SOX11

Gene Summary

Gene:SOX11; SRY (sex determining region Y)-box 11
Aliases: MRD27
Location:2p25
Summary:This intronless 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 regulator after forming a protein complex with other proteins. The protein may function in the developing nervous system and play a role in tumorigenesis. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-11
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (57)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 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.

  • Epithelial-Mesenchymal Transition
  • Mantle-Cell Lymphoma
  • Transcriptional Activation
  • Oligonucleotide Array Sequence Analysis
  • DNA Sequence Analysis
  • Cell Proliferation
  • Transcription Factors
  • Neoplasm Invasiveness
  • Trans-Activators
  • Prostate Cancer
  • Messenger RNA
  • Promoter Regions
  • Chromosome 2
  • Cell Movement
  • SOXC Transcription Factors
  • Urothelium
  • Young Adult
  • Gene Expression Profiling
  • Base Sequence
  • Tumor Markers
  • Transforming Growth Factor beta
  • Cultured Cells
  • Transcription
  • High Mobility Group Proteins
  • DNA Methylation
  • Leukemic Gene Expression Regulation
  • Validation Studies as Topic
  • FISH
  • Cervical Cancer
  • MicroRNAs
  • Cyclin D1
  • RTPCR
  • Transfection
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Immunohistochemistry
  • Breast Cancer
  • Gene Expression
  • Translocation
  • gamma Catenin
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: SOX11 (cancer-related)

Al-Kawaaz M, Mathew S, Liu Y, et al.
Cyclin D1-positive diffuse large B-cell lymphoma with IGH-CCND1 translocation and BCL6 rearrangement: a report of two cases.
Am J Clin Pathol. 2015; 143(2):288-99 [PubMed] Related Publications
OBJECTIVES: To demonstrate and confirm the existence of cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) with IGH-CCND1 rearrangement and discuss the rationale of differentiating this entity from blastoid and pleomorphic variants of mantle cell lymphoma (MCL).
METHODS: Two cyclin D1-positive lymphomas with morphologic features of DLBCL and IGH-CCND1 translocations were characterized with respect to clinical features, as well as morphologic, immunophenotypic, cytogenetic, and molecular findings.
RESULTS: The large tumor cells were CD20+, CD5-, CD10-, BCL6+, MUM1+, and cyclin D1+ in both cases. SOX11 was negative. Epstein-Barr virus-encoded RNA in situ hybridization demonstrated diffuse positivity in case 1. BCL6 and IGH-CCND1 rearrangements were identified by fluorescence in situ hybridization in both cases. Specifically, the diagnosis of a relapsed DLBCL with acquisition of IGH-CCND1 was rendered for case 1, molecularly confirmed by the detection of identical monoclonal IGH rearrangements between the initial diagnostic DLBCL and relapse lymphoma.
CONCLUSIONS: Our study demonstrates convincingly that IGH-CCND1 rearrangement leading to cyclin D1 overexpression can occur in DLBCL and pose a potential diagnostic pitfall, requiring thorough knowledge of the clinicopathologic findings to allow accurate discrimination from a blastoid or pleomorphic MCL. The coexistence of IGH-CCND1 and IGH-BCL6 rearrangements suggest that BCL6 and cyclin D1 may cooperate in the pathogenesis of DLBCL.

Liu F, Ji F, Ji Y, et al.
Dissecting the mechanism of colorectal tumorigenesis based on RNA-sequencing data.
Exp Mol Pathol. 2015; 98(2):246-53 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify the differentially expressed genes (DEGs), mutated genes and fusion genes in colorectal cancer.
MATERIALS AND METHODS: RNA-sequencing data (ID: SRP009386) from cancerous, paracancerous non-tumor and distant normal tissue from one Chinese patient with stage III colorectal cancer were downloaded from Sequence Read Archive. Quality control was checked using FastQC, followed by sequence alignment against the hg19 reference genome using TopHat v1.3.3. The expression levels were quantified using Cufflinks, followed by DEGs screening using NOISeq. Enrichment analysis was performed using DAVID. Transcription factors were screened using TRANSFA. Mutated loci were identified using SAMTools and VCFTools. Gene fusion events were detected by TopHat-fusion.
RESULTS: In total 2440, 1887 and 834 DEGs were respectively detected in cancerous vs. normal tissue, cancerous vs. paracancerous tissue and paracancerous vs. normal tissue. The up-regulated genes from cancerous and paracancerous tissue compared with normal tissue were enriched in "extracellular matrix receptor interaction" and "focal adhesion pathway" as well as some biological processes except for "negative regulation of programmed cell death" uniquely presenting in cancer. Dysregulated transcription factors including SOX4, BCL6, CEBPB and MSX2 were enriched in the unique biological process. Trp53 was identified with one mutated locus 7577142 (C → T) on chromosome 17. BCL6 also experienced missense mutation. Additionally, COL1A1-PPP2R2C and EXPH5-COL1A2 were observed fusion genes in cancer tissue.
CONCLUSIONS: The unique biological process in cancer tissue may be the cause for colorectal carcinogenesis. The screened transcription factors, mutated genes and fusion genes may contribute to the progression of colorectal cancer.

Davidson B, Holth A, Hellesylt E, et al.
The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions.
Hum Pathol. 2015; 46(1):1-8 [PubMed] Related Publications
We recently identified gene signatures that allow classification of ovarian carcinoma into 5 distinct clinically relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11, and vimentin was assessed in 100 advanced-stage (International Federation of Gynecology and Obstetrics stages III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathological parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (P = .015). HMGA2 and NCAM expression was related to stage III disease (P = .011 and P = .023, respectively), and NCAM was overexpressed in peritoneal compared with pleural effusions (P = .001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (P = .005 and P = .017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (P = .187), but emerged as an independent prognosticator in Cox multivariate analysis (P = .042). This study identifies vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter.

Murakami I, Takata K, Matsushita M, et al.
Immunoglobulin expressions are only associated with MCPyV-positive Merkel cell carcinomas but not with MCPyV-negative ones: comparison of prognosis.
Am J Surg Pathol. 2014; 38(12):1627-35 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, often associated with Merkel cell polyomavirus (MCPyV). Recently, immunoglobulin (Ig) expression was reported in MCC, thereby suggesting that B cells might be their cellular ancestors. We tested 30 MCCs (20 MCPyV-positive and 10 MCPyV-negative) using immunohistochemistry for the expressions of IgG, IgA, IgM, Igκ, Igλ, terminal desoxynucleotidyl transferase, paired box gene 5 (PAX5), octamer transcription factor-2 (Oct-2), and sex-determining region Y-box 11 (SOX11). We performed in situ hybridization for Igκ-mRNA or Igλ-mRNA and Ig heavy chain (IgH) gene rearrangement (IgH-R) analyses. The expressions of PAX5, TdT, Oct-2, and SOX11 were not significantly different between MCPyV-positive and MCPyV-negative MCCs. At least 1 of IgG, IgA, IgM, or Igκ was expressed in MCPyV-positive (14/20, 70%) and none in MCPyV-negative MCCs (P=0.0003). There was a higher tendency for Igκ-mRNA expression (7/19, using in situ hybridization) and IgH-R (10/20, using polymerase chain reaction) in MCPyV-positive than in MCPyV-negative MCCs (0/10 and 2/10, respectively), thus suggesting a different Ig production pattern and pathogenesis between the 2 types of MCC. Ig expression or IgH-R in MCPyV-positive MCCs might be associated with MCPyV gene integration or expression in cancer cells but do not necessarily suggest a B-cell origin for MCCs. IgH expression or IgH-R nonsignificantly correlated with improved prognosis. However, these might be important factors that influence the survival of neoplastic cells and might allow the development of novel therapies for patients with MCPyV-positive MCCs.

Zhang J, Shen C, Wang L, et al.
Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4.
Biochem Biophys Res Commun. 2014; 452(3):746-52 [PubMed] Related Publications
Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p=0.013), Vimentin (p=0.002) and the decrease of E-cadherin (p=0.0023) and β-catenin (p=0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P<0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.

Han SS, Han S, Kamberos NL
Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance.
Biochem Biophys Res Commun. 2014; 452(3):669-75 [PubMed] Related Publications
Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL.

Wang W, Zhang J, Zhan X, et al.
SOX4 is associated with poor prognosis in cholangiocarcinoma.
Biochem Biophys Res Commun. 2014; 452(3):614-21 [PubMed] Related Publications
Overexpressions of EGFR and HER2 are thought to be prognostic factors of cholangiocarcinoma (CCA). The SOX4 transcription factor is involved in the development and cell fate decision. Although up-regulation of SOX4 has been described in multiple human malignancies, the prognostic value of SOX4 and its relationship to EGFR/HER2 in CCA remain unclear. In the current study, we showed that SOX4 and EGFR were overexpressed in 17 (29.3%), and 13 (22.4%) of the 58 intrahepatic cholangiocarcinomas (IHCCs), as well as 28 (29.8%), and 33 (35.1%) of the 94 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, with the rate being 4.4% (4/90). In all, amplification of EGFR was identified in 1.8% (1/52) of IHCC cases, and in 2% (3/82) of EHCC cases. By contrast, HER2 amplification was present only in 3.5% (3/94) of the EHCC cases. Notably, Kaplan-Meier survival analysis suggested that SOX4 expression is a significant prognostic factor for poor prognosis in IHCC patients. Importantly, our findings suggested significant association of SOX4 and EGFR expression both in IHCC (P<0.001) and EHCC (P=0.014). SOX4 may modulate expression of EGFR, and SOX4+/EGFR+ defines a subset of CCA patients with poor prognosis. Finally, in vitro data indicated that SOX4 inhibits cellular migratory capacity and promotes epithelial-mesenchymal transition (EMT) process of CCA cells. Collectively, our results define an important role for SOX4 in CCA by orchestrating EMT and modulation on EGFR expression. SOX4 expression may serve as a prognostic marker for patients with IHCC.

Palomero J, Vegliante MC, Rodríguez ML, et al.
SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma.
Blood. 2014; 124(14):2235-47 [PubMed] Related Publications
SOX11 is overexpressed in several solid tumors and in the vast majority of aggressive mantle cell lymphomas (MCLs). We have recently proven that SOX11 silencing reduces tumor growth in a MCL xenograft model, consistent with the indolent clinical course of the human SOX11-negative mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. Here, we observed that SOX11-positive xenograft and human primary MCL tumors overexpressed angiogenic gene signatures and had a higher microvascular density compared with their SOX11-negative counterparts. Conditioned media of SOX11-positive MCL cell lines induced in vitro endothelial cell proliferation, migration, tube formation, and activation of downstream angiogenic pathways. We identified PDGFA as a SOX11 direct target gene upregulated in MCL cells whose inhibition impaired SOX11-enhanced in vitro angiogenic effects on endothelial cells. In addition, platelet-derived growth factor A (PDGFA) was overexpressed in SOX11-positive but not in SOX11-negative MCL. In vivo, imatinib impaired tumor angiogenesis and lymphoma growth in SOX11-positive MCL xenograft tumors. Overall, our results demonstrate a prominent role for SOX11 as a driver of proangiogenic signals in MCL, and highlight the SOX11-PDGFA axis as a potential therapeutic target for the treatment of this aggressive disease.

Wu G, Zhu YZ, Zhang JC
Sox4 up-regulates Cyr61 expression in colon cancer cells.
Cell Physiol Biochem. 2014; 34(2):405-12 [PubMed] Related Publications
BACKGROUND/AIMS: Genetic changes leading to aberrant activation of oncogenes are viewed as a crucial step in colon cancer. Sox4, a member of Sox (Sry-box) family of transcription factors, plays a critical role in tumorigenesis.
METHODS: PCR-based microarrays were used to identify potential transcriptional target of Sox4. siRNA was used to knockdown the expression of Sox4. Luciferase and chromatin immunoprecipitation (ChIP) assays were used to test the transcriptional regulations.
RESULTS: PCR-based microarrays found that Cyr61, a secreted extracellular matrix-associated signaling protein, was a transcriptional target of Sox4. Overexpression of Sox4 increased, while its knockdown using small interfering RNA (siRNA) reduced Cyr61 expression. A potential Sox4 binding motif located at the proximal Cyr61 promoter was identified.
CONCLUSION: Thus, our results suggest a previously unknown Sox4-Cyr61 molecular network, which may control colon cancer cell proliferation and survival.

Liu DT, Peng-Zhao, Han JY, et al.
Clinical and prognostic significance of SOX11 in breast cancer.
Asian Pac J Cancer Prev. 2014; 15(13):5483-6 [PubMed] Related Publications
Recently, the transcription factor SOX11 has gained extensive attention as a diagnostic marker in a series of cancers. However, to date, the possible roles of SOX11 in breast cancer has not been investigated. In this study, immunohistochemical staining for SOX11 was performed for 116 cases of breast cancer. Nuclear SOX11 was observed in 42 (36.2%) and cytoplasmic SOX11 in 52 (44.8%) of breast cancer samples. Moreover, high expression of cytoplasmic and nuclear SOX11 was associated with clinicopathological factors, including earlier tumor grade, absence of lymph node metastasis and smaller tumor size. Kaplan-Meier survival curves demonstrated high nuclear SOX11 expression to be associated with more prolonged overall survival than those with low expression and it could be an independent predictor of survival for breast cancer patients. It is worthwhile to note that cytoplasmic SOX11 was not correlated with prognosis of breast cancer patients. These data suggest the possibility that nuclear SOX11 could be as a potential target for breast cancer therapy.

Ma H, Mallampati S, Lu Y, et al.
The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia.
Haematologica. 2014; 99(10):1591-8 [PubMed] Free Access to Full Article Related Publications
The transcription factor Sox4 plays an indispensable role in the development of early progenitor B cells from hematopoietic stem cells. However, its role in B-cell acute lymphoblastic leukemia, a malignant counterpart of normal progenitor B cells, is not fully understood. Here we show that SOX4 is highly expressed in human acute lymphoblastic leukemia cells. To systematically study the function of Sox4 in acute lymphoblastic leukemia, we established a genetically defined mouse leukemia model by transforming progenitor B cells carrying a floxed Sox4 allele and inducing deletion of the allele by the self-excising Cre recombinase. This model allowed us to work with two groups of leukemic cells that had either one copy or both copies of Sox4 deleted. We found that depletion of Sox4 in transformed cells in vitro reduced cell growth in vitro and the progression of leukemia in vivo. Moreover, depletion of Sox4 in leukemic cells in vivo prolonged the survival of the mice, suggesting that it could be a potential target in acute lymphoblastic leukemia therapy. Our microarray and bioChIP studies revealed that Tcf7l1 was the key gene directly regulated by Sox4. Knockdown of Tcf7l1 reduced cell proliferation, just as did knockout of Sox4, and ectopic expression of Tcf7l1 could reverse the effect of Sox4 knockout on cell proliferation. These data suggest that Sox4 and Tcf7l1 form a functional axis that promotes the progression of BCR-ABL-positive acute lymphoblastic leukemia.

Duquet A, Melotti A, Mishra S, et al.
A novel genome-wide in vivo screen for metastatic suppressors in human colon cancer identifies the positive WNT-TCF pathway modulators TMED3 and SOX12.
EMBO Mol Med. 2014; 6(7):882-901 [PubMed] Free Access to Full Article Related Publications
The progression of tumors to the metastatic state involves the loss of metastatic suppressor functions. Finding these, however, is difficult as in vitro assays do not fully predict metastatic behavior, and the majority of studies have used cloned cell lines, which do not reflect primary tumor heterogeneity. Here, we have designed a novel genome-wide screen to identify metastatic suppressors using primary human tumor cells in mice, which allows saturation screens. Using this unbiased approach, we have tested the hypothesis that endogenous colon cancer metastatic suppressors affect WNT-TCF signaling. Our screen has identified two novel metastatic suppressors: TMED3 and SOX12, the knockdown of which increases metastatic growth after direct seeding. Moreover, both modify the type of self-renewing spheroids, but only knockdown of TMED3 also induces spheroid cell spreading and lung metastases from a subcutaneous xenograft. Importantly, whereas TMED3 and SOX12 belong to different families involved in protein secretion and transcriptional regulation, both promote endogenous WNT-TCF activity. Treatments for advanced or metastatic colon cancer may thus not benefit from WNT blockers, and these may promote a worse outcome.

Simonsen AT, Sørensen CD, Ebbesen LH, et al.
SOX11 as a minimal residual disease marker for Mantle cell lymphoma.
Leuk Res. 2014; 38(8):918-24 [PubMed] Related Publications
Recent studies have identified SOX11 as a novel diagnostic marker for mantle cell lymphoma (MCL). We quantified SOX11 by a truly mRNA specific qPCR assay in longitudinal peripheral blood samples from 20 patients and evidenced a close relationship of SOX11 expression and clinical status of the patients. In eight patient courses we validated the expression of SOX11 using t(11;14) and demonstrated positive correlation of SOX11 and t(11;14) levels. To the best of our knowledge this is the first report stating that quantification of SOX11 can be used as an minimal residual disease marker equal to the key translocation t(11;14) in MCL.

Chong PS, Zhou J, Cheong LL, et al.
LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia.
Cancer Res. 2014; 74(11):3043-53 [PubMed] Related Publications
PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N=24; P<0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML.

Kuo PY, Leshchenko VV, Fazzari MJ, et al.
High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma.
Oncogene. 2015; 34(10):1231-40 [PubMed] Related Publications
Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

Qu Y, Zhou C, Zhang J, et al.
The metastasis suppressor SOX11 is an independent prognostic factor for improved survival in gastric cancer.
Int J Oncol. 2014; 44(5):1512-20 [PubMed] Free Access to Full Article Related Publications
SOX11 is involved in gastrulation and in malignant diseases. The aim of this study was to investigate the role of SOX11 in gastric cancer and its expression pattern and clinical significance. SOX11 overexpression cell model was used to examine in vitro and in vivo the role of SOX11 in cell growth and metastasis. Cell cycle analysis and Annexin V/PI double staining were used to investigate the effect of SOX11 on cell cycle progression and apoptosis. The expression of SOX11 in human gastric cancer was examined by immunohistochemistry. The correlation of SOX11 expression with clinicopathological characteristics and survival of patients was analyzed by Pearson's χ(2) and Kaplan-Meier analyses, respectively. Cox's proportional hazard model was employed in multivariate analysis. SOX11 overexpression did not inhibit cell growth but strongly suppressed cell migration/invasion in vitro and in vivo. We found a significant correlation between high SOX11 protein levels and Lauren's classification (intestinal type), differentiation status (high and medium), and early TNM stage. SOX11 is an independent prognostic factor for improved survival in gastric cancer patients. SOX11 was a potential tumor-suppressor and an independent positive prognostic factor in gastric cancer patients with less advanced clinicopathological features.

Huang YW, Kuo CT, Chen JH, et al.
Hypermethylation of miR-203 in endometrial carcinomas.
Gynecol Oncol. 2014; 133(2):340-5 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Aberrant expression of SOX4 in endometrial cancer has been identified and partially was contributed to hypermethylation of miR-129-2. Other miRNAs are suspected to influence SOX 4 as well. The current study seeks to identify other hypermethylated miRNAs that regulate SOX4 in endometrial carcinomas.
METHODS: Methylation levels of miRNA promoter regions were measured by combined bisulfite restriction analysis (COBRA) and pyrosequencing assays. Gene expression was determined by RT-qPCR. Methylation level of a miRNA locus was corrected with clinicopathologic factors for 252 gynecological specimens.
RESULTS: In silico analysis identified 13 miRNA loci bound on the 3'-UTR of SOX4. Using COBRA assays, increased methylation of miR-203, miR-219-2, miR-596, and miR-618 was detected in endometrial cancer cells relative to those seen in a normal cell line and in normal endometrium. Transfection of a miR-203 mimic decreased SOX4 gene expression. Hypermethylation of miR-203 was detected in 52% of type I endometrioid endometrial carcinomas (n=131) but was not seen in any of 10 uninvolved normal endometria (P<0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas.
CONCLUSIONS: Hypermethylation of miR-203 is a frequent event in endometrial carcinomas and is strongly associated with microsatellite instability and MLH1 methylation status. Thus, miR-203 methylation level might represent a marker for patients with endometrioid and clear endometrial sub-cancers.

Wang L, Li Y, Yang X, et al.
ERG-SOX4 interaction promotes epithelial-mesenchymal transition in prostate cancer cells.
Prostate. 2014; 74(6):647-58 [PubMed] Related Publications
BACKGROUND: Approximately 50% of prostate cancer (PCa) patients in Western countries harbor ERG rearrangement with concurrent ERG overexpression. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations was unclear.
METHODS: Fluorescence in situ hybridization and immunohistochemistry were utilized to detect ERG rearrangement and SOX4 expression. Cellular function was evaluated by transwell, wound healing assays, and cell adhesion assay, respectively. Interaction between ERG and SOX4 was arrayed by co-immunoprecipitation, Real-time PCR, Western blot, and siRNA. Direct binding of ERG to the promoter of SOX4, as well as epigenetic modifications of their promoters after TGF-β1 treatment was monitored by chromatin immunoprecipitation.
RESULTS: ERG regulated SOX4 expression via binding to its promoter. Silencing both of them showed duplicate effects on restoring the epithelial characteristics, increasing cellular adhesion and decreasing capacity of cellular migration and invasion. ERG and SOX4 have cooperative roles in TGF-β1-induced epithelial to mesenchymal transition (EMT) process. In addition, TGF-β1 stimulation increased levels of chromatin marks associated with active genes (H3K4me3, H416ac), and decreased levels of repressive marks (H3K27me3) at their promoters. 5-aza and TSA treatment changed expressions of ERG and SOX4. Clinically, overexpression of SOX4 is associated with ERG rearrangement status in PCa and ERG+/SOX4+ defined a subset of PCa patients with poor prognosis.
CONCLUSION: Our findings define a key role for ERG/SOX4 in the development of a subset of PCa and highlight the clinical importance of identifying molecularly defined tumor subgroups.

Misemer BS, Skubitz AP, Carlos Manivel J, et al.
Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
Cancer Med. 2014; 3(1):81-90 [PubMed] Free Access to Full Article Related Publications
Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy.

Espinet B, Ferrer A, Bellosillo B, et al.
Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry.
Clin Cancer Res. 2014; 20(4):1007-19 [PubMed] Related Publications
PURPOSE: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases.
EXPERIMENTAL DESIGN: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry.
RESULTS: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification.
CONCLUSION: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.

Rajurkar M, Huang H, Cotton JL, et al.
Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis.
Oncogene. 2014; 33(46):5370-8 [PubMed] Free Access to Full Article Related Publications
Dysregulation of the Hedgehog (Hh)-Gli signaling pathway is implicated in a variety of human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB) and embryonal rhabdhomyosarcoma (eRMS), three principle tumors associated with human Gorlin syndrome. However, the cells of origin of these tumors, including eRMS, remain poorly understood. In this study, we explore the cell populations that give rise to Hh-related tumors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages in postnatal mice. Interestingly, we find that unlike BCC and MB, eRMS originates from the stem/progenitor populations that do not normally receive active Hh signaling. Furthermore, we find that the myogenic lineage in postnatal mice is largely Hh quiescent and that Pax7-expressing muscle satellite cells are not able to give rise to eRMS upon Smo or Gli1/2 overactivation in vivo, suggesting that Hh-induced skeletal muscle eRMS arises from Hh/Gli quiescent non-myogenic cells. In addition, using the Gli1 null allele and a Gli3 repressor allele, we reveal a specific genetic requirement for Gli proteins in Hh-induced eRMS formation and provide molecular evidence for the involvement of Sox4/11 in eRMS cell survival and differentiation.

Fung TK, Leung AY, So CW
Sox4you: a new player in C/EBPα leukemia.
Cancer Cell. 2013; 24(5):557-9 [PubMed] Related Publications
Although CEBPA mutations are among the most common genetic abnormalities in acute myeloid leukemia (AML), the transformation mechanism remains largely obscure. In this issue of Cancer Cell, Zhang and colleagues report that SOX4 is a direct target and crucial mediator of C/EBPα mutants in AML, revealing a potential therapeutic avenue.

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.

Bilir B, Kucuk O, Moreno CS
Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells.
J Transl Med. 2013; 11:280 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%-20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC.
METHODS: Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell proliferation and apoptosis were tested in vitro. The inhibitory effects of iCRT-3 on canonical Wnt signaling in TNBC was evaluated by quantitative real-time RT-PCR analysis of Axin2 and dual-luciferase reporter assays. The effects of shRNA knockdown of SOX4 in combination with iCRT-3 and/or genistein treatments on cell proliferation, migration and invasion on BT-549 cells were also evaluated.
RESULTS: Immunofluorescence staining of β-catenin in TNBC cell lines showed both nuclear and cytoplasmic localization, indicating activation of Wnt pathway in TNBC cells. iCRT-3 was the most effective compound for inhibiting proliferation and antagonizing Wnt signaling in TNBC cells. In addition, treatment with iCRT-3 resulted in increased apoptosis in vitro. Knockdown of the Wnt pathway transcription factor, SOX4 in triple negative BT-549 cells resulted in decreased cell proliferation and migration, and combination treatment of iCRT-3 with SOX4 knockdown had a synergistic effect on inhibition of cell proliferation and induction of apoptosis.
CONCLUSIONS: These data suggest that targeting SOX4 and/or the Wnt pathway could have therapeutic benefit for TNBC patients.

Zhang H, Alberich-Jorda M, Amabile G, et al.
Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia.
Cancer Cell. 2013; 24(5):575-88 [PubMed] Free Access to Full Article Related Publications
Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ∼10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

Soldini D, Valera A, Solé C, et al.
Assessment of SOX11 expression in routine lymphoma tissue sections: characterization of new monoclonal antibodies for diagnosis of mantle cell lymphoma.
Am J Surg Pathol. 2014; 38(1):86-93 [PubMed] Related Publications
The diagnosis of mantle cell lymphoma (MCL) can be difficult, especially when no t(11;14) translocation and cyclin D1 overexpression can be detected. In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far. A reliable anti-SOX11 antibody is therefore a very useful tool for routine diagnosis. Here, we characterize the new monoclonal anti-SOX11 antibodies, suitable for Western blot assay and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tissue; we tested them on a large series of primary lymphoid tumors and compared these results with those of other routinely used antibodies. Moreover, we show that IHC results depend on transcription levels of SOX11, which suggests that posttranscriptional and posttranslational modifications do not significantly affect cutoff levels for IHC detection of SOX11.

Yu X, Song H, Xia T, et al.
Growth inhibitory effects of three miR-129 family members on gastric cancer.
Gene. 2013; 532(1):87-93 [PubMed] Related Publications
Reduced expression of microRNA-129 (miR-129) has been reported in several types of tumor cell lines as well as in primary tumor tissues. However, little is known about how miR-129 affects cell proliferation in gastric cancer. Here, we show that all miR-129 family members, miR-129-1-3p, miR-129-2-3p, and miR-129-5p, are down-regulated in gastric cancer cell lines compared with normal gastric epithelial cells. Furthermore, using the real-time cell analyzer assay to observe the growth effects of miR-129 on gastric cancer cells, we found that all three mature products of miR-129 showed tumor suppressor activities. To elucidate the molecular mechanisms underlying down-regulation of miR-129 in gastric cancer, we analyzed the effects of miR-129 mimics on the cell cycle. We found that increased miR-129 levels in gastric cancer cells resulted in significant G0/G1 phase arrest. Interestingly, we showed that cyclin dependent kinase 6 (CDK6), a cell cycle-associated protein involved in G1-S transition, was a target of miR-129. We also found that expression of the sex determining region Y-box 4 (SOX4) was inversely associated with that of miR-129-2-3p and miR-129-5p but not of miR-129-1-3p. Together, our data indicate that all miR-129 family members, not only miR-129-5p, as previously thought, play an important role in regulating cell proliferation in gastric cancer.

Margue C, Philippidou D, Reinsbach SE, et al.
New target genes of MITF-induced microRNA-211 contribute to melanoma cell invasion.
PLoS One. 2013; 8(9):e73473 [PubMed] Free Access to Full Article Related Publications
The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential expression patterns of miRNAs are currently being exploited for identification of biomarkers for early disease diagnosis, prediction of progression for melanoma and other cancers and as promising drug targets, since they can easily be inhibited or replaced in a given cellular context. Before successfully manipulating miRNAs in clinical settings, their precise expression levels, endogenous functions and thus their target genes have to be determined. MiR-211, a melanocyte lineage-specific small non-coding miRNA, is located in an intron of TRPM1, a target gene of the microphtalmia-associated transcription factor (MITF). By transcriptionally up-regulating TRPM1, MITF, which is critical for both melanocyte differentiation and survival and for melanoma progression, indirectly drives the expression of miR-211. Expression of this miRNA is often reduced in melanoma samples. Here, we investigated functional roles of miR-211 by identifying and studying new target genes. We show that MITF-correlated miR-211 expression levels are mostly but not always reduced in a panel of 11 melanoma cell lines and in primary and metastatic melanoma compared to normal melanocytes and nevi, respectively. MiR-211 itself only marginally impacted on cell invasion and migration, while perturbation of some new miR-211 target genes, such as AP1S2, SOX11, IGFBP5, and SERINC3 significantly increased invasion. These results and the variable expression levels of miR-211 raise serious doubts on the value of miR-211 as a melanoma tumor-suppressing miRNA and/or as a biomarker for melanoma.

Parvani JG, Schiemann WP
Sox4, EMT programs, and the metastatic progression of breast cancers: mastering the masters of EMT.
Breast Cancer Res. 2013; 15(4):R72 [PubMed] Free Access to Full Article Related Publications
Epithelial-mesenchymal transition (EMT) programs require the expression of a variety of so-called master regulators of EMT, including members of the Snail, Zeb, and Twist transcription factor families. Teleologically, the requirement for such a diverse group of 'master regulators' seems evolutionarily cumbersome, and emerging evidence indicates that these transcription factors do in fact mediate unique and specialized functions, suggesting the existence of higher-order 'masters' that truly direct and coordinate EMT programs. Accordingly, Tiwari and colleagues recently delineated an elegant pathway wherein transforming growth factor-beta stimulates Sox4 expression, which induces that of the histone methyltransferase, Ezh2, thereby reprogramming the epigenome to elicit EMT programs and metastasis of breast cancers. This viewpoint highlights Sox4 as a 'new' master of EMT programs and metastatic breast cancer.

Wang L, Zhang J, Yang X, et al.
SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro.
Prostate Cancer Prostatic Dis. 2013; 16(4):301-7 [PubMed] Related Publications
BACKGROUND: The SOX4 transcription factor is involved in the development and cell fate decision. Although upregulation of SOX4 has been described in human prostate cancer (PCa), the prognostic value of SOX4 and its exact role in PCa progression remain unclear.
METHODS: Three tissue microarrays were constructed from 241 Chinese PCa patients who underwent TURP. Immunohistochemistry (IHC) was used to detect the expression of SOX4. Genetic aberrations of epidermal growth factor receptor and HER2 were detected by fluorescence in situ hybridization. The effect of SOX4 on proliferation was evaluated by MTT (methyl thiazolyl tetrazelium), and cell migration and invasion were evaluated by transwell and wound-healing assays. The distribution of cell-cycle phase was analyzed by flow cytometry. Real-time PCR and western blot were used to study transcript and protein levels.
RESULTS: Using tissue microarray, we found that SOX4 was overexpressed in 33.0% (76/230) Chinese PCa patients by IHC. SOX4 overexpression was significantly associated with high Gleason scores (P=0.009) and the presence of distant metastasis (P=0.023). Additionally, SOX4 overexpression was significantly correlated with high Ki67 labeling index (P=0.005) and tended to associate with amplification of HER2 (P=0.052) in our cohort. Notably, SOX4 was correlated with cancer-specific mortality of PCa patients by Kaplan-Meier analysis (P=0.001). Multivariate Cox regression analysis indicated that SOX4 was an unfavorable independent prognostic factor in Chinese PCas (P=0.017). SOX4 overexpression enhanced proliferation of Vcap cells and siRNA knockdown of SOX4 significantly decreased Vcap cell migration and invasion, suggesting a role of SOX4 in cancer metastasis. Additionally, flow cytometry DNA analysis revealed that siRNA SOX4 leads to significant accumulation of cells in the S phase and marked decrease of cells in the G2/M phase. Further in vitro study revealed that SOX4 silencing could inhibit TGF-β (transforming growth factor-β)-induced epithelial-mesenchymal transition (EMT) in Vcap cells. Overexpression of SOX4 could promote the EMT phenotype in Vcap cells.
CONCLUSIONS: Our results define an important role for SOX4 in the progression of PCa by orchestrating EMT and may serve as a prognostic marker for PCa patients.

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