Gene Summary

Gene:SOX9; SRY-box transcription factor 9
Aliases: CMD1, SRA1, CMPD1, SRXX2, SRXY10
Summary:The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-9
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (104)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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

  • Western Blotting
  • Sex-Determining Region Y Protein
  • Breast Cancer
  • Epithelial-Mesenchymal Transition
  • Disease Progression
  • Mutation
  • Neoplasm Invasiveness
  • Cell Proliferation
  • Oligonucleotide Array Sequence Analysis
  • Small Molecule Libraries
  • Neoplastic Cell Transformation
  • Transcriptional Activation
  • Mice, Transgenic
  • SOX9 Transcription Factor
  • Messenger RNA
  • RNA Interference
  • Cell Movement
  • Lung Cancer
  • DNA Methylation
  • Knockout Mice
  • Prostate Cancer
  • Pancreatic Cancer
  • Down-Regulation
  • Cancer Stem Cells
  • Colorectal Cancer
  • Stomach Cancer
  • Phenotype
  • Cell Differentiation
  • Adenocarcinoma
  • Immunohistochemistry
  • Cancer RNA
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Promoter Regions
  • Biomarkers, Tumor
  • Tumor Suppressor Proteins
  • Apoptosis
  • MicroRNAs
  • RT-PCR
  • Chromosome 17
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: SOX9 (cancer-related)

Xiao B, Zhang W, Kuang Z, et al.
SOX9 promotes nasopharyngeal carcinoma cell proliferation, migration and invasion through BMP2 and mTOR signaling.
Gene. 2019; 715:144017 [PubMed] Related Publications
SRY-related high-mobility-group box 9 (SOX9) is a member of the SOX family of transcription factors. Accumulating evidence has shown that SOX9 plays a significant role in various malignancies. However, the role of SOX9 in nasopharyngeal carcinoma (NPC) remains unknown. In the present study, up-regulation of SOX9 was observed in both NPC tissues and different NPC cells. Overexpression of SOX9 promoted NPC cell proliferation, migration and invasion. Conversely, knock down of SOX9 inhibited NPC proliferation, colony formation, migration and invasion. Mechanistically, SOX9 bound directly to the promoter region of BMP2 and increased BMP2 expression. In addition, overexpression of SOX9 activated the mTOR pathway partly through BMP2. Collectively, these results identify a novel role for SOX9 as a potential therapeutic marker for the prevention and treatment of NPC.

Li B, Liu D, Yang P, et al.
miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway.
Gene. 2019; 707:78-85 [PubMed] Related Publications
Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed miR-613 expression was downregulated in both chemoresistant and recurrent HCC patients. A remarkable decrease in miR-613 was detected in CD24 or OV6-positive liver CSCs and CSC-enriched hepatoma spheres. Down-regulation of miR-613 facilitated liver CSCs expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, bioinformatic and luciferase reporter analysis identified SOX9 as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of SOX9 in HCC cells. Special SOX9 siRNA abolished the discrepancy in liver CSCs proportion and the self-renewal capacity between miR-613 overexpression hepatoma cells and control cells, which further confirmed that SOX9 was required in miR-613-inhibited liver CSCs expansion. Furthermore, hepatoma cells with miR-613 overexpression performed more sensitivity to cisplatin or sorafenib treatment. Conclusion: miR-613 could inhibit HCC cell dedifferentiation and liver CSCs expansion by targeting SOX9 signaling and may prove to be a novel therapeutic target for HCC patients.

Sherman-Samis M, Onallah H, Holth A, et al.
SOX2 and SOX9 are markers of clinically aggressive disease in metastatic high-grade serous carcinoma.
Gynecol Oncol. 2019; 153(3):651-660 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to analyze the expression, biological role and clinical relevance of cancer stem cell markers in high-grade serous carcinoma (HGSC).
METHODS: mRNA expression by qRT-PCR of NANOG, OCT4, SOX2, SOX4, SOX9, LIN28A and LIN28B was analyzed in 134 HGSC specimens (84 effusions, 50 surgical specimens). Nanog, OCT3/4, SOX2 and SOX9 protein expression by immunohistochemistry was analyzed in 52 HGSC effusions. Nanog protein expression in exosomes from 80 HGSC effusions was studied by Western Blotting. OVCAR3 cells underwent CRISPR/Cas9 Nanog knockout (KO), and the effect of Nanog KO on migration, invasion, proliferation and proteolytic activity was analyzed in OVCAR3 and OVCAR8 cells.
RESULTS: OCT4 mRNA was overexpressed in effusions compared to solid specimens (p = 0.046), whereas SOX9 was overexpressed in the ovarian tumors compared to effusions and solid metastases (p = 0.003). Higher SOX2 and SOX9 expression was associated with primary (intrinsic) chemoresistance (p = 0.009 and p = 0.02, respectively). Higher SOX9 levels were associated with shorter overall survival in univariate (p = 0.04) and multivariate (p = 0.049) analysis. OCT3/4, SOX2 and SOX9 proteins were found in HGSC cells, whereas Nanog was detected only in exosomes. Higher SOX2 protein expression was associated with shorter overall survival in univariate analysis (p = 0.049). OVCAR cells exposed to OVCAR3 NANOG KO exosomes had reduced migration, invasion and MMP9 activity.
CONCLUSIONS: SOX2 and SOX9 mRNA levels in HGSC effusions may be markers of clinically aggressive disease. Nanog is secreted in HGSC exosomes in effusions and modulates tumor-promoting cellular processes in vitro.

Kong X, Zhao Y, Li X, et al.
Overexpression of HIF-2α-Dependent NEAT1 Promotes the Progression of Non-Small Cell Lung Cancer through miR-101-3p/SOX9/Wnt/β-Catenin Signal Pathway.
Cell Physiol Biochem. 2019; 52(3):368-381 [PubMed] Related Publications
BACKGROUND/AIMS: The present study aimed to explore the function of NEAT1 on non-small cell lung cancer (NSCLC), as well as its underlying mechanisms.
METHODS: Quantitative realtime PCR (qRT-PCR) was used to measure NEAT1 expression in NSCLC tissues and cells. MTT assay and transwell assay were performed to detect cell proliferation, migration and invasion. Potential target genes were identified via luciferase reporter assay. Protein analysis was performed through western blotting.
RESULTS: The expressions of NEAT1 were significantly higher in both of NSCLC tissues and cells than in normal controls. High expression of NEAT1 was significantly associated with TNM stage (P=0.000) and metastasis (P=0.000). NEAT1 knockdown inhibited the proliferation, migration and invasion of NSCLC cells. Hypoxia induction mediated by HIF-2α promoted EMT and NEAT1 expressions. Moreover, miR-101-3p was a target of NEAT1. We also found that SOX9 was a target of miR-101-3p. Oncogenic function of NEAT1 on NSCLC progression was mediated by miR-101-3p/SOX9/Wnt/β-catenin signaling pathway.
CONCLUSION: NEAT1 up-regulation induced by HIF-2α over-expression could promote the progression of NSCLC under hypoxic condition. Moreover, NEAT1 also takes part in NSCLC progression via miR-101-3p/SOX9/Wnt/β-catenin axis.

Hamdane N, Jühling F, Crouchet E, et al.
HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response.
Gastroenterology. 2019; 156(8):2313-2329.e7 [PubMed] Related Publications
BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice with humanized livers.
METHODS: We performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection.
RESULTS: We found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n = 216), a subset of which (n = 21) achieved viral clearance.
CONCLUSIONS: In an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection.

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

Strekalova E, Malin D, Weisenhorn EMM, et al.
S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells.
Breast Cancer Res Treat. 2019; 175(1):39-50 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
PURPOSE: Many transformed cells and embryonic stem cells are dependent on the biosynthesis of the universal methyl-donor S-adenosylmethionine (SAM) from methionine by the enzyme MAT2A to maintain their epigenome. We hypothesized that cancer stem cells (CSCs) rely on SAM biosynthesis and that the combination of methionine depletion and MAT2A inhibition would eradicate CSCs.
METHODS: Human triple (ER/PR/HER2)-negative breast carcinoma (TNBC) cell lines were cultured as CSC-enriched mammospheres in control or methionine-free media. MAT2A was inhibited with siRNAs or cycloleucine. The effects of methionine restriction and/or MAT2A inhibition on the formation of mammospheres, the expression of CSC markers (CD44
RESULTS: Methionine restriction inhibited mammosphere formation and reduced the CD44
CONCLUSIONS: Our findings point to SAM biosynthesis as a unique metabolic vulnerability of CSCs that can be targeted by combining methionine depletion with MAT2A inhibition to eradicate drug-resistant CSCs.

Fortin JP, Tan J, Gascoigne KE, et al.
Multiple-gene targeting and mismatch tolerance can confound analysis of genome-wide pooled CRISPR screens.
Genome Biol. 2019; 20(1):21 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Genome-wide loss-of-function screens using the CRISPR/Cas9 system allow the efficient discovery of cancer cell vulnerabilities. While several studies have focused on correcting for DNA cleavage toxicity biases associated with copy number alterations, the effects of sgRNAs co-targeting multiple genomic loci in CRISPR screens have not been discussed.
RESULTS: In this work, we analyze CRISPR essentiality screen data from 391 cancer cell lines to characterize biases induced by multi-target sgRNAs. We investigate two types of multi-targets: on-targets predicted through perfect sequence complementarity and off-targets predicted through sequence complementarity with up to two nucleotide mismatches. We find that the number of on-targets and off-targets both increase sgRNA activity in a cell line-specific manner and that existing additive models of gene knockout effects fail at capturing genetic interactions that may occur between co-targeted genes. We use synthetic lethality between paralog genes to show that genetic interactions can introduce biases in essentiality scores estimated from multi-target sgRNAs. We further show that single-mismatch tolerant sgRNAs can confound the analysis of gene essentiality and lead to incorrect co-essentiality functional networks. Lastly, we also find that single nucleotide polymorphisms located in protospacer regions can impair on-target activity as a result of mismatch tolerance.
CONCLUSION: We show the impact of multi-target effects on estimating cancer cell dependencies and the impact of off-target effects caused by mismatch tolerance in sgRNA-DNA binding.

Yu Y, Yin W, Yu ZH, et al.
miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer.
J Exp Clin Cancer Res. 2019; 38(1):22 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. Therapies targeting ERα have been successfully used in patients with ERα
METHODS: The effect of miR-190 on breast cancer anti-estrogen sensitivity was investigated both in vitro and in vivo. The protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of the zinc-finger E-box binding homeobox 1/ ERα-miR-190-SRY-related high mobility group box 9 (ZEB1/ERα-miR-190-SOX9) axis.
RESULTS: miR-190 increased the anti-estrogen sensitivity of breast cancer cells both in vitro and in vivo. miR-190 inhibited Wnt/β-catenin signaling by targeting SOX9, and its expression inversely correlated with that of SOX9 in breast cancer samples. Furthermore, ERα and ZEB1 competitively regulated miR-190 expression.
CONCLUSIONS: Our data uncover the ZEB1/ERα-miR-190-SOX9 axis and suggest a mechanism by which the Wnt/β-catenin signaling pathway is involved in breast cancer anti-estrogen therapy.

Yang X, Liang R, Liu C, et al.
SOX9 is a dose-dependent metastatic fate determinant in melanoma.
J Exp Clin Cancer Res. 2019; 38(1):17 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma.
METHODS: Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases.
RESULTS: High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling.
CONCLUSIONS: These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.

Domenici G, Aurrekoetxea-Rodríguez I, Simões BM, et al.
A Sox2-Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells.
Oncogene. 2019; 38(17):3151-3169 [PubMed] Related Publications
Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.

Du B, Wang T, Yang X, et al.
SOX9, miR-495, miR-590-3p, and miR-320d were identified as chemoradiotherapy-sensitive genes and miRNAs in colorectal cancer patients based on a microarray dataset.
Neoplasma. 2019; 66(1):8-19 [PubMed] Related Publications
The study aimed to identify chemoradiotherapy (CRT)-sensitive biomarkers in colorectal cancer (CRC) patients. The GSE15781 dataset used in this study contains 42 samples: 22 CRC tissues (non-CRT: n = 13; CRT: n = 9) and 20 normal colorectal tissues (non-CRT: n = 10; CRT: n = 10). Following pretreatment, differentially expressed genes were selected using the limma package. Potential CRT-sensitive genes were identified with Venn analysis and then enriched in function and pathway clusters using the DAVID online tool. Moreover, protein-protein interaction (PPI) network analysis was implemented using the STRING database. The TRRUST database was used to establish a transcription factor (TF)-target transcriptional network. A miRNA-mRNA network was constructed based on relevant databases. miRNA and mRNA expression levels were analyzed using real-time quantitative PCR. A group of 259 candidate CRT-sensitive genes were identified that were mainly enriched in cell cycle regulation, adhesion-associated processes, and the p53 signaling pathway. A PPI network was established that contained striking nodes, including ITGA2, MYC, ESR1, and dihydropyrimidine dehydrogenase (DPYD), among which ESR1 was linked to MYC, and the two nodes were also highlighted in the TF-target regulation network. SRY-box 9 (SOX9) was another key TF. Hsa-miR-590-3p, hsa-miR-495, hsa-miR-320c, and hsa-miR-320d were predominant in the miRNA-mRNA network. Expression levels of SOX9, DPYD mRNA, miR-495, and miR-590-3p were clearly reduced after X-ray treatment in irradiated HT-29 cells, whereas that of miR-320d was notably enhanced. SOX9 may be a CRT-sensitive gene in CRC patients, and hsa-miR-590-3p, hsa-miR-495, and hsa-miR-320d may be CRT-sensitive microRNAs in CRC patients. Therefore, SOX9, hsa-miR-590-3p, hsa-miR-495, and hsa-miR-320d may be used as sensitive biomarkers in CRC patients.

Sharma A, Cao EY, Kumar V, et al.
Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy.
Nat Commun. 2018; 9(1):4931 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Chemo-resistance is one of the major causes of cancer-related deaths. Here we used single-cell transcriptomics to investigate divergent modes of chemo-resistance in tumor cells. We observed that higher degree of phenotypic intra-tumor heterogeneity (ITH) favors selection of pre-existing drug-resistant cells, whereas phenotypically homogeneous cells engage covert epigenetic mechanisms to trans-differentiate under drug-selection. This adaptation was driven by selection-induced gain of H3K27ac marks on bivalently poised resistance-associated chromatin, and therefore not expressed in the treatment-naïve setting. Mechanistic interrogation of this phenomenon revealed that drug-induced adaptation was acquired upon the loss of stem factor SOX2, and a concomitant gain of SOX9. Strikingly we observed an enrichment of SOX9 at drug-induced H3K27ac sites, suggesting that tumor evolution could be driven by stem cell-switch-mediated epigenetic plasticity. Importantly, JQ1 mediated inhibition of BRD4 could reverse drug-induced adaptation. These results provide mechanistic insights into the modes of therapy-induced cellular plasticity and underscore the use of epigenetic inhibitors in targeting tumor evolution.

Barkeer S, Chugh S, Karmakar S, et al.
Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells.
BMC Cancer. 2018; 18(1):1157 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Glycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs.
METHODS: Effect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of Kras
RESULTS: Inhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co-expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs.
CONCLUSIONS: Taken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers.

Wang L, Zhang Z, Yu X, et al.
Unbalanced YAP-SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma.
Oncogene. 2019; 38(12):2042-2055 [PubMed] Related Publications
Yes-associated protein (YAP) has been identified as a key regulator of tissue homeostasis. However, the precise role and regulatory mechanism of YAP in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we report that the genetic or pharmacological inhibition of YAP repressed cancer stem cell (CSC)-like properties, including tumorsphere-forming potential, cell motility, and chemoresistance in vitro, and was sufficient to attenuate tumor growth and CSC marker expression in ESCC xenografts. Mechanistically, YAP transcriptionally activated its downstream target SOX9 via TEAD1-mediated binding. We also observed a positive correlation between YAP signaling and SOX9 expression in two independent clinical cohorts. Intriguingly, YAP-targeting microRNAs, including miR-506-3p, which were induced by SOX9, post-transcriptionally repressed YAP expression, contributing to a negative feedback mechanism. Dual inhibition of YAP and SOX9 robustly suppressed malignant phenotypes. Notably, ESCC samples from The Cancer Genome Atlas (TCGA) dataset had frequent (44%) instances of YAP gene amplification and genetic inactivation of Hippo pathway regulators. Nuclear YAP expression was elevated in 197 ESCC tissues from a Chinese cohort. Together, our findings provide evidence that genetic hyperactivation of YAP unbalances the YAP-SOX9 feedback loop and confers CSC-like features in ESCC, suggesting that this YAP-SOX9 circuit represents a potential therapeutic target.

Hayashi Y, Yamaguchi J, Kokuryo T, et al.
Loss of trefoil factor 1 inhibits biliary regeneration but accelerates the hepatic differentiation of progenitor cells in mice.
Biochem Biophys Res Commun. 2018; 506(1):12-19 [PubMed] Related Publications
Although the regeneration of the adult liver depends on hepatic progenitor cells (HPCs), many uncertainties regarding hepatic regeneration in the injured liver remain. Trefoil factor family 1 (TFF1), a secretory protein predominantly expressed in the gastrointestinal tract, is responsible for mucosal restitution. Here, we investigated the role of TFF1 in liver regeneration using a mouse model of hepatic injury (choline-deficient ethionine-supplemented diet and carbon tetrachloride administration) and genetically engineered mice (TFF1 knockout (TFF1-/-)). Immunohistochemistry analysis of human liver samples revealed TFF1 expression in the hepatocytes close to ductular reaction and the regenerating biliary epithelium in injured liver. The number of cytokeratin 19 (CK19)-positive bile ducts was significantly decreased in the TFF1-/- mice after liver injury. Notch pathway in the TFF1-/- mice was also downregulated. HPCs in the control mice differentiated into biliary cells (CK19

Yan J, Huang W, Huang X, et al.
A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression, and act as important gene expression modulators. Recent evidence indicates that lncRNA neuroblastoma associated transcript 1 (NBAT1) functions as a tumor suppressor in some types of human cancers. However, its functional role in the development of gastric cancer (GC) remains unknown. The aim of this research was to investigate the clinical significance and biological functions of NBAT1 in GC. NBAT1 was found to be significantly down-regulated in GC tissue. Decreased NBAT1 expression was correlated with poor differentiation, higher tumor stage and lymph node metastasis, and poor prognosis. Functional assays showed that NBAT1 inhibited GC proliferation, migration, and invasion. NBAT1 also suppressed proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, NBAT1 interacted with Sox9, and reduced its protein stability by promoting it from polyubiquitination and proteasome-dependent degradation. Moreover, we revealed that Sox9 could occupy the NBAT1 promoter to inactivate its transcription. The negative feedback loop of NBAT1 and Sox9 continuously enhanced the suppressive effects. In conclusion, these findings suggest that feedback regulation of NBAT1 and Sox9 served as a critical effector in GC progression.

Zhao Y, Pang W, Yang N, et al.
MicroRNA-511 inhibits malignant behaviors of breast cancer by directly targeting SOX9 and regulating the PI3K/Akt pathway.
Int J Oncol. 2018; 53(6):2715-2726 [PubMed] Related Publications
Numerous studies have revealed that a subset of microRNAs (miRNAs) is aberrantly expressed in breast cancer. The dysregulation of miRNAs is involved in the tumorigenesis and progression of breast cancer due to their negative regulation of downstream target genes. Therefore, the identification of deregulated miRNAs in breast cancer may provide important insights into the diagnosis and treatment of patients with this disease. miRNA‑511 (miR‑511) has been identified to be deregulated in diverse human cancer types; however, neither the expression status nor the detailed roles of miR‑511 in breast cancer have been clarified. Thus, it was aimed to determine the expression of miR‑511 in breast cancer, examine the role in malignant progression and explore its downstream targets. The results of the present study revealed that the expression of miR‑511 was downregulated in breast cancer tissues and cell lines. Decreased expression of miR‑511 was significantly associated with lymph node metastasis and tumor stage in patients with breast cancer. Functional analyses revealed that restoring miR‑511 expression suppressed breast cancer cell proliferation and colony formation, promoted apoptosis and reduced metastasis in vitro, while it attenuated tumor growth in vivo. Additionally, it was revealed that SRY‑box 9 (SOX9) was a direct target gene of miR‑511 in breast cancer cells. SOX9 was upregulated in breast cancer tissues and its expression was inversely correlated with that of miR‑511. Furthermore, SOX9 inhibition simulated the tumor‑suppressive roles of miR‑511 overexpression in breast cancer cells, while SOX9 reintroduction partially rescued these effects of miR‑511. Notably, the upregulation of miR‑511 targeted SOX9 to deactivate the PI3K/Akt signaling in breast cancer in vitro and in vivo. In conclusion, miR‑511 was downregulated in breast cancer, and impeded its malignant progression by directly targeting SOX9 and regulating the PI3K/Akt pathway. Thus, miR‑511 is a potential therapeutic target in breast cancer.

Yuan CW, Wang ZC, Liu K, Liu DJ
Incomplete radiofrequency ablation promotes the development of CD133
Hepatobiliary Pancreat Dis Int. 2018; 17(5):416-422 [PubMed] Related Publications
BACKGROUND: Cancer stem cells (CSCs) accelerate the growth of hepatocellular carcinoma (HCC) residual after incomplete radiofrequency ablation (In-RFA). The present study aimed to detect the effects of In-RFA on stemness transcription factors (STFs) expression which are important for the production and function of CSCs, and to find which STFs promote HCC stemness after In-RFA.
METHODS: HepG2 cells were used for in vitro and in vivo studies. Flow cytometry and sphere-formation assays were used to detect the level and function of CD133
RESULTS: In-RFA was identified to induce CD133
CONCLUSION: In-RFA-induced SOX9 stimulates CD133

Xicola RM, Manojlovic Z, Augustus GJ, et al.
Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans.
Carcinogenesis. 2018; 39(11):1331-1341 [PubMed] Article available free on PMC after 13/12/2019 Related Publications
African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.

Song H, Xu Y, Shi L, et al.
LncRNA THOR increases the stemness of gastric cancer cells via enhancing SOX9 mRNA stability.
Biomed Pharmacother. 2018; 108:338-346 [PubMed] Related Publications
This work aims to explore the roles and mechanisms of long non coding RNA (lncRNA) THOR in regulating the stemness of gastric cancer cells. RNA-sequencing combined with quantitative real-time PCR (qRT-PCR) indicated that lncRNA THOR level was significantly upregulated in gastric cancer tissues compared with that in normal adjacent tissues. Knockdown of THOR attenuated the stemnness of gastric cancer cells, evident by the decrease of stemness markers expression and capacity of cells spheroid formation. Further RNA-sequencing combined with qRT-PCR and western blot analysis demonstrated that expression of transcriptional factor SOX9 was remarkably decreased in gastric cancer cells with THOR stable knockdown. Additionally, RNA immunoprecipitation (RIP) combined with luciferase reporter assay revealed that THOR directly bound to SOX9 3' untranslated region (3'UTR), but not its 5'UTR or coding area. Notably, overexpression of SOX9 rescued THOR knockdown-mediated inhibition on the stemness of gastric cancer cells. Thus, our results suggest that THOR could potentiate the stemness of gastric cancer cells via directly binding to SOX9 3'UTR.

Gnatenko DA, Kopantzev EP, Sverdlov ED
Variable Effects of Growth Factors on Developmental Gene Expression in Pancreatic Cancer Cells.
Dokl Biochem Biophys. 2018; 481(1):217-218 [PubMed] Related Publications
Stimulation of BxPC-3, Panc-1, and MIA PaCA-2 pancreatic cancer cells with EGF, HGF, FGF-1, FGF-2, FGF-7, and FGF-10 growth factors caused changes in the expression of master genes regulating pancreatic development (SOX9, HNF3b, GATA-4, GATA-6, and HES1). This, in turn, caused changes in the expression profile of important transcription factors, embryonic development regulators. It was also found that the master genes belonging to the same family may cause opposite effects (suppression or enhancement of expression of a particular transcriptional regulator) in the same cell line.

Kondratyeva LG, Chernov IP, Zinovyeva MV, et al.
Heterogeneous Expression of Embryonal Development Master Regulator SOX9 in Patients with Pancreatic Cancer.
Dokl Biochem Biophys. 2018; 481(1):208-211 [PubMed] Related Publications
The expression levels of the SOX9 gene in fetal, postnatal, and neoplastic pancreatic tissues were compared. In the fetal pancreatic samples, the mean relative level of the SOX9 gene expression was 8 times greater than the normal level. The tumor samples were divided into three groups depending on the SOX9 expression level. The first group showed a 6.5-fold increased expression level of SOX9 with respect to the normal one. The second and normal groups had approximately equal levels expression. The third group showed a 25-fold decreased expression level of SOX9. The discrepancy in the SOX9 expression, associated with the predominance of different functions of this master gene, depends on the poorly predictable individual factors and indicates that SOX9 should be excluded from the potential diagnostic biomarkers of pancreatic cancer.

Yan S, Shan X, Chen K, et al.
LINC00052/miR-101-3p axis inhibits cell proliferation and metastasis by targeting SOX9 in hepatocellular carcinoma.
Gene. 2018; 679:138-149 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have emerged as critical regulators in a variety of diseases, including many tumors, such as hepatocellular carcinoma (HCC). However, the function and mechanisms responsible for these molecules in HCC are not thoroughly understood. In our previous study, we found that LINC00052 was acted as a tumor suppressor in HCC. In this study, we performed transcription microarray analysis to investigate the target gene of LINC00052, and found that knockdown of LINC00052 significantly increased the expression of SRY-related HMG-box gene 9 (SOX9), which plays an oncogenic role in HCC. Moreover, luciferase reporter assay revealed that LINC00052 promoted miR-101-3p expression by enhancing its promoter activity. In addition, online database analysis tools and luciferase assays showed that miR-101-3p could target SOX9. Quantitative real-time polymerase chain reaction (qRT-PCR) demonstrated that miR-101-3p was downregulated in HCC tissues and HCC cell lines. And we found a positive relationship between LINC00052 and miR-101-3p, and a negative relationship between miR-101-3p and SOX9 in HCC tissues. Besides, miR-101-3p was involved in LINC00052 inhibits HCC cells proliferation and metastasis. At the molecular level, LINC00052 downgulated SOX9 to inhibit HCC cells proliferation and metastasis by interacting with miR-101-3p. It might be a potential application for HCC therapy.

Huang YH, Klingbeil O, He XY, et al.
POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.
Genes Dev. 2018; 32(13-14):915-928 [PubMed] Article available free on PMC after 13/12/2019 Related Publications
Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a

Higo N, Okumura H, Uchikado Y, et al.
Expression of SOX9 Is Related to Prognosis in Patients with Oesophageal Squamous Cell Carcinoma.
In Vivo. 2018 Jul-Aug; 32(4):835-838 [PubMed] Article available free on PMC after 13/12/2019 Related Publications
BACKGROUND: Sex-determining region Y-box 9 (SOX9) is an important transcription factor for the development and differentiation of cells and their organization. In the present study, the clinical significance of SOX9 expression in oesophageal squamous cell carcinoma was examined.
MATERIALS AND METHODS: SOX9 expression in surgical specimens of primary tumours were immunohistochemically investigated in 175 patients with oesophageal squamous cell carcinomas.
RESULTS: SOX9 was expressed (moderately or strongly) in 62.9% of samples. Expression of SOX9 was significantly positively correlated with depth of invasion, advanced stage, lymphatic and venous invasion, and poor prognosis. Univariate analysis showed that depth of invasion, lymph node metastasis, distant metastasis, stage, lymphatic invasion, venous invasion, and SOX9 expression were prognostic factors. Multivariate analysis indicated that depth of invasion and stage were independent prognostic factors, but SOX9 expression was not.
CONCLUSION: SOX9 expression is related to prognosis in patients with oesophageal squamous cell carcinoma, although it is not an independent prognostic factor.

Navas T, Pfister TD, Colantonio S, et al.
Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells.
PLoS One. 2018; 13(6):e0199361 [PubMed] Article available free on PMC after 13/12/2019 Related Publications
The presence of cancer stem cells (CSCs) and the induction of epithelial-to-mesenchymal transition (EMT) in tumors are associated with tumor aggressiveness, metastasis, drug resistance, and poor prognosis, necessitating the development of reagents for unambiguous detection of CSC- and EMT-associated proteins in tumor specimens. To this end, we generated novel antibodies to EMT- and CSC-associated proteins, including Goosecoid, Sox9, Slug, Snail, and CD133. Importantly, unlike several widely used antibodies to CD133, the anti-CD133 antibodies we generated recognize epitopes distal to known glycosylation sites, enabling analyses that are not confounded by differences in CD133 glycosylation. For all target proteins, we selected antibodies that yielded the expected target protein molecular weights by Western analysis and the correct subcellular localization patterns by immunofluorescence microscopy assay (IFA); binding selectivity was verified by immunoprecipitation-mass spectrometry and by immunohistochemistry and IFA peptide blocking experiments. Finally, we applied these reagents to assess modulation of the respective markers of EMT and CSCs in xenograft tumor models by IFA. We observed that the constitutive presence of human hepatocyte growth factor (hHGF) in the tumor microenvironment of H596 non-small cell lung cancer tumors implanted in homozygous hHGF knock-in transgenic mice induced a more mesenchymal-like tumor state (relative to the epithelial-like state when implanted in control SCID mice), as evidenced by the elevated expression of EMT-associated transcription factors detected by our novel antibodies. Similarly, our new anti-CD133 antibody enabled detection and quantitation of drug-induced reductions in CD133-positive tumor cells following treatment of SUM149PT triple-negative breast cancer xenograft models with the CSC/focal adhesion kinase (FAK) inhibitor VS-6063. Thus, our novel antibodies to CSC- and EMT-associated factors exhibit sufficient sensitivity and selectivity for immunofluorescence microscopy studies of these processes in preclinical xenograft tumor specimens and the potential for application with clinical samples.

Chen W, Zhao W, Chen S, et al.
Expression and correlation of MALAT1 and SOX9 in non-small cell lung cancer.
Clin Respir J. 2018; 12(7):2284-2291 [PubMed] Related Publications
INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths in the world. MALAT1 and SOX9 have important roles in tumour formation and development in several types of cancers. However, little is known about the function and co-relationship of these 2 factors in NSCLC in vivo.
OBJECTIVES: To explore the role of MALAT1 and SOX9 expression relationship, their clinical pathological characteristics and OS on NSCLC patients.
METHODS: Paired of primary lung cancer tissues and the matched tumour adjacent tissues were collected in 121 NSCLC patients. MALAT1 and SOX9 mRNA expression was measured by SYBR green q RT-PCR assay. SOX-9 protein expression was measured by streptavidin-peroxidase (SP) staining method.
RESULTS: MALAT1and SOX9 expression was higher in NSCLC tissues than the adjacent tissues, and they have positive correlation. Moreover, SOX9 protein expression was higher in NSCLC tissues, especially in MALAT1 mRNA higher expressed NSCLC tissues. MALAT1 and SOX9 mRNA expression were associated with age (x
CONCLUSIONS: MALAT1 and SOX9 could be used as prognostic co-biomarker in NSCLC.

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

Izadi F
Differential Connectivity in Colorectal Cancer Gene Expression Network
Iran Biomed J. 2019; 23(1):34-46 [PubMed] Article available free on PMC after 13/12/2019 Related Publications
Background: Colorectal cancer (CRC) is one of the challenging types of cancers; thus, exploring effective biomarkers related to colorectal could lead to significant progresses toward the treatment of this disease.
Methods: In the present study, CRC gene expression datasets have been reanalyzed. Mutual differentially expressed genes across 294 normal mucosa and adjacent tumoral samples were then utilized in order to build two independent transcriptional regulatory networks. By analyzing the networks topologically, genes with differential global connectivity related to cancer state were determined for which the potential transcriptional regulators including transcription factors were identified.
Results: The majority of differentially connected genes (DCGs) were up-regulated in colorectal transcriptome experiments. Moreover, a number of these genes have been experimentally validated as cancer or CRC-associated genes. The DCGs, including GART, TGFB1, ITGA2, SLC16A5, SOX9, and MMP7, were investigated across 12 cancer types. Functional enrichment analysis followed by detailed data mining exhibited that these candidate genes could be related to CRC by mediating in metastatic cascade in addition to shared pathways with 12 cancer types by triggering the inflammatory events.
Discussion: Our study uncovered correlated alterations in gene expression related to CRC susceptibility and progression that the potent candidate biomarkers could provide a link to disease.

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