(4):843-855.e19 [PubMed] Related Publications
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.

Seo N, Akiyoshi K, Shiku H
Exosome-mediated regulation of tumor immunology.
Cancer Sci. 2018; 109(10):2998-3004 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8

Shoji H, Miura N, Ueno H, Honda K
Measurement of copy number of ACTN4 to optimize the therapeutic strategy for locally advanced pancreatic cancer.
Pancreatology. 2018; 18(6):624-629 [PubMed] Related Publications
The standard therapeutic strategy recommended for locally advanced pancreatic cancer (LAPC) is typically chemotherapy or chemoradiotherapy (CRT). Although the clinical benefit of chemotherapy alone versus CRT for LAPC has been compared in a number of clinical trials, the optimal therapy for LAPC remains unclear. Moreover, the clinical benefit derived from treatment in each clinical trial is a matter of controversy, and the superiority of one treatment over another has yet to be definitively demonstrated. The poor outcomes seen among patients with LAPC owe largely to the emergence of metastatic disease; therefore, accurately evaluating occult distant metastasis before choosing a therapeutic strategy could be expected to help stratify patients with LAPC into the most appropriate treatment regimen, namely local control or systemic therapy. In 1998, we identified the actinin-4 gene (ACTN4) as an actin-binding protein and showed its molecular mechanisms had clinical implications for cancer metastasis. We also identified ACTN4 gene amplification in pancreatic, ovarian, and salivary gland cancer, and demonstrated its utility as a strong prognostic biomarker for stage I lung adenocarcinoma in patients who had never received chemotherapy. Moreover, we recently reported that ACTN4 gene amplification could be a useful biomarker for predicting the efficacy of CRT for LAPC. In the present review, we summarize current knowledge regarding therapeutic strategies for LAPC and discuss the potential development of personalized medicine using ACTN4 measurement for patients with LAPC.

Harbhajanka A, Chahar S, Miskimen K, et al.
Clinicopathological, immunohistochemical and molecular correlation of neural crest transcription factor SOX10 expression in triple-negative breast carcinoma.
Hum Pathol. 2018; 80:163-169 [PubMed] Related Publications
The transcription factor SOX10 mediates the differentiation of neural crest-derived cells, and SOX10 by immunohistochemistry (IHC) is used primarily for the diagnosis of melanoma. SOX10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple-negative breast carcinoma (TNBC). The aim was to study the clinical, pathologic and molecular profiles of SOX10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for SOX10 expression in 48 cases. SOX10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from formalin-fixed paraffin-embedded (FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of SOX10 with androgen receptor (AR), WT1, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, epidermal growth factor receptor (EGFR), CK5/6 and GATA transcription factor 3 (GATA3) were also assessed. The mean age was 59.38 (range, 28-90 years). Overall, 37.5% cases (18/48) were SOX10+. There was no association between SOX10 expression and age, grade or stage of patients; 6 of 10 (60%) cases of basal-like 1 (BL1), and 5 of 8 cases of unstable (UNS) molecular subtype were SOX10+. One of 5 basal-like-2 (BL2), 1 of 6 immunomodulatory (IM), 1 of 4 mesenchymal (M), 1 of 5 luminal androgen receptor (LAR) and 2 of 8 mesenchymal stem cell (MSL) showed lower frequencies of SOX10 expression. There was negative correlation between SOX10 and AR+ subtypes (P < .002). SOX10 was positively correlated with WT1 (P = .05). SOX10 did not show significant correlation with mammaglobin, GCDFP15, EGFR, CK5/6 and GATA3. SOX10 expression in the basal-like and unstable molecular subtypes supports the concept that these neoplasms show myoepithelial differentiation.

Ong RKS, Flores SK, Reddick RL, et al.
A Unique Case of Metastatic, Functional, Hereditary Paraganglioma Associated With an SDHC Germline Mutation.
J Clin Endocrinol Metab. 2018; 103(8):2802-2806 [PubMed] Related Publications
Context: Mutations in genes encoding for the succinate dehydrogenase (SDH) complex are linked to hereditary paraganglioma syndromes. Paraganglioma syndrome 3 is associated with mutations in SDHC and typically manifests as benign, nonfunctional head and neck paragangliomas.
Design: We describe a case of a 51-year-old woman who initially presented with diarrhea and hypertension and was found to have a retroperitoneal mass, which was resected with a pathology consistent with paraganglioma. Five years later, her symptoms recurred, and she was found to have new retroperitoneal lymphadenopathy and lytic lesions in the first lumbar vertebral body and the right iliac crest, which were visualized on CT scan and octreoscan but not on iodine-123-meta-iodobenzylguanidine (123I-MIBG) and bone scans. She had significantly elevated 24-hour urine norepinephrine and dopamine. The patient received external beam radiation and a series of different antineoplastic agents. Her disease progressed, and she eventually expired within 2 years. Genetic testing revealed a heterozygous SDHC c.43C>T, p.Arg15X mutation, which was also detected in her daughter and her grandson, both of whom have no biochemical or imaging evidence of paraganglioma syndrome yet.
Conclusion: We report a unique case of functional, metastatic abdominal paraganglioma associated with SDHC germline mutation. Our case exemplifies that SDHC germline mutation has variable penetrance, which may manifest with an aggressive biology that could be missed by a 123I-MIBG scan.

Zhang J, Jiang J, Luo Y, et al.
Molecular evaluation of a sporadic paraganglioma with concurrent IDH1 and ATRX mutations.
Endocrine. 2018; 61(2):216-223 [PubMed] Related Publications
PURPOSE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of neural crest origin. Germline or somatic mutations of numerous genes have been implicated in the pathogenesis of PPGLs, including the isocitrate dehydrogenase 1 (IDH1) gene and alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene. Although concurrent IDH1 and ATRX mutations are frequently seen in gliomas, they have never been reported together in PPGLs. The aim of this study was to characterize one paraganglioma with concurrent IDH1 and ATRX mutations identified by whole exome sequencing.
METHODS: Leukocyte and tumor DNA were used for whole exome sequencing and Sanger sequencing. 2-hydroxyglurarate level and the global DNA methylation status in the tumor were measured. ATRX's cDNA transcripts were analyzed. Tyrosine hydroxylase (TH), HIF1α and ATRX staining, as well as telomere-specific FISH was also performed.
RESULTS: The presence of a somatic IDH1 (c.394C>T, p.R132C) mutation and a concurrent somatic ATRX splicing mutation (c.4318-2A>G) in the current case was confirmed. Dramatic accumulation of 2-hydroxyglutarate was detected in the paraganglioma without the global DNA hypermethylation, and pseudohypoxia was also activated. Importantly, immunohistochemistry revealed negative TH staining in the tumor and the first exon region of TH gene was hypermethylated resulting in normal plasma metanephrines. The splicing ATRX mutation resulted in two transcripts, causing frameshifts. Immunohistochemistry revealed scarce ATRX staining in the tumor. Alternative lengthening of telomeres (ALT) was detected by FISH.
CONCLUSIONS: This case represents the first concurrence of IDH1 and ATRX mutations in PPGLs. Although relatively rare, a somatic R132C mutation of IDH1 might play a role in a small subset of sporadic PPGLs.

Rasche L, Angtuaco EJ, Alpe TL, et al.
The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma.
Blood. 2018; 132(1):59-66 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Spatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm

Kosnopfel C, Sinnberg T, Sauer B, et al.
YB-1 Expression and Phosphorylation Regulate Tumorigenicity and Invasiveness in Melanoma by Influencing EMT.
Mol Cancer Res. 2018; 16(7):1149-1160 [PubMed] Related Publications
Cutaneous melanoma represents one of the most aggressive human tumor entities possessing a high tendency to metastasize. Cancer cells frequently exploit a highly conserved developmental program, the epithelial-to-mesenchymal transition (EMT), to gain migratory and invasive properties promoting their metastatic spread. Cytoplasmic localization of the oncogenic transcription and translation factor Y-box binding protein 1 (YB-1) is a powerful inducer of EMT in breast carcinoma cells. Interestingly, EMT-like processes have also been observed in cutaneous melanoma despite its neural crest origin. Here, increased expression of YB-1 negatively affects patient survival in malignant melanoma and promotes melanoma cell tumorigenicity both

Boudjadi S, Chatterjee B, Sun W, et al.
The expression and function of PAX3 in development and disease.
Gene. 2018; 666:145-157 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.

Doménech M, Jové M, Aso S, et al.
Successful treatment with brigatinib in a patient with ALK-rearranged lung adenocarcinoma who developed crizotinib-induced interstitial lung disease.
Lung Cancer. 2018; 119:99-102 [PubMed] Related Publications
We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib.

Nieto MA
A snail tale and the chicken embryo.
Int J Dev Biol. 2018; 62(1-2-3):121-126 [PubMed] Related Publications
Some 25 years ago, a clone was identified that contained the chicken Slug sequences (now called Snail2 ). How could we anticipate at that time how much the chick embryo would help us to understand the ins and outs of cell migration during development and in disease? Indeed, the chick embryo helped us identify Snail2 as the first transcription factor that could induce the epithelial-mesenchymal transition (EMT), key for the migration of embryonic and cancer cells.

Zuo Y, Li X, Wu X, et al.
Multifocal Paraganglioma and Pheochromocytoma Due to Truncated SDHD Mutation.
Urology. 2018; 116:63-67 [PubMed] Related Publications
OBJECTIVE: Pheochromocytoma and paraganglioma (PPGL) are rare autosomal dominant disorders derived from the neural crest chromaffin tissues of the autonomic nervous system. The succinate dehydrogenase complex subunit D (SDHD) gene has been implicated as one of the pathogenic genes. Although more than 100 SDHD mutations have been reported, the phenotype-genotype association remains unclear.
METHODS: We reported a case of a patient who presented with multifocal PPGLs and with a rare SDHD mutation, and reviewed the phenotype-genotype association of SDHD.
RESULTS: We identified a pathogenic variant of SDHD (c.170-1G>T, NM_003002.3), which caused the complete deletion of exon 3 in the transcript and resulted in a shorter and unstable SDHD mRNA. And truncated SDHD mutations were prone to cause multifocal PPGL, whereas missense SDHD mutations usually caused unifocal lesions.
CONCLUSION: This is the first report linking the c.170-1G>T variant to multifocal tumors. We recommend whole-body imaging examinations and close, regular follow-up for these patients, given the risk of multifocal tumor development.

Itoh H, Kadomatsu T, Tanoue H, et al.
TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma.
Oncogene. 2018; 37(22):2903-2920 [PubMed] Related Publications
The tumor microenvironment promotes epigenetic changes in tumor cells associated with tumor aggressiveness. Here we report that in primary tumor cells, increased interleukin-6 (IL-6) expression brought on by DNA demethylation of its promoter by ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma (OS). Xenograft experiments show increased IL-6 expression and decreased methylation of its promoter in OS cells after implantation relative to before implantation. In addition, changes in IL-6 methylation and expression seen in OS cells at the primary site were maintained at the metastatic site. TET2 knockdown in OS cells suppressed upregulation of IL-6 and demethylation of its promoter in xenograft tumors and decreased tumor metastasis. We also present evidence showing that tumor cell-derived IL-6 facilitates glycolytic metabolism in tumor cells by activating the MEK/ERK1/2/hypoxia-inducible transcription factor-1α (HIF-1α) pathway and increases lung colonization by OS cells by upregulating expression of intercellular adhesion molecule-1 (ICAM-1), enhancing tumor metastasis. Blocking IL-6 signaling with a humanized monoclonal antibody against the IL-6 receptor reduced lung metastasis and prolonged survival of xenografted mice. These findings suggest that TET2-dependent IL-6 induction enables acquisition of aggressive phenotypes in OS cells via the tumor microenvironment and that blocking IL-6 signaling could be serve as a potential therapy to antagonize metastasis.

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