SOX10

Gene Summary

Gene:SOX10; SRY (sex determining region Y)-box 10
Aliases: DOM, WS4, PCWH, WS2E, WS4C
Location:22q13.1
Summary:This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-10
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
Show (26)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: SOX10 (cancer-related)

Shirai CL, Ley JN, White BS, et al.
Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.
Cancer Cell. 2015; 27(5):631-43 [PubMed] Article available free on PMC after 11/05/2016 Related Publications
Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.

Maggi LB, Weber JD
Targeting PTEN-defined breast cancers with a one-two punch.
Breast Cancer Res. 2015; 17:51 [PubMed] Article available free on PMC after 11/05/2016 Related Publications
With tremendous advances in sequencing and analysis in recent years, a wealth of genetic information has become available to identify and classify breast cancer into five main subtypes - luminal A, luminal B, claudin-low, human epidermal growth factor receptor 2-enriched, and basal-like. Current treatment decisions are often based on these classifications, and while more beneficial than any single treatment for all breast cancers, targeted therapeutics have exhibited limited success with most of the subtypes. Luminal B breast cancers are associated with early relapse following endocrine therapy and often exhibit a poor prognosis that is similar to that of the aggressive basal-like breast cancers. Identifying genetic components that contribute to the luminal B endocrine resistant phenotype has become imperative. To this end, numerous groups have identified activation of the phosphatidylinositol 3-kinase (PI3K) pathway as a common recurring event in luminal B cancers with poor outcome. Examining the pathways downstream of PI3K, Fu and colleagues have recreated a human model of the luminal B subtype of breast cancer. The authors were able to reduce expression of phosphatase and tensin homolog (PTEN), the negative regulator of PI3K, using inducible short hairpin RNAs. By varying the expression of PTEN, the authors effectively conferred endocrine resistance and recapitulated the luminal B gene expression signature. Using this system in vitro and in vivo, they then tested the ability of selective kinase inhibitors downstream of PI3K to enhance current endocrine therapies. A combination of fulvestrant, which blocks ligand-dependent and -independent estrogen receptor signaling, with protein kinase B inhibition was found to overcome endocrine resistance. These findings squarely place PTEN expression levels at the nexus of luminal B breast cancers and indicates that patients with PTEN-low estrogen receptor-positive tumors might benefit from combined endocrine and PI3K pathway therapies.

Diamond MI, Cai S, Boudreau A, et al.
Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of profilin-1.
J Biol Chem. 2015; 290(14):9075-86 [PubMed] Article available free on PMC after 03/04/2016 Related Publications
The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-l-proline (PLP) binding pocket. Here we confirm that Ser-137 phosphorylation disrupts Pfn1 binding to its PLP-containing ligands with little effect on actin binding. We find in mouse xenografts of breast cancer cells that mimicking Ser-137 phosphorylation abolishes cell cycle arrest and apoptotic sensitization by Pfn1 and confers a growth advantage to tumors. This indicates a previously unrecognized role of PLP binding in Pfn1 antitumor effects. Spatial restriction of Pfn1 to the nucleus or cytoplasm indicates that inhibition of tumor cell growth by Pfn1 requires its nuclear localization, and this activity is abolished by a phosphomimetic mutation on Ser-137. In contrast, cytoplasmic Pfn1 lacks inhibitory effects on tumor cell growth but rescues morphological and proliferative defects of PFN1 null mouse chondrocytes. These results help reconcile seemingly opposed cellular effects of Pfn1, provide new insights into the antitumor mechanism of Pfn1, and implicate Ser-137 phosphorylation as a potential therapeutic target for breast cancer.

Shakhova O, Cheng P, Mishra PJ, et al.
Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma.
PLoS Genet. 2015; 11(1):e1004877 [PubMed] Article available free on PMC after 03/04/2016 Related Publications
Melanoma is the most fatal skin cancer, but the etiology of this devastating disease is still poorly understood. Recently, the transcription factor Sox10 has been shown to promote both melanoma initiation and progression. Reducing SOX10 expression levels in human melanoma cells and in a genetic melanoma mouse model, efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis. Here, we show that this anti-tumorigenic effect functionally involves SOX9, a factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10. Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the formation of hyperplastic lesions, and melanoma initiation. To the contrary, SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene expression profile shared by melanoma cells with reduced SOX10 expression. Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10 expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high ant,m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10 and SOX9 are functionally antagonistic regulators of melanoma development.

Tacha D, Qi W, Ra S, et al.
A newly developed mouse monoclonal SOX10 antibody is a highly sensitive and specific marker for malignant melanoma, including spindle cell and desmoplastic melanomas.
Arch Pathol Lab Med. 2015; 139(4):530-6 [PubMed] Related Publications
CONTEXT: Recent immunohistochemical studies have demonstrated Sry-related HMG-Box gene 10 (SOX10) expression in malignant melanomas, malignant peripheral nerve sheath tumors, a subset of breast carcinomas, and gliomas. SOX10 has shown important clinical utility in its ability to detect desmoplastic and spindle cell melanomas. To date, most publications have employed a research use-only goat polyclonal SOX10 antibody for immunohistochemical staining.
OBJECTIVE: To describe the development of a new mouse monoclonal SOX10 antibody (BC34) and evaluate its immunohistochemical staining profile in a wide range of normal and neoplastic tissues, with an emphasis on melanoma.
DESIGN: SOX10 antibody was optimized for staining using a polymer detection system and visualization with diaminobenzidine.
RESULTS: In normal tissues, SOX10 was expressed in skin melanocytes and eccrine cells, breast myoepithelial and lobular epithelial cells, salivary gland myoepithelial cells, peripheral nerve Schwann cells, and central nervous system glial cells. SOX10 was expressed in 238 of 257 melanomas (92.6%), including 50 of 51 of both spindle cell and desmoplastic melanomas (98%). SOX10 was expressed in 100% of nevi (20 of 20) and schwannomas (28 of 28). In other neoplasms, SOX10 was expressed in 18 of 109 invasive ductal breast carcinomas (16.5%). All other carcinomas were negative for SOX10. SOX10 was identified in 25 of 52 central nervous system neoplasms, primarily in astrocytomas (22 of 41; 53.7%), and in 4 of 99 various sarcomas examined (4.0%).
CONCLUSIONS: The newly developed mouse monoclonal SOX10 antibody BC34 is highly sensitive and specific for malignant melanoma, including desmoplastic and spindle cell variants, and appears highly suitable for clinical use.

Tran HD, Luitel K, Kim M, et al.
Transient SNAIL1 expression is necessary for metastatic competence in breast cancer.
Cancer Res. 2014; 74(21):6330-40 [PubMed] Related Publications
SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis.

Choi H, Jin SH, Han MH, et al.
Human melanocytes form a PAX3-expressing melanocyte cluster on Matrigel by the cell migration process.
J Dermatol Sci. 2014; 76(1):60-6 [PubMed] Related Publications
BACKGROUND: The interactions between human epidermal melanocytes and their cellular microenvironment are important in the regulation of human melanocyte functions or in their malignant transformation into melanoma. Although the basement membrane extracellular matrix (BM-ECM) is one of major melanocyte microenvironments, the effects of BM-ECM on the human melanocyte functions are not fully explained at a molecular level.
OBJECTIVE: This study was aimed to characterize the molecular and cellular interactions between normal human melanocytes (NHMs) and BM-ECM.
METHODS: We investigated cell culture models of normal human melanocytes or melanoma cells on three-dimensional (3D) Matrigel to understand the roles of the basement membrane microenvironment in human melanocyte functions. Melanogenesis and melanobast biomarker expression in both primary human melanocytes and melanoma cells on 3D Matrigel were evaluated.
RESULTS: We found that NHMs migrated and formed reversible paired box 3 (PAX3) expressing cell clusters on three-dimensional (3D) Matrigel. The melanogenesis was significantly decreased in the PAX3 expressing cell cluster. The expression profile of PAX3, SOX10, and MITF in the melanocyte cluster on 3D Matrigel was similar to that of melanoblasts. Interestingly, PAX3 and SOX10 showed an inverse expression profile in NHMs, whereas the inverse expression pattern of PAX3 and SOX10 was disrupted in melanoma MNT1 and WM266-4 cells.
CONCLUSION: The human melanocyte culture on 3D Matrigel provides an alternative model system to study functions of human melanoblasts. In addition, this system will contribute to the elucidation of PAX3-related tumorigenic mechanisms to understand human melanoma.

Liu J, Fukunaga-Kalabis M, Li L, Herlyn M
Developmental pathways activated in melanocytes and melanoma.
Arch Biochem Biophys. 2014; 563:13-21 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Cutaneous malignant melanomas originate primarily within epidermal melanocytic cells. Melanoma cells share many characteristics with melanocyte precursors, suggesting that melanoma cells utilize the developmental programs of their normal counterpart for their own progression. The pigmentation system provides an advantageous model to assess survival pathway interactions in the melanocytic lineage, as genetic alterations controlling melanocyte development can be easily detectable by coat color phenotype that do not affect the viability of an animal. By integrating combinatorial gene knockout approaches, cell-based assays and immunohistochemical observations, recent studies have illustrated several genes and pathways that play important roles both in melanocyte specification and maintenance and in melanoma formation and progression. We are reviewing those genes and pathways to understand the connection between normal and cancerous development and to reveal therapeutic potential of targeting developmental pathways for melanoma therapy.

Zhou D, Bai F, Zhang X, et al.
SOX10 is a novel oncogene in hepatocellular carcinoma through Wnt/β-catenin/TCF4 cascade.
Tumour Biol. 2014; 35(10):9935-40 [PubMed] Related Publications
SOX (high mobility group) genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of SOXs in the human hepatocellular carcinoma (HCC). The gene expression changes of SOXs in HCC tissues compared with those in noncancerous hepatic tissues were detected using real-time quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) analysis and immunohistochemistry. In addition, we identified the gene SOX10 that was significantly upregulated in HCC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that SOX10 promoted cancer cell proliferation in vitro, and SOX10 expression correlated with elevated β-catenin levels in HCC, and β-catenin function was required for SOX10's oncogenic effects. Mechanistically, SOX10 facilitates TCF4 to bind to β-catenin and form a stable SOX10/TCF4/β-catenin complex and trans-activate its downstream target gene. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevent its function in tumor cells. All in all, SOX10 is a commonly activated tumor promoter that activates Wnt/β-catenin signaling in cancer cells of HCC.

Alonso-Curbelo D, Riveiro-Falkenbach E, Pérez-Guijarro E, et al.
RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway.
Cancer Cell. 2014; 26(1):61-76 [PubMed] Related Publications
Although common cancer hallmarks are well established, lineage-restricted oncogenes remain less understood. Here, we report an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF, the best-characterized melanocyte lineage-specific transcription factor. Instead, we describe the neuroectodermal master modulator SOX10 and the oncogene MYC as RAB7 regulators. These results reveal a unique wiring of the lysosomal pathway that melanomas exploit to foster tumor progression.

Clevenger J, Joseph C, Dawlett M, et al.
Reliability of immunostaining using pan-melanoma cocktail, SOX10, and microphthalmia transcription factor in confirming a diagnosis of melanoma on fine-needle aspiration smears.
Cancer Cytopathol. 2014; 122(10):779-85 [PubMed] Related Publications
BACKGROUND: Accurate fine-needle aspiration (FNA) diagnosis of metastatic melanoma is of therapeutic and prognostic significance and often requires ancillary studies. To the authors' knowledge, the reliability of immunostaining using a pan-melanoma cocktail, Sry-related HMG-BOX gene 10 (SOX10), and microphthalmia transcription factor (MITF) in confirming a diagnosis of melanoma on FNA smears has not been studied to date.
METHODS: This retrospective study included 50 FNA cases with a definitive diagnosis of melanoma. Twenty-nine cases were epithelioid type (group 1), and 21 cases were predominantly spindle cell type with or without an epithelioid component (group 2). Each case was immunostained using pan-melanoma cocktail, SOX10, and MITF. Staining intensity and the percentage of positive cells were recorded.
RESULTS: The pan-melanoma cocktail was positive in 43 cases (86%), SOX10 was positive in 50 cases (100%), and MITF in 45 cases (90%). SOX10 and MITF demonstrated nuclear staining with stronger and more diffuse staining with less or no background staining compared with pan-melanoma cocktail, which displayed cytoplasmic staining. For pan-melanoma cocktail and SOX10, the detection rates were identical in groups 1 and 2 (86% with pan-melanoma cocktail and 100% with SOX10). For MITF, the detection rate was higher in group 1 compared with Group 2 (93% vs 86%).
CONCLUSIONS: In the current study, SOX10 was found to have the highest overall detection rate, followed by MITF and pan-melanoma cocktail. The pan-melanoma cocktail and SOX10 performed equally well for groups 1 and 2, and MITF had a higher detection rate in group 1. Overall, SOX10 and MITF appeared to be superior to the pan-melanoma cocktail and SOX10 seemed better than MITF in confirming a diagnosis of melanoma on FNA smears.

Das D, Kaur I, Ali MJ, et al.
Exome sequencing reveals the likely involvement of SOX10 in uveal melanoma.
Optom Vis Sci. 2014; 91(7):e185-92 [PubMed] Related Publications
PURPOSE: To identify the spectrum of somatic mutations in an Asian Indian patient with uveal melanoma (UM) without metastasis using exome sequencing.
CASE REPORT: A 49-year-old man from India was diagnosed as having cilio-choroidal (uveal) melanoma (UM), without metastasis, in his right eye with the help of magnetic resonance imaging. This was later confirmed by histopathological evaluation. Two individuals from India with non-neoplastic blind eyes were recruited as controls. The affected eyes from the UM patient and the two control individuals were enucleated, and uveal tissues were collected. DNA was extracted from uveal tissue, and the matched blood sample from each of the three individuals was followed by exome sequencing. Statistical and bioinformatic analyses were done to identify somatic mutations and their putative associations with UM. Thirty-one somatic mutations (25 amino acid altering) in protein-coding (exonic) regions were detected in the UM patient. Of the amino acid-altering somatic mutations, 16 mutations were predicted to be candidate mutations relevant to UM. Somatic mutations, putatively causal for UM, were identified in GNAQ, SF3B1, and SOX10.
CONCLUSIONS: Somatic mutations in GNAQ and SF3B1 genes were probable drivers of UM in the Indian patient; these were also reported earlier in some White patients. In addition, a frameshift deletion of 20 base pairs has been identified in SOX10 in the UM patient. Somatic mutations in SOX10, a transcription factor, which acts upstream of microphthalmia-associated transcription factor and synergizes with microphthalmia-associated transcription factor, was identified in some melanoma cell lines. The transcription factor SOX10 was found to have an essential role in melanocyte development and pigmentation. Our finding of the frameshift deletion (p.H387fs) in exon 4 of SOX10 in UM provides an important insight and complements earlier findings of mutations in GNAQ and SF3B1 on the genomic basis of UM.

Cabanski CR, Magrini V, Griffith M, et al.
cDNA hybrid capture improves transcriptome analysis on low-input and archived samples.
J Mol Diagn. 2014; 16(4):440-51 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The use of massively parallel sequencing for studying RNA expression has greatly enhanced our understanding of the transcriptome through the myriad ways these data can be characterized. In particular, clinical samples provide important insights about RNA expression in health and disease, yet these studies can be complicated by RNA degradation that results from the use of formalin as a clinical preservative and by the limited amounts of RNA often available from these precious samples. In this study we describe the combined use of RNA sequencing with an exome capture selection step to enhance the yield of on-exon sequencing read data when compared with RNA sequencing alone. In particular, the exome capture step preserves the dynamic range of expression, permitting differential comparisons and validation of expressed mutations from limited and FFPE preserved samples, while reducing the data generation requirement. We conclude that cDNA hybrid capture has the potential to significantly improve transcriptome analysis from low-yield FFPE material.

Redmer T, Welte Y, Behrens D, et al.
The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells.
PLoS One. 2014; 9(5):e92596 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Large-scale genomic analyses of patient cohorts have revealed extensive heterogeneity between individual tumors, contributing to treatment failure and drug resistance. In malignant melanoma, heterogeneity is thought to arise as a consequence of the differentiation of melanoma-initiating cells that are defined by cell-surface markers like CD271 or CD133.
RESULTS: Here we confirmed that the nerve growth factor receptor (CD271) is a crucial determinant of tumorigenicity, stem-like properties, heterogeneity and plasticity in melanoma cells. Stable shRNA mediated knock-down of CD271 in patient-derived melanoma cells abrogated their tumor-initiating and colony-forming capacity. A genome-wide expression profiling and gene-set enrichment analysis revealed novel connections of CD271 with melanoma-associated genes like CD133 and points to a neural crest stem cell (NCSC) signature lost upon CD271 knock-down. In a meta-analysis we have determined a shared set of 271 differentially regulated genes, linking CD271 to SOX10, a marker that specifies the neural crest. To dissect the connection of CD271 and CD133 we have analyzed 10 patient-derived melanoma-cell strains for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271+ cells in the majority of cell strains analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell strains harbored a CD133+ sub-set that in addition comprised a fraction of cells of a CD271+/CD133+ phenotype. Those cells were found in the label-retaining fraction and in vitro deduced from CD271+ but not CD271 knock-down cells.
CONCLUSIONS: Our present study provides a deeper insight into the regulation of melanoma cell properties and points CD271 out as a regulator of several melanoma-associated genes. Further, our data strongly suggest that CD271 is a crucial determinant of stem-like properties of melanoma cells like colony-formation and tumorigenicity.

Alisoltani A, Fallahi H, Ebrahimi M, et al.
Prediction of potential cancer-risk regions based on transcriptome data: towards a comprehensive view.
PLoS One. 2014; 9(5):e96320 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
A novel integrative pipeline is presented for discovery of potential cancer-susceptibility regions (PCSRs) by calculating the number of altered genes at each chromosomal region, using expression microarray datasets of different human cancers (HCs). Our novel approach comprises primarily predicting PCSRs followed by identification of key genes in these regions to obtain potential regions harboring new cancer-associated variants. In addition to finding new cancer causal variants, another advantage in prediction of such risk regions is simultaneous study of different types of genomic variants in line with focusing on specific chromosomal regions. Using this pipeline we extracted numbers of regions with highly altered expression levels in cancer condition. Regulatory networks were also constructed for different types of cancers following the identification of altered mRNA and microRNAs. Interestingly, results showed that GAPDH, LIFR, ZEB2, mir-21, mir-30a, mir-141 and mir-200c, all located at PCSRs, are common altered factors in constructed networks. We found a number of clusters of altered mRNAs and miRNAs on predicted PCSRs (e.g.12p13.31) and their common regulators including KLF4 and SOX10. Large scale prediction of risk regions based on transcriptome data can open a window in comprehensive study of cancer risk factors and the other human diseases.

Sun C, Wang L, Huang S, et al.
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.
Nature. 2014; 508(7494):118-22 [PubMed] Related Publications
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.

Zhang S, Zhu C, Zhu L, et al.
Oncogenicity of the transcription factor SOX8 in hepatocellular carcinoma.
Med Oncol. 2014; 31(4):918 [PubMed] Related Publications
SOX genes play an important role in a number of developmental processes. SOXs have been demonstrated to have potential roles as either tumor suppressors or promoters in various neoplastic tissues depending on the tumor status and type. The aim of this study was to investigate the functional role of SOXs in human cancers. Gene expression changes of SOXs in human hepatocellular carcinoma (HCC) tissues were detected using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry and compared with those in non-cancerous hepatic tissues. We found by qRT-PCR analysis and immunohistochemistry that the gene SOX8 was significantly upregulated in HCC. Furthermore, we discovered that SOX8 promoted cancer cell proliferation in vitro and that its expression was correlated with elevated β-catenin levels in HCC, whose function was required for the oncogenic effects of SOX8.

Kiuru M, McDermott G, Berger M, et al.
Desmoplastic melanoma with sarcomatoid dedifferentiation.
Am J Surg Pathol. 2014; 38(6):864-70 [PubMed] Related Publications
Desmoplastic melanoma (DM) is a variant of melanoma, which typically affects chronically sun-damaged skin of elderly patients. Pure DM displays a low density of fusiform melanocytes in a collagen-rich matrix. In mixed DM, tumor cell density is higher, and parts of the tumor lack abundant stromal fibrosis. Both pure and mixed DMs usually express S100 protein homogenously. We report herein an unusual biphenotypic tumor characterized by the association of a pure DM with an undifferentiated solid spindle cell nodule. It occurred on the scalp of a 66-year-old man. A biopsy of the undifferentiated spindle cell nodule was initially interpreted at a commercial laboratory as atypical fibroxanthoma. The pure DM was seen only in the excisional specimen. All cells of the pure DM stained for S100 protein and SOX10. The adjacent solid sarcomatoid spindle cell nodule lacked expression of S100 protein, SOX10, as well as melan-A, gp100, and microphthalmia-associated transcription factor in >95% of its tumor cells. Although focal expression of melanocyte differentiation antigens in the solid tumor component made us favor a combined DM with sarcomatoid dedifferentiation, we also considered the possibility of a collision scenario, that is, a pleomorphic dermal sarcoma incidentally colliding with a DM. To further assess a possible relationship of the sarcomatoid nodule with the DM, we performed next-generation sequencing analysis on each component separately. The analysis revealed shared chromosomal copy number changes and a high number of common mutations, thereby supporting the concept of a DM with a dedifferentiated sarcomatoid component. An interesting finding is the presence of mutations of the neurofibromin 1 (NF1) gene in both tumor components.

Fonseca NA, Gregório AC, Valério-Fernandes A, et al.
Bridging cancer biology and the patients' needs with nanotechnology-based approaches.
Cancer Treat Rev. 2014; 40(5):626-35 [PubMed] Related Publications
Cancer remains as stressful condition and a leading cause of death in the western world. Actual cornerstone treatments of cancer disease rest as an elusive alternative, offering limited efficacy with extensive secondary effects as a result of severe cytotoxic effects in healthy tissues. The advent of nanotechnology brought the promise to revolutionize many fields including oncology, proposing advanced systems for cancer treatment. Drug delivery systems rest among the most successful examples of nanotechnology. Throughout time they have been able to evolve as a function of an increased understanding from cancer biology and the tumor microenvironment. Marketing of Doxil® unleashed a remarkable impulse in the development of drug delivery systems. Since then, several nanocarriers have been introduced, with aspirations to overrule previous technologies, demonstrating increased therapeutic efficacy besides decreased toxicity. Spatial and temporal targeting to cancer cells has been explored, as well as the use of drug combinations co-encapsulated in the same particle as a mean to take advantage of synergistic interactions in vivo. Importantly, targeted delivery of siRNA for gene silencing therapy has made its way to the clinic for a "first in man" trial using lipid-polymeric-based particles. Focusing in state-of-the-art technology, this review will provide an insightful vision on nanotechnology-based strategies for cancer treatment, approaching them from a tumor biology-driven perspective, since their early EPR-based dawn to the ones that have truly the potential to address unmet medical needs in the field of oncology, upon targeting key cell subpopulations from the tumor microenvironment.

Graf SA, Busch C, Bosserhoff AK, et al.
SOX10 promotes melanoma cell invasion by regulating melanoma inhibitory activity.
J Invest Dermatol. 2014; 134(8):2212-20 [PubMed] Related Publications
The transcription factor SOX10 (SRY (sex determining region Y)-box 10) has a key role in the embryonic development of melanocytes. Recently, it has been suggested that SOX10 is highly relevant for melanoma development and survival. However, the distinct functions and downstream targets of SOX10 in melanoma remain widely unknown. In this study, we inhibited SOX10 via RNA interference in different human melanoma cell lines and found a significantly reduced invasion capacity in vitro and in the chick embryo model. At later time points, SOX10 inhibition reduced proliferation and induced cell death. We identified melanoma inhibitory activity (MIA) as a direct target gene of SOX10, which is an essential protein for melanoma cell migration and invasion. Expression levels of SOX10 and MIA strictly correlated in melanoma cell lines, and SOX10 inhibition reduced MIA expression and promoter activity. Direct binding of SOX10 to the MIA promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. Ectopic expression of MIA in SOX10-inhibited melanoma cells restored the invasion capacity, supporting the hypothesis that MIA is responsible for SOX10-mediated melanoma cell invasion. Our data provide evidence for a critical role of SOX10 in melanoma cell invasion through the regulation of MIA and highlight its role as a therapeutic target in melanoma.

Zupkó I, Molnár J, Réthy B, et al.
Anticancer and multidrug resistance-reversal effects of solanidine analogs synthetized from pregnadienolone acetate.
Molecules. 2014; 19(2):2061-76 [PubMed] Related Publications
A set of solanidine analogs with antiproliferative properties were recently synthetized from pregnadienolone acetate, which occurs in Nature. The aim of the present study was an in vitro characterization of their antiproliferative action and an investigation of their multidrug resistance-reversal activity on cancer cells. Six of the compounds elicited the accumulation of a hypodiploid population of HeLa cells, indicating their apoptosis-inducing character, and another one caused cell cycle arrest at the G2/M phase. The most effective agents inhibited the activity of topoisomerase I, as evidenced by plasmid supercoil relaxation assays. One of the most potent analogs down-regulated the expression of cell-cycle related genes at the mRNA level, including tumor necrosis factor alpha and S-phase kinase-associated protein 2, and induced growth arrest and DNA damage protein 45 alpha. Some of the investigated compounds inhibited the ABCB1 transporter and caused rhodamine-123 accumulation in murine lymphoma cells transfected by human MDR1 gene, expressing the efflux pump (L5178). One of the most active agents in this aspect potentiated the antiproliferative action of doxorubicin without substantial intrinsic cytostatic capacity. The current results indicate that the modified solanidine skeleton is a suitable substrate for the rational design and synthesis of further innovative drug candidates with anticancer activities.

Fried I, Sitthinamsuwan P, Muangsomboon S, et al.
SOX-10 and MiTF expression in cellular and 'mixed' neurothekeoma.
J Cutan Pathol. 2014; 41(8):640-5 [PubMed] Related Publications
BACKGROUND: Neurothekeoma and nerve sheath myxoma have long been interpreted as related tumors that share nerve sheath linage. Lack of S100 expression in neurothekeoma and similarities of gene expression profiles between neurothekeoma and fibrohistiocytic tumors have created reasonable doubt about this concept. SOX-10 represents a marker for schwannian and melanocytic differentiation, and is expressed in other tumors of nerve sheath linage. Microphthalmia transcription factor (MiTF) expression has been repeatedly reported in cellular neurothekeoma in the recent literature and was proposed as a helpful marker in this entity.
METHODS: We investigated 25 cases of cellular neurothekeoma, 8 cases of mixed neurothekeoma and 1 case of nerve sheath myxoma for the expression of SOX-10, MiTF, S100, NKI/C3, Melan-A and smooth muscle actin (SMA) using immunohistochemistry.
RESULTS: A lack of SOX-10 expression was demonstrated in 100% of cellular and mixed neurothekeomas, but was present in the case of nerve sheath myxoma. More than two thirds of neurothekeomas showed very focal or no reactivity with MiTF.
CONCLUSIONS: Our data suggest that neurothekeoma and nerve sheath myxoma are unrelated, and that cellular and mixed neurothekeoma may not be of nerve sheath lineage. In addition, MiTF should not be regarded as a useful marker in neurothekeoma.

Shakhova O
Neural crest stem cells in melanoma development.
Curr Opin Oncol. 2014; 26(2):215-21 [PubMed] Related Publications
PURPOSE OF REVIEW: Metastatic melanoma is the most aggressive skin cancer and despite tremendous efforts and considerable progress in clinical treatment of melanoma patients within recent years, it remains a deadly disease. Current treatments affect melanoma cells indiscriminately, while accumulating evidence suggests that melanoma might be a disease of stem cells. This review aims to summarize the important accomplishments in the field and to emphasize the common molecular and cellular mechanisms regulating self-renewal of neural crest stem cells (NCSCs) and melanoma cells.
RECENT FINDINGS: A growing number of publications highlight the existence of phenotypic and functional similarities between embryonic NCSCs and melanoma cells. These studies provide compelling evidence that the propagation of melanoma cells critically depends on genes instrumental in neural crest development. The example of Sox10 and Rac1 genes provides detailed illustration of how interfering with these important genes for neural crest development can prevent melanoma formation.
SUMMARY: The development of new therapies, targeting RAF-MEK-ERK pathway, provided major improvements in outcomes for patients with metastatic melanoma; however, acquired resistance followed by tumor recurrence represents a major clinical challenge. The striking parallels between embryonic NCSCs (eNCSCs) and melanoma cells might lead to the development of new targeted therapeutics selectively eliminating cell populations accountable for tumor initiation, progression and relapse.

Naujokas A, Charli-Joseph Y, Ruben BS, et al.
SOX-10 expression in cutaneous myoepitheliomas and mixed tumors.
J Cutan Pathol. 2014; 41(4):353-63 [PubMed] Related Publications
BACKGROUND: SOX-10 expression can be demonstrated by immunohistochemistry in salivary gland myoepitheliomas, but its expression in cutaneous myoepitheliomas and in cutaneous mixed tumors with prominent myoepithelial cells has not been studied.
METHODS: We assessed the staining pattern of SOX-10 in five cutaneous myoepitheliomas and six cutaneous mixed tumors with a prominent myoepithelial component among both the myoepithelial cells and cells lining lumens. In addition, we examined the staining of S100, microphthalmia-associated transcription factor (MiTF), keratin cocktail, HMK903, smooth muscle actin (SMA) and epithelial membrane antigen (EMA).
RESULTS: SOX-10 positivity was seen in three of five (60%) cutaneous myoepitheliomas and in the myoepithelial cells of all cutaneous mixed tumors. SOX-10 expression on the cells lining the glandular structures in mixed tumors was variable. All myoepitheliomas and mixed tumors stained positively with S100 and negatively with MiTF. Pan-keratin, HMK903, SMA and EMA showed variable expression.
CONCLUSIONS: SOX-10 is a relatively reliable marker for staining cutaneous myoepitheliomas. Cutaneous myoepitheliomas are notoriously difficult to diagnose, and the addition of SOX-10 to the repertoire of stains that can label this tumor is of practical utility. These results further support that cutaneous myoepitheliomas and cutaneous mixed tumors exist on a morphologic and immunophenotypic spectrum.

Rizza W, Veronese N, Fontana L
What are the roles of calorie restriction and diet quality in promoting healthy longevity?
Ageing Res Rev. 2014; 13:38-45 [PubMed] Related Publications
Epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many age-associated chronic diseases, and in the biology of aging itself. Data from several animal studies suggest that the degree and time of calorie restriction (CR) onset, the timing of food intake as well as diet composition, play major roles in promoting health and longevity, breaking the old dogma that only calorie intake is important in extending healthy lifespan. Data from human studies indicate that long-term CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of developing type 2 diabetes, hypertension, cardiovascular disease and cancer. Moreover, CR opposes the expected age-associated alterations in myocardial stiffness, autonomic function, and gene expression in the human skeletal muscle. However, it is possible that some of the beneficial effects on metabolic health are not entirely due to CR, but to the high quality diets consumed by the CR practitioners, as suggested by data collected in individuals consuming strict vegan diets. More studies are needed to understand the interactions among single nutrient modifications (e.g. protein/aminoacid, fatty acids, vitamins, phytochemicals, and minerals), the degree of CR and the frequency of food consumption in modulating anti-aging metabolic and molecular pathways, and in the prevention of age-associated diseases.

Chan JK
Newly available antibodies with practical applications in surgical pathology.
Int J Surg Pathol. 2013; 21(6):553-72 [PubMed] Related Publications
Selected antibodies that have become available in recent years and have applications in diagnostic pathology are discussed. They include antibodies that are organ-related, provide information on cellular differentiation or histogenetic type, have predictive value in tumors, and highlight infective agents. PAX8 (paired box gene 8) is a marker expressed in the lower female genital tract, thyroid, and kidney and their tumors. Napsin A is expressed in the lung and kidney and is an alternative marker for pulmonary adenocarcinoma. Arginase A is a sensitive and specific marker for liver tumors. ERG (Ets-related gene) is an excellent marker for endothelium and vascular tumors as well as prostatic cancer (about 50% of cases). SOX10 (SRY-related HMG box) is expressed predominantly in melanocytic and Schwann cells and the corresponding tumors. DOG1 (discovered on GIST 1) is an excellent marker for gastrointestinal stromal tumor (GIST) and acinic cell carcinoma. OCT3/4 is a pan-germ cell tumor marker, except yolk sac tumor. SALL4 is positive in various types of germ cell tumors, including yolk sac tumor. MUC4 (mucin-related antigen 4) is a sensitive and specific marker for low-grade fibromyxoid sarcoma. Langerin is a specific marker for Langerhans cells and their tumors. SOX11 is a sensitive marker for mantle cell lymphoma. New generation antibodies against anaplastic lymphoma kinase (ALK) are required to reliably demonstrate ALK gene translocation in pulmonary carcinomas. Lack of expression of succinate dehydrogenase B is seen in paragangliomas of the hereditary form and in the pediatric type of GIST. Antibodies against Trepenoma pallidum can facilitate the diagnosis of syphilis, whereas those against SV40 (simian virus 40) are helpful for diagnosis of BK virus infection and progressive multifocal leukoencephalopathy.

Bobinet M, Vignard V, Florenceau L, et al.
Overexpression of meloe gene in melanomas is controlled both by specific transcription factors and hypomethylation.
PLoS One. 2013; 8(9):e75421 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The melanoma antigens MELOE-1 and MELOE-2 are encoded by a messenger, called meloe, overexpressed in melanomas compared with other tumour cell types and healthy tissues. They are both able to elicit melanoma-specific T cell responses in melanoma patients, and MELOE-1-specific CD8 T cells have been involved in melanoma immunosurveillance. With the aim to develop immunotherapies targeting this antigen, we investigated the transcriptional mechanisms leading to the preferential expression of meloe messenger in the melanocytic lineage. We defined the minimal promoter region of meloe gene and identified binding motifs for a set of transcription factors. Using mutagenesis, co-transfection experiments and chromatin immunoprecipitation, we showed that transcription factors involved in meloe promoter activity in melanomas were the melanocytic specific SOX9 and SOX10 proteins together with the activated P-CREB protein. Furthermore, we showed that meloe promoter was hypomethylated in melanomas and melanocytes, and hypermethylated in colon cancer cell lines and mesotheliomas, thus explaining the absence of P-CREB binding in these cell lines. This was a second key to explain the overerexpression of meloe messenger in the melanocytic lineage. To our knowledge, such a dual transcriptional control conferring tissue-specificity has never been described for the expression of tumour antigens.

Ellis MJ
Mutational analysis of breast cancer: guiding personalized treatments.
Breast. 2013; 22 Suppl 2:S19-21 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The application of high throughput techniques to profile DNA, RNA and protein in breast cancer samples from hundreds of patients has profoundly increased our knowledge of the disease. However there remain many knowledge gaps that will require a long process of extended clinical correlation studies, deeper integrated 'omic analysis and functional annotation to address. This article reviews conclusions from recent breast cancer 'omics profiling' papers and considers pathways forward for extracting medically valuable information from large dimension data sets.

Beard RE, Abate-Daga D, Rosati SF, et al.
Gene expression profiling using nanostring digital RNA counting to identify potential target antigens for melanoma immunotherapy.
Clin Cancer Res. 2013; 19(18):4941-50 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PURPOSE: The success of immunotherapy for the treatment of metastatic cancer is contingent on the identification of appropriate target antigens. Potential targets must be expressed on tumors but show restricted expression on normal tissues. To maximize patient eligibility, ideal target antigens should be expressed on a high percentage of tumors within a histology and, potentially, in multiple different malignancies.
DESIGN: A Nanostring probeset was designed containing 97 genes, 72 of which are considered potential candidate genes for immunotherapy. Five established melanoma cell lines, 59 resected metastatic melanoma tumors, and 31 normal tissue samples were profiled and analyzed using Nanostring technology.
RESULTS: Of the 72 potential target genes, 33 were overexpressed in more than 20% of studied melanoma tumor samples. Twenty of those genes were identified as differentially expressed between normal tissues and tumor samples by ANOVA analysis. Analysis of normal tissue gene expression identified seven genes with limited normal tissue expression that warrant further consideration as potential immunotherapy target antigens: CSAG2, MAGEA3, MAGEC2, IL13RA2, PRAME, CSPG4, and SOX10. These genes were highly overexpressed on a large percentage of the studied tumor samples, with expression in a limited number of normal tissue samples at much lower levels.
CONCLUSION: The application of Nanostring RNA counting technology was used to directly quantitate the gene expression levels of multiple potential tumor antigens. Analysis of cell lines, 59 tumors, and normal tissues identified seven potential immunotherapy targets for the treatment of melanoma that could increase the number of patients potentially eligible for adoptive immunotherapy.

McWhinney-Glass S, Winham SJ, Hertz DL, et al.
Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.
Clin Cancer Res. 2013; 19(20):5769-76 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PURPOSE: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.
PATIENTS AND METHODS: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.
RESULTS: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.
CONCLUSIONS: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.

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